Статті в журналах: "Cadmium, blood-brain barrier, neurodegenerative diseases"

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Branca, Jacopo Junio Valerio, Mario Maresca, Gabriele Morucci, Tommaso Mello, Matteo Becatti, Luigia Pazzagli, Ilaria Colzi, et al. "Effects of Cadmium on ZO-1 Tight Junction Integrity of the Blood Brain Barrier." International Journal of Molecular Sciences 20, no. 23 (November 29, 2019): 6010. http://dx.doi.org/10.3390/ijms20236010.

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Cadmium (Cd) is a highly toxic environmental pollutant released from the smelting and refining of metals and cigarette smoking. Oral exposure to cadmium may result in adverse effects on a number of tissues, including the central nervous system (CNS). In fact, its toxicity has been related to neurological disorders, as well as neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Under normal conditions, Cd barely reaches the brain in adults because of the presence of the blood–brain barrier (BBB); however, it has been demonstrated that Cd-dependent BBB alteration contributes to pathogenesis of neurodegeneration. However, the mechanism underlying Cd-dependent BBB alteration remain obscure. Here, we investigated the signaling pathway of Cd-induced tight junction (TJ), F-actin, and vimentin protein disassembly in a rat brain endothelial cell line (RBE4). RBE4 cells treated with 10 μM cadmium chloride (CdCl2) showed a dose- and time-dependent significant increase in reactive oxygen species (ROS) production. This phenomenon was coincident with the alteration of the TJ zonula occludens-1 (ZO-1), F-actin, and vimentin proteins. The Cd-dependent ROS increase elicited the upregulation of GRP78 expression levels, a chaperone involved in endoplasmic reticulum (ER) stress that induces caspase-3 activation. Further signal profiling by the pannexin-1 (PANX1) specific inhibitor 10Panx revealed a PANX1-independent increase in ATP spillage in Cd-treated endothelial cells. Our results point out that a ROS-dependent ER stress-mediated signaling pathway involving caspase-3 activation and ATP release is behind the BBB morphological alterations induced by Cd.

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Bressler, Joseph P., Luisa Olivi, Jae Hoon Cheong, Yongbae Kim, Alex Maerten, and Desmond Bannon. "Metal transporters in intestine and brain: their involvement in metal-associated neurotoxicities." Human & Experimental Toxicology 26, no. 3 (March 2007): 221–29. http://dx.doi.org/10.1177/0960327107070573.

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The transport of essential metals and other nutrients across tightmembrane barriers such as the gastrointestinal tract and blood-brain barrier is mediated by specific transport mechanisms. Specific transporters take up metals at the apical surface and export them at the basolateral surface, and are involved in their intracellular distribution. Transporters for each of the major essential metals, calcium, iron and zinc, have been identified. These transporters also mediate the transport of non-essential metals across tight membrane barriers. For example, the intestinal iron transporter divalent metal transporter 1 mediates the uptake of lead and cadmium. The levels of essential metals are strictly regulated by transporters. When dietary levels of essential metals are low, levels of the corresponding transporters increase in the intestine, after which there is a greater potential for increased transport of toxic metals. In the brain, the strict regulation of metals prevents injury that potentially would result from oxidative damage induced by the essential metals iron, copper and zinc. Indeed, the oxidative damage found in neurodegenerative diseases is likely to be due to higher levels of these metals. Involvement of intracellular transporters for copper and zinc has been shown in animal models of Alzheimer's disease, raising the possibility that higher levels of iron, zinc and copper might be due to a disruption in the activity of transporters. Accordingly, exposure to toxicants that affect the activity of transporters potentially could contribute to the aetiology/progression of neurodegenerative diseases.

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Kakaroubas, Nicholas, Samuel Brennan, Matthew Keon, and Nitin K. Saksena. "Pathomechanisms of Blood-Brain Barrier Disruption in ALS." Neuroscience Journal 2019 (July 10, 2019): 1–16. http://dx.doi.org/10.1155/2019/2537698.

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The blood-brain barrier (BBB) and the blood-spinal cord barrier (BSCB) are responsible for controlling the microenvironment within neural tissues in humans. These barriers are fundamental to all neurological processes as they provide the extreme nutritional demands of neural tissue, remove wastes, and maintain immune privileged status. Being a semipermeable membrane, both the BBB and BSCB allow the diffusion of certain molecules, whilst restricting others. In amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, these barriers become hyperpermeable, allowing a wider variety of molecules to pass through leading to more severe and more rapidly progressing disease. The intention of this review is to discuss evidence that BBB hyperpermeability is potentially a disease driving feature in ALS and other neurodegenerative diseases. The various biochemical, physiological, and genomic factors that can influence BBB permeability in ALS and other neurodegenerative diseases are also discussed, in addition to novel therapeutic strategies centred upon the BBB.

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Weber, Callie M., and Alisa Morss Clyne. "Sex differences in the blood–brain barrier and neurodegenerative diseases." APL Bioengineering 5, no. 1 (March 1, 2021): 011509. http://dx.doi.org/10.1063/5.0035610.

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Karamanos, Yannis, Fabien Gosselet, Marie-Pierre Dehouck, and Roméo Cecchelli. "Blood–Brain Barrier Proteomics: Towards the Understanding of Neurodegenerative Diseases." Archives of Medical Research 45, no. 8 (November 2014): 730–37. http://dx.doi.org/10.1016/j.arcmed.2014.11.008.

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Wu, Ying-Chieh, Tuuli-Maria Sonninen, Sanni Peltonen, Jari Koistinaho, and Šárka Lehtonen. "Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells." International Journal of Molecular Sciences 22, no. 14 (July 19, 2021): 7710. http://dx.doi.org/10.3390/ijms22147710.

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The blood–brain barrier (BBB) regulates the delivery of oxygen and important nutrients to the brain through active and passive transport and prevents neurotoxins from entering the brain. It also has a clearance function and removes carbon dioxide and toxic metabolites from the central nervous system (CNS). Several drugs are unable to cross the BBB and enter the CNS, adding complexity to drug screens targeting brain disorders. A well-functioning BBB is essential for maintaining healthy brain tissue, and a malfunction of the BBB, linked to its permeability, results in toxins and immune cells entering the CNS. This impairment is associated with a variety of neurological diseases, including Alzheimer’s disease and Parkinson’s disease. Here, we summarize current knowledge about the BBB in neurodegenerative diseases. Furthermore, we focus on recent progress of using human-induced pluripotent stem cell (iPSC)-derived models to study the BBB. We review the potential of novel stem cell-based platforms in modeling the BBB and address advances and key challenges of using stem cell technology in modeling the human BBB. Finally, we highlight future directions in this area.

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Sharma, Chanchal, Hanwoong Woo, and Sang Ryong Kim. "Addressing Blood–Brain Barrier Impairment in Alzheimer’s Disease." Biomedicines 10, no. 4 (March 22, 2022): 742. http://dx.doi.org/10.3390/biomedicines10040742.

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The blood–brain barrier (BBB) plays a vital role in maintaining the specialized microenvironment of the brain tissue. It facilitates communication while separating the peripheral circulation system from the brain parenchyma. However, normal aging and neurodegenerative diseases can alter and damage the physiological properties of the BBB. In this review, we first briefly present the essential pathways maintaining and regulating BBB integrity, and further review the mechanisms of BBB breakdown associated with normal aging and peripheral inflammation-causing neurodegeneration and cognitive impairments. We also discuss how BBB disruption can cause or contribute to Alzheimer’s disease (AD), the most common form of dementia and a devastating neurological disorder. Next, we document overlaps between AD and vascular dementia (VaD) and briefly sum up the techniques for identifying biomarkers linked to BBB deterioration. Finally, we conclude that BBB breakdown could be used as a biomarker to help diagnose cognitive impairment associated with normal aging and neurodegenerative diseases such as AD.

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Cui, Weitong, Wei Fu, Yunfeng Lin, and Tianxu Zhang. "Application of Nanomaterials in Neurodegenerative Diseases." Current Stem Cell Research & Therapy 16, no. 1 (December 1, 2021): 83–94. http://dx.doi.org/10.2174/1574888x15666200326093410.

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Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease are very harmful brain lesions. Due to the difficulty in obtaining therapeutic drugs, the best treatment for neurodegenerative diseases is often not available. In addition, the bloodbrain barrier can effectively prevent the transfer of cells, particles and macromolecules (such as drugs) in the brain, resulting in the failure of the traditional drug delivery system to provide adequate cellular structure repair and connection modes, which are crucial for the functional recovery of neurodegenerative diseases. Nanomaterials are designed to carry drugs across the blood-brain barrier for targets. Nanotechnology uses engineering materials or equipment to interact with biological systems at the molecular level to induce physiological responses through stimulation, response and target site interactions, while minimizing the side effects, thus revolutionizing the treatment and diagnosis of neurodegenerative diseases. Some magnetic nanomaterials play a role as imaging agents or nanoprobes for Magnetic Resonance Imaging to assist in the diagnosis of neurodegenerative diseases. Although the current research on nanomaterials is not as useful as expected in clinical applications, it achieves a major breakthrough and guides the future development direction of nanotechnology in the application of neurodegenerative diseases. This review briefly discusses the application and advantages of nanomaterials in neurodegenerative diseases. Data for this review were identified by searches of PubMed, and references from relevant articles published in English between 2015 and 2019 using the search terms “nanomaterials”, “neurodegenerative diseases” and “blood-brain barrier”.

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Silva Adaya, Daniela, Lucinda Aguirre-Cruz, Jorge Guevara, and Emma Ortiz-Islas. "Nanobiomaterials’ applications in neurodegenerative diseases." Journal of Biomaterials Applications 31, no. 7 (November 11, 2016): 953–84. http://dx.doi.org/10.1177/0885328216659032.

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The blood–brain barrier is the interface between the blood and brain, impeding the passage of most circulating cells and molecules, protecting the latter from foreign substances, and maintaining central nervous system homeostasis. However, its restrictive nature constitutes an obstacle, preventing therapeutic drugs from entering the brain. Usually, a large systemic dose is required to achieve pharmacological therapeutic levels in the brain, leading to adverse effects in the body. As a consequence, various strategies are being developed to enhance the amount and concentration of therapeutic compounds in the brain. One such tool is nanotechnology, in which nanostructures that are 1–100 nm are designed to deliver drugs to the brain. In this review, we examine many nanotechnology-based approaches to the treatment of neurodegenerative diseases. The review begins with a brief history of nanotechnology, followed by a discussion of its definition, the properties of most reported nanomaterials, their biocompatibility, the mechanisms of cell–material interactions, and the current status of nanotechnology in treating Alzheimer’s, Parkinson’s diseases, and amyotrophic lateral sclerosis. Of all strategies to deliver drug to the brain that are used in nanotechnology, drug release systems are the most frequently reported.

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Fang, Yao-Ching, Yi-Chen Hsieh, Chaur-Jong Hu, and Yong-Kwang Tu. "Endothelial Dysfunction in Neurodegenerative Diseases." International Journal of Molecular Sciences 24, no. 3 (February 2, 2023): 2909. http://dx.doi.org/10.3390/ijms24032909.

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The cerebral vascular system stringently regulates cerebral blood flow (CBF). The components of the blood–brain barrier (BBB) protect the brain from pathogenic infections and harmful substances, efflux waste, and exchange substances; however, diseases develop in cases of blood vessel injuries and BBB dysregulation. Vascular pathology is concurrent with the mechanisms underlying aging, Alzheimer’s disease (AD), and vascular dementia (VaD), which suggests its involvement in these mechanisms. Therefore, in the present study, we reviewed the role of vascular dysfunction in aging and neurodegenerative diseases, particularly AD and VaD. During the development of the aforementioned diseases, changes occur in the cerebral blood vessel morphology and local cells, which, in turn, alter CBF, fluid dynamics, and vascular integrity. Chronic vascular inflammation and blood vessel dysregulation further exacerbate vascular dysfunction. Multitudinous pathogenic processes affect the cerebrovascular system, whose dysfunction causes cognitive impairment. Knowledge regarding the pathophysiology of vascular dysfunction in neurodegenerative diseases and the underlying molecular mechanisms may lead to the discovery of clinically relevant vascular biomarkers, which may facilitate vascular imaging for disease prevention and treatment.

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Kim, Hong Nam. "Engineered models for studying blood-brain-barrier-associated brain physiology and pathology." Organoid 1 (June 19, 2021): e10. http://dx.doi.org/10.51335/organoid.2021.1.e10.

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The blood-brain barrier (BBB) is a transport barrier that suppresses the translocation of potentially harmful substances to the brain tissue. Although the BBB is known to be associated with many kinds of neuropathology, such as neuroinflammation and neurodegenerative diseases, the conventionally used animal and Transwell models cannot provide sufficient information due to genetic and functional heterogeneity in comparison with humans and limited monitoring capabilities. Recently, human cell-based three-dimensional BBB models have been developed, and these models provide in vivo-like BBB structures and functions. In this review, we provide an overview of the recent advances in BBB models with a particular focus on the simulation of BBB-associated brain physiology and neuropathology. To this end, important factors for recapitulating the in vivo characteristics of the BBB are described. Furthermore, approaches to recapitulate the BBB physiology using engineering methods are summarized. The applications of BBB models in the study of neuropathology, such as inflammation and neurodegenerative diseases, are also presented.

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Saraiva, Cláudia, Catarina Praça, Raquel Ferreira, Tiago Santos, Lino Ferreira, and Liliana Bernardino. "Nanoparticle-mediated brain drug delivery: Overcoming blood–brain barrier to treat neurodegenerative diseases." Journal of Controlled Release 235 (August 2016): 34–47. http://dx.doi.org/10.1016/j.jconrel.2016.05.044.

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13

Spuch, Carlos, and Carmen Navarro. "Liposomes for Targeted Delivery of Active Agents against Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease)." Journal of Drug Delivery 2011 (December 13, 2011): 1–12. http://dx.doi.org/10.1155/2011/469679.

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Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease represent a huge unmet medical need. The prevalence of both diseases is increasing, but the efficacy of treatment is still very limited due to various factors including the blood brain barrier (BBB). Drug delivery to the brain remains the major challenge for the treatment of all neurodegenerative diseases because of the numerous protective barriers surrounding the central nervous system. New therapeutic drugs that cross the BBB are critically needed for treatment of many brain diseases. One of the significant factors on neurotherapeutics is the constraint of the blood brain barrier and the drug release kinetics that cause peripheral serious side effects. Contrary to common belief, neurodegenerative and neurological diseases may be multisystemic in nature, and this presents numerous difficulties for their potential treatment. Overall, the aim of this paper is to summarize the last findings and news related to liposome technology in the treatment of neurodegenerative diseases and demonstrate the potential of this technology for the development of novel therapeutics and the possible applications of liposomes in the two most widespread neurodegenerative diseases, Alzheimer's disease and Parkinson's disease.

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Rosenberg, Gary A. "Neurological Diseases in Relation to the Blood–Brain Barrier." Journal of Cerebral Blood Flow & Metabolism 32, no. 7 (January 18, 2012): 1139–51. http://dx.doi.org/10.1038/jcbfm.2011.197.

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Disruption of the blood–brain barrier (BBB) has an important part in cellular damage in neurological diseases, including acute and chronic cerebral ischemia, brain trauma, multiple sclerosis, brain tumors, and brain infections. The neurovascular unit (NVU) forms the interface between the blood and brain tissues. During an injury, the cascade of molecular events ends in the final common pathway for BBB disruption by free radicals and proteases, which attack membranes and degrade the tight junction proteins in endothelial cells. Free radicals of oxygen and nitrogen and the proteases, matrix metalloproteinases and cyclooxgyenases, are important in the early and delayed BBB disruption as the neuroinflammatory response progresses. Opening of the BBB occurs in neurodegenerative diseases and contributes to the cognitive changes. In addition to the importance of the NVU in acute injury, angiogenesis contributes to the recovery process. The challenges to treatment of the brain diseases involve not only facilitating drug entry into the brain, but also understanding the timing of the molecular cascades to block the early NVU injury without interfering with recovery. This review will describe the molecular and cellular events associated with NVU disruption and potential strategies directed toward restoring its integrity.

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Rice, Antonie, Mary L. Michaelis, Gunda Georg, Yanbin Liu, Brandon Turunen, and Kenneth L. Audus. "Overcoming the Blood-Brain Barrier to Taxane Delivery for Neurodegenerative Diseases and Brain Tumors." Journal of Molecular Neuroscience 20, no. 3 (2003): 339–44. http://dx.doi.org/10.1385/jmn:20:3:339.

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Chia, Yvonne Cashinn, Clarice Evey Anjum, Hui Rong Yee, Yenny Kenisi, Mike K. S. Chan, Michelle B. F. Wong, and Shing Yi Pan. "Stem Cell Therapy for Neurodegenerative Diseases: How Do Stem Cells Bypass the Blood-Brain Barrier and Home to the Brain?" Stem Cells International 2020 (September 4, 2020): 1–8. http://dx.doi.org/10.1155/2020/8889061.

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Blood-brain barrier (BBB) is a term describing the highly selective barrier formed by the endothelial cells (ECs) of the central nervous system (CNS) homeostasis by restricting movement across the BBB. An intact BBB is critical for normal brain functions as it maintains brain homeostasis, modulates immune cell transport, and provides protection against pathogens and other foreign substances. However, it also prevents drugs from entering the CNS to treat neurodegenerative diseases. Stem cells, on the other hand, have been reported to bypass the BBB and successfully home to their target in the brain and initiate repair, making them a promising approach in cellular therapy, especially those related to neurodegenerative disease. This review article discusses the mechanism behind the successful homing of stem cells to the brain, their potential role as a drug delivery vehicle, and their applications in neurodegenerative diseases.

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Silva, Diana Filipa, Nuno Empadinhas, Sandra Morais Cardoso, and Ana Raquel Esteves. "Neurodegenerative Microbially-Shaped Diseases: Oxidative Stress Meets Neuroinflammation." Antioxidants 11, no. 11 (October 28, 2022): 2141. http://dx.doi.org/10.3390/antiox11112141.

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Inflammation and oxidative stress characterize a number of chronic conditions including neurodegenerative diseases and aging. Inflammation is a key component of the innate immune response in Alzheimer’s disease and Parkinson’s disease of which oxidative stress is an important hallmark. Immune dysregulation and mitochondrial dysfunction with concomitant reactive oxygen species accumulation have also been implicated in both diseases, both systemically and within the Central Nervous System. Mitochondria are a centrally positioned signalling hub for inflammatory responses and inflammatory cells can release reactive species at the site of inflammation often leading to exaggerated oxidative stress. A growing body of evidence suggests that disruption of normal gut microbiota composition may induce increased permeability of the gut barrier leading to chronic systemic inflammation, which may, in turn, impair the blood–brain barrier function and promote neuroinflammation and neurodegeneration. The gastrointestinal tract is constantly exposed to myriad exogenous substances and microbial pathogens, which are abundant sources of reactive oxygen species, oxidative damage and pro-inflammatory events. Several studies have demonstrated that microbial infections may also affect the balance in gut microbiota composition (involving oxidant and inflammatory processes by the host and indigenous microbiota) and influence downstream Alzheimer’s disease and Parkinson’s disease pathogenesis, in which blood–brain barrier damage ultimately occurs. Therefore, the oxidant/inflammatory insults triggered by a disrupted gut microbiota and chronic dysbiosis often lead to compromised gut barrier function, allowing inflammation to “escape” as well as uncontrolled immune responses that may ultimately disrupt mitochondrial function upwards the brain. Future therapeutic strategies should be designed to “restrain” gut inflammation, a goal that could ideally be attained by microbiota modulation strategies, in alternative to classic anti-inflammatory agents with unpredictable effects on the microbiota architecture itself.

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Avsenik, Jernej, Sotirios Bisdas, and Katarina Surlan Popovic. "Blood-brain barrier permeability imaging using perfusion computed tomography." Radiology and Oncology 49, no. 2 (June 1, 2015): 107–14. http://dx.doi.org/10.2478/raon-2014-0029.

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Abstract Background. The blood-brain barrier represents the selective diffusion barrier at the level of the cerebral microvascular endothelium. Other functions of blood-brain barrier include transport, signaling and osmoregulation. Endothelial cells interact with surrounding astrocytes, pericytes and neurons. These interactions are crucial to the development, structural integrity and function of the cerebral microvascular endothelium. Dysfunctional blood-brain barrier has been associated with pathologies such as acute stroke, tumors, inflammatory and neurodegenerative diseases. Conclusions. Blood-brain barrier permeability can be evaluated in vivo by perfusion computed tomography - an efficient diagnostic method that involves the sequential acquisition of tomographic images during the intravenous administration of iodinated contrast material. The major clinical applications of perfusion computed tomography are in acute stroke and in brain tumor imaging.

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Liu, Yanan, Youcong Gong, Wenjie Xie, Anlian Huang, Xiaoyu Yuan, Hui Zhou, Xufeng Zhu, et al. "Microbubbles in combination with focused ultrasound for the delivery of quercetin-modified sulfur nanoparticles through the blood brain barrier into the brain parenchyma and relief of endoplasmic reticulum stress to treat Alzheimer's disease." Nanoscale 12, no. 11 (2020): 6498–511. http://dx.doi.org/10.1039/c9nr09713a.

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Aragón-González, Ana, Pamela J. Shaw, and Laura Ferraiuolo. "Blood–Brain Barrier Disruption and Its Involvement in Neurodevelopmental and Neurodegenerative Disorders." International Journal of Molecular Sciences 23, no. 23 (December 3, 2022): 15271. http://dx.doi.org/10.3390/ijms232315271.

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The blood–brain barrier (BBB) is a highly specialized and dynamic compartment which regulates the uptake of molecules and solutes from the blood. The relevance of the maintenance of a healthy BBB underpinning disease prevention as well as the main pathomechanisms affecting BBB function will be detailed in this review. Barrier disruption is a common aspect in both neurodegenerative diseases, such as amyotrophic lateral sclerosis, and neurodevelopmental diseases, including autism spectrum disorders. Throughout this review, conditions altering the BBB during the earliest and latest stages of life will be discussed, revealing common factors involved. Due to the barrier’s role in protecting the brain from exogenous components and xenobiotics, drug delivery across the BBB is challenging. Potential therapies based on the BBB properties as molecular Trojan horses, among others, will be reviewed, as well as innovative treatments such as stem cell therapies. Additionally, due to the microbiome influence on the normal function of the brain, microflora modulation strategies will be discussed. Finally, future research directions are highlighted to address the current gaps in the literature, emphasizing the idea that common therapies for both neurodevelopmental and neurodegenerative pathologies exist.

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Mansor, Nur Izzati, Norshariza Nordin, Farahidah Mohamed, King Hwa Ling, Rozita Rosli, and Zurina Hassan. "Crossing the Blood-Brain Barrier: A Review on Drug Delivery Strategies for Treatment of the Central Nervous System Diseases." Current Drug Delivery 16, no. 8 (October 9, 2019): 698–711. http://dx.doi.org/10.2174/1567201816666190828153017.

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: Many drugs have been designed to treat diseases of the central nervous system (CNS), especially neurodegenerative diseases. However, the presence of tight junctions at the blood-brain barrier has often compromised the efficiency of drug delivery to target sites in the brain. The principles of drug delivery systems across the blood-brain barrier are dependent on substrate-specific (i.e. protein transport and transcytosis) and non-specific (i.e. transcellular and paracellular) transport pathways, which are crucial factors in attempts to design efficient drug delivery strategies. This review describes how the blood-brain barrier presents the main challenge in delivering drugs to treat brain diseases and discusses the advantages and disadvantages of ongoing neurotherapeutic delivery strategies in overcoming this limitation. In addition, we discuss the application of colloidal carrier systems, particularly nanoparticles, as potential tools for therapy for the CNS diseases.

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Pérez-Carrión, María Dolores, and Inmaculada Posadas. "Dendrimers in Neurodegenerative Diseases." Processes 11, no. 2 (January 18, 2023): 319. http://dx.doi.org/10.3390/pr11020319.

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Neurodegenerative diseases (NDs), such as Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Multiple Sclerosis (MS) and amyotrophic lateral sclerosis (ALS), are characterized by progressive loss of structure or function of neurons. Current therapies for NDs are only symptomatic and long-term ineffective. This challenge has promoted the development of new therapies against relevant targets in these pathologies. In this review, we will focus on the most promising therapeutic approaches based on dendrimers (DDs) specially designed for the treatment and diagnosis of NDs. DDs are well-defined polymeric structures that provide a multifunctional platform for developing different nanosystems for a myriad of applications. DDs have been proposed as interesting drug delivery systems with the ability to cross the blood–brain barrier (BBB) and increase the bioavailability of classical drugs in the brain, as well as genetic material, by reducing the synthesis of specific targets, as β-amyloid peptide. Moreover, DDs have been shown to be promising anti-amyloidogenic systems against amyloid-β peptide (Aβ) and Tau aggregation, powerful agents for blocking α-synuclein (α-syn) fibrillation, exhibit anti-inflammatory properties, promote cellular uptake to certain cell types, and are potential tools for ND diagnosis. In summary, DDs have emerged as promising alternatives to current ND therapies since they may limit the extent of damage and provide neuroprotection to the affected tissues.

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Zolotoff, Cindy, Laurent Bertoletti, David Gozal, Valentine Mismetti, Pascale Flandrin, Frédéric Roche, and Nathalie Perek. "Obstructive Sleep Apnea, Hypercoagulability, and the Blood–Brain Barrier." Journal of Clinical Medicine 10, no. 14 (July 14, 2021): 3099. http://dx.doi.org/10.3390/jcm10143099.

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Obstructive sleep apnea (OSA) is characterized by repeated episodes of intermittent hypoxia (IH) and is recognized as an independent risk factor for vascular diseases that are mediated by a multitude of mechanistic pathophysiological cascades including procoagulant factors. The pro-coagulant state contributes to the development of blood clots and to the increase in the permeability of the blood–brain barrier (BBB). Such alteration of BBB may alter brain function and increase the risk of neurodegenerative diseases. We aim to provide a narrative review of the relationship between the hypercoagulable state, observed in OSA and characterized by increased coagulation factor activity, as well as platelet activation, and the underlying neural dysfunction, as related to disruption of the BBB. We aim to provide a critical overview of the existing evidence about the effect of OSA on the coagulation balance (characterized by increased coagulation factor activity and platelet activation) as on the BBB. Then, we will present the emerging data on the effect of BBB disruption on the risk of underlying neural dysfunction. Finally, we will discuss the potential of OSA therapy on the coagulation balance and the improvement of BBB.

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Storck, Steffen E., and Claus U. Pietrzik. "The Blood brain-barrier and its role in Alzheimer’s disease." Neuroforum 24, no. 4 (November 27, 2018): A197—A205. http://dx.doi.org/10.1515/nf-2018-a014.

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Abstract The blood brain-barrier (BBB), built up by the interaction of different cell types in vessels of the brain, is essential for brain homeostasis. As a gatekeeper of the central nervous system (CNS), the BBB controls the exchange of molecules between brain and blood. In many neurodegenerative diseases including Alzheimer’s disease (AD) the BBB show alterations which impair brain function and promote neurodegeneration. As an important elimination route for neurotoxic amyloid-beta (Aβ), the BBB is crucial for the healthy brain by regulating the concentration of soluble Aβ in the interstitial fluid (ISF) in the brain. Here, we discuss the composition and distinctive physiological features of CNS vasculature and the pathological alterations that are present in AD and disturb BBB function.

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Lackovic, Maja, Maja Ivkovic, Sreten Vicentic, Stefan Jerotic, Milica Nestorovic, Tihomir Stojkovic, and Aleksandra Pavlovic. "The role of the blood-brain barrier in psychiatric disorders." Srpski arhiv za celokupno lekarstvo, no. 00 (2022): 81. http://dx.doi.org/10.2298/sarh220417081l.

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The blood-brain barrier (BBB) is formed by continuous, closely connected endothelial cells, enveloped in the basal lamina, pericytes, and foot extensions of astrocytes. BBB has a vital role in brain metabolism and protects the brain parenchyma from harmful agents present in the systemic circulation. Damage to the BBB and an increase in its permeability have an important role in many neurodegenerative diseases. This paper aims to review the literature on the impact of the BBB damage on psychiatric illness, a largely neglected and under researched area. Links between BBB impairment and specific neuropsychiatric disorders are described including schizophrenia, affective disorders, dementias with behavioral disorders, and alcohol use disorder, with comparison to typical hereditary small vessel diseases affecting the BBB such as cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). The authors critically summarize possible pathogenic mechanisms linking BBB damage and these common disorders.

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Ruzha, Yelizhati, Junjun Ni, Zhenzhen Quan, Hui Li, and Hong Qing. "Role of Vitronectin and Its Receptors in Neuronal Function and Neurodegenerative Diseases." International Journal of Molecular Sciences 23, no. 20 (October 16, 2022): 12387. http://dx.doi.org/10.3390/ijms232012387.

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Vitronectin (VTN), a multifunctional glycoprotein with various physiological functions, exists in plasma and the extracellular matrix. It is known to be involved in the cell attachment, spreading and migration through binding to the integrin receptor, mainly via the RGD sequence. VTN is also widely used in the maintenance and expansion of pluripotent stem cells, but its effects go beyond that. Recent evidence shows more functions of VTN in the nervous system as it participates in neural differentiation, neuronutrition and neurogenesis, as well as in regulating axon size, supporting and guiding neurite extension. Furthermore, VTN was proved to play a key role in protecting the brain as it can reduce the permeability of the blood–brain barrier by interacting with integrin receptors in vascular endothelial cells. Moreover, evidence suggests that VTN is associated with neurodegenerative diseases, such as Alzheimer’s disease, but its function has not been fully understood. This review summarizes the functions of VTN and its receptors in neurons and describes the role of VTN in the blood–brain barrier and neurodegenerative diseases.

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Su, Rui. "Mesenchymal Stem Cell Exosomes as Nanotherapeutic Agents for Neurodegenerative Diseases." Highlights in Science, Engineering and Technology 2 (June 22, 2022): 7–14. http://dx.doi.org/10.54097/hset.v2i.549.

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Neurodegenerative diseases are systemic diseases with high heterogeneity and complicated etiology dependent on proper interneuronal communication, resulting in severe syndromes including cognitive impairment and dementia. The blood-brain barrier (BBB) remains Central nervous system (CNS) therapeutic delivery, a significant challenge without effective vivo therapeutic methods in clinical practice. Mesenchymal stem cells (MSC) with multi-directional differentiation potential have the characteristics of low immunogenicity, strong proliferation ability, immune regulation, and multi-directional differentiation potential. The repair effects have been identified mediated by transplanted MSCs paracrine factors, including exosomes and nanometer-sized cell communication mediators, to reduce tissue injury and enhance repair, growth, and regeneration. MSC-derived exosomes have become an attractive vehicle by passing through the blood-brain barrier (BBB), delivering therapeutic agents targeting the brain for treating autoimmune and neurodegenerative diseases. Safeties, convenience, and the effectiveness of MSC-derived exosomes have been demonstrated mainly through mechanistic clinical and preclinical evidence of potential nanotherapeutic agents for further prevalent use. Thus, we want to investigate the clinical applications of MSC-derived exosomes to reveal their regenerative treatment capacity from direct and indirect neuron repairment effect, reduced neuroinflammation, and nanotherapeutic agent advantage. This paper discusses the potential and practicality of using this novel cell-free entity of mesenchymal stem cell derivatives such as exosomes in vivo administration as a therapeutic modality for treating degenerative disease and pathologies and innovation and emerging trends in the field.

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Cunha, Anthony, Alexandra Gaubert, Laurent Latxague, and Benjamin Dehay. "PLGA-Based Nanoparticles for Neuroprotective Drug Delivery in Neurodegenerative Diseases." Pharmaceutics 13, no. 7 (July 8, 2021): 1042. http://dx.doi.org/10.3390/pharmaceutics13071042.

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Treatment of neurodegenerative diseases has become one of the most challenging topics of the last decades due to their prevalence and increasing societal cost. The crucial point of the non-invasive therapeutic strategy for neurological disorder treatment relies on the drugs’ passage through the blood-brain barrier (BBB). Indeed, this biological barrier is involved in cerebral vascular homeostasis by its tight junctions, for example. One way to overcome this limit and deliver neuroprotective substances in the brain relies on nanotechnology-based approaches. Poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) are biocompatible, non-toxic, and provide many benefits, including improved drug solubility, protection against enzymatic digestion, increased targeting efficiency, and enhanced cellular internalization. This review will present an overview of the latest findings and advances in the PLGA NP-based approach for neuroprotective drug delivery in the case of neurodegenerative disease treatment (i.e., Alzheimer’s, Parkinson’s, Huntington’s diseases, Amyotrophic Lateral, and Multiple Sclerosis).

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Latif, Sana, and Young-Sook Kang. "Blood–Brain Barrier Solute Carrier Transporters and Motor Neuron Disease." Pharmaceutics 14, no. 10 (October 11, 2022): 2167. http://dx.doi.org/10.3390/pharmaceutics14102167.

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Defective solute carrier (SLC) transporters are responsible for neurotransmitter dysregulation, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We provided the role and kinetic parameters of transporters such as ASCTs, Taut, LAT1, CAT1, MCTs, OCTNs, CHT, and CTL1, which are mainly responsible for the transport of essential nutrients, acidic, and basic drugs in blood–brain barrier (BBB) and motor neuron disease. The affinity for LAT1 was higher in the BBB than in the ALS model cell line, whereas the capacity was higher in the NSC-34 cell lines than in the BBB. Affinity for MCTs was lower in the BBB than in the NSC-34 cell lines. CHT in BBB showed two affinity sites, whereas no expression was observed in ALS cell lines. CTL1 was the main transporter for choline in ALS cell lines. The half maximal inhibitory concentration (IC50) analysis of [3H]choline uptake indicated that choline is sensitive in TR-BBB cells, whereas amiloride is most sensitive in ALS cell lines. Knowledge of the transport systems in the BBB and motor neurons will help to deliver drugs to the brain and develop the therapeutic strategy for treating CNS and neurological diseases.

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30

Cassano, Roberta, Camilla Servidio, and Sonia Trombino. "Biomaterials for Drugs Nose–Brain Transport: A New Therapeutic Approach for Neurological Diseases." Materials 14, no. 7 (April 6, 2021): 1802. http://dx.doi.org/10.3390/ma14071802.

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In the last years, neurological diseases have resulted in a global health issue, representing the first cause of disability worldwide. Current therapeutic approaches against neurological disorders include oral, topical, or intravenous administration of drugs and more invasive techniques such as surgery and brain implants. Unfortunately, at present, there are no fully effective treatments against neurodegenerative diseases, because they are not associated with a regeneration of the neural tissue but rather act on slowing the neurodegenerative process. The main limitation of central nervous system therapeutics is related to their delivery to the nervous system in therapeutic quantities due to the presence of the blood–brain barrier. In this regard, recently, the intranasal route has emerged as a promising administration site for central nervous system therapeutics since it provides a direct connection to the central nervous system, avoiding the passage through the blood–brain barrier, consequently increasing drug cerebral bioavailability. This review provides an overview of the nose-to-brain route: first, we summarize the anatomy of this route, focusing on the neural mechanisms responsible for the delivery of central nervous system therapeutics to the brain, and then we discuss the recent advances made on the design of intranasal drug delivery systems of central nervous system therapeutics to the brain, focusing in particular on stimuli-responsive hydrogels.

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Kim, Yeonjae, A. Yeon Cho, Hong Cheol Kim, Dajung Ryu, Sangmee Ahn Jo, and Yi-Sook Jung. "Effects of Natural Polyphenols on Oxidative Stress-Mediated Blood-Brain Barrier Dysfunction." Antioxidants 11, no. 2 (January 20, 2022): 197. http://dx.doi.org/10.3390/antiox11020197.

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The blood-brain barrier (BBB), which consists mainly of brain microvascular endothelial cells and astrocytes connected by tight junctions (TJs) and adhesion molecules (AMs), maintains the homeostatic balance between brain parenchyma and extracellular fluid. Accumulating evidence shows that BBB dysfunction is a common feature of neurodegenerative diseases, including stroke, traumatic brain injury, and Alzheimer’s disease. Among the various pathological pathways of BBB dysfunction, reactive oxygen species (ROS) are known to play a key role in inducing BBB disruption mediated via TJ modification, AM induction, cytoskeletal reorganization, and matrix metalloproteinase activation. Thus, antioxidants have been suggested to exert beneficial effects on BBB dysfunction-associated brain diseases. In this review, we summarized the sources of ROS production in multiple cells that constitute or surround the BBB, such as BBB endothelial cells, astrocytes, microglia, and neutrophils. We also reviewed various pathological mechanisms by which BBB disruption is caused by ROS in these cells. Finally, we summarized the effects of various natural polyphenols on BBB dysfunction to suggest a therapeutic strategy for BBB disruption-related brain diseases.

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Maiuolo, Jessica, Micaela Gliozzi, Vincenzo Musolino, Miriam Scicchitano, Cristina Carresi, Federica Scarano, Francesca Bosco, et al. "The “Frail” Brain Blood Barrier in Neurodegenerative Diseases: Role of Early Disruption of Endothelial Cell-to-Cell Connections." International Journal of Molecular Sciences 19, no. 9 (September 10, 2018): 2693. http://dx.doi.org/10.3390/ijms19092693.

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The main neurovascular unit of the Blood Brain Barrier (BBB) consists of a cellular component, which includes endothelial cells, astrocytes, pericytes, microglia, neurons, and oligodendrocytes as well as a non-cellular component resulting from the extracellular matrix. The endothelial cells are the major vital components of the BBB able to preserve the brain homeostasis. These cells are situated along the demarcation line between the bloodstream and the brain. Therefore, an alteration or the progressive disruption of the endothelial layer may clearly impair the brain homeostasis. The proper functioning of the brain endothelial cells is generally ensured by two elements: (1) the presence of junction proteins and (2) the preservation of a specific polarity involving an apical-luminal and a basolateral-abluminal membrane. This review intends to identify the molecular mechanisms underlying BBB function and their changes occurring in early stages of neurodegenerative processes in order to develop novel therapeutic strategies aimed to counteract neurodegenerative disorders.

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Azam, Shofiul, Ju-Young Park, In-Su Kim, and Dong-Kug Choi. "Piperine and Its Metabolite’s Pharmacology in Neurodegenerative and Neurological Diseases." Biomedicines 10, no. 1 (January 12, 2022): 154. http://dx.doi.org/10.3390/biomedicines10010154.

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Piperine (PIP) is an active alkaloid of black and long peppers. An increasing amount of evidence is suggesting that PIP and its metabolite’s could be a potential therapeutic to intervene different disease conditions including chronic inflammation, cardiac and hepatic diseases, neurodegenerative diseases, and cancer. In addition, the omnipresence of PIP in food and beverages made this compound an important investigational material. It has now become essential to understand PIP pharmacology and toxicology to determine its merits and demerits, especially its effect on the central nervous system (CNS). Although several earlier reports documented that PIP has poor pharmacokinetic properties, such as absorption, bioavailability, and blood–brain barrier permeability. However, its interaction with metabolic enzyme cytochrome P450 superfamily and competitive hydrophobic interaction at Monoamine oxide B (MAO-B) active site have made PIP both a xenobiotics bioenhancer and a potential MAO-B inhibitor. Moreover, recent advancements in pharmaceutical technology have overcome several of PIP’s limitations, including bioavailability and blood–brain barrier permeability, even at low doses. Contrarily, the structure activity relationship (SAR) study of PIP suggesting that its several metabolites are reactive and plausibly responsible for acute toxicity or have pharmacological potentiality. Considering the importance of PIP and its metabolites as an emerging drug target, this study aims to combine the current knowledge of PIP pharmacology and biochemistry with neurodegenerative and neurological disease therapy.

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Tawfik, Amany, Nehal M. Elsherbiny, Yusra Zaidi, and Pragya Rajpurohit. "Homocysteine and Age-Related Central Nervous System Diseases: Role of Inflammation." International Journal of Molecular Sciences 22, no. 12 (June 10, 2021): 6259. http://dx.doi.org/10.3390/ijms22126259.

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Hyperhomocysteinemia (HHcy) is remarkably common among the aging population. The relation between HHcy and the development of neurodegenerative diseases, such as Alzheimer’s disease (AD) and eye diseases, and age-related macular degeneration (AMD) and diabetic retinopathy (DR) in elderly people, has been established. Disruption of the blood barrier function of the brain and retina is one of the most important underlying mechanisms associated with HHcy-induced neurodegenerative and retinal disorders. Impairment of the barrier function triggers inflammatory events that worsen disease pathology. Studies have shown that AD patients also suffer from visual impairments. As an extension of the central nervous system, the retina has been suggested as a prominent site of AD pathology. This review highlights inflammation as a possible underlying mechanism of HHcy-induced barrier dysfunction and neurovascular injury in aging diseases accompanied by HHcy, focusing on AD.

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35

Zhou, Yutong, Feiyan Zhu, Yang Liu, Meng Zheng, Yibin Wang, Dongya Zhang, Yasutaka Anraku, et al. "Blood-brain barrier–penetrating siRNA nanomedicine for Alzheimer’s disease therapy." Science Advances 6, no. 41 (October 2020): eabc7031. http://dx.doi.org/10.1126/sciadv.abc7031.

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Toxic aggregated amyloid-β accumulation is a key pathogenic event in Alzheimer’s disease (AD), which derives from amyloid precursor protein (APP) through sequential cleavage by BACE1 (β-site APP cleavage enzyme 1) and γ-secretase. Small interfering RNAs (siRNAs) show great promise for AD therapy by specific silencing of BACE1. However, lack of effective siRNA brain delivery approaches limits this strategy. Here, we developed a glycosylated “triple-interaction” stabilized polymeric siRNA nanomedicine (Gal-NP@siRNA) to target BACE1 in APP/PS1 transgenic AD mouse model. Gal-NP@siRNA exhibits superior blood stability and can efficiently penetrate the blood-brain barrier (BBB) via glycemia-controlled glucose transporter-1 (Glut1)–mediated transport, thereby ensuring that siRNAs decrease BACE1 expression and modify relative pathways. Noticeably, Gal-NP@siBACE1 administration restored the deterioration of cognitive capacity in AD mice without notable side effects. This “Trojan horse” strategy supports the utility of RNA interference therapy in neurodegenerative diseases.

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36

Hurtado-Alvarado, G., E. Domínguez-Salazar, L. Pavon, J. Velázquez-Moctezuma, and B. Gómez-González. "Blood-Brain Barrier Disruption Induced by Chronic Sleep Loss: Low-Grade Inflammation May Be the Link." Journal of Immunology Research 2016 (2016): 1–15. http://dx.doi.org/10.1155/2016/4576012.

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Sleep is a vital phenomenon related to immunomodulation at the central and peripheral level. Sleep deficient in duration and/or quality is a common problem in the modern society and is considered a risk factor to develop neurodegenerative diseases. Sleep loss in rodents induces blood-brain barrier disruption and the underlying mechanism is still unknown. Several reports indicate that sleep loss induces a systemic low-grade inflammation characterized by the release of several molecules, such as cytokines, chemokines, and acute-phase proteins; all of them may promote changes in cellular components of the blood-brain barrier, particularly on brain endothelial cells. In the present review we discuss the role of inflammatory mediators that increase during sleep loss and their association with general disturbances in peripheral endothelium and epithelium and how those inflammatory mediators may alter the blood-brain barrier. Finally, this manuscript proposes a hypothetical mechanism by which sleep loss may induce blood-brain barrier disruption, emphasizing the regulatory effect of inflammatory molecules on tight junction proteins.

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Lopes van den Broek, Sara, Vladimir Shalgunov, Rocío García Vázquez, Natalie Beschorner, Natasha S. R. Bidesi, Maiken Nedergaard, Gitte M. Knudsen, Dag Sehlin, Stina Syvänen, and Matthias M. Herth. "Pretargeted Imaging beyond the Blood–Brain Barrier—Utopia or Feasible?" Pharmaceuticals 15, no. 10 (September 27, 2022): 1191. http://dx.doi.org/10.3390/ph15101191.

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Pretargeting is a promising nuclear imaging technique that allows for the usage of antibodies (Abs) with enhanced imaging contrast and reduced patient radiation burden. It is based on bioorthogonal chemistry with the tetrazine ligation—a reaction between trans-cyclooctenes (TCOs) and tetrazines (Tzs)—currently being the most popular reaction due to its high selectivity and reactivity. As Abs can be designed to bind specifically to currently ‘undruggable’ targets such as protein isoforms or oligomers, which play a crucial role in neurodegenerative diseases, pretargeted imaging beyond the BBB is highly sought after, but has not been achieved yet. A challenge in this respect is that large molecules such as Abs show poor brain uptake. Uptake can be increased by receptor mediated transcytosis; however, it is largely unknown if the achieved brain concentrations are sufficient for pretargeted imaging. In this study, we investigated whether the required concentrations are feasible to reach. As a model Ab, we used the bispecific anti-amyloid beta (Aβ) anti-transferrin receptor (TfR) Ab 3D6scFv8D3 and conjugated it to a different amount of TCOs per Ab and tested different concentrations in vitro. With this model in hand, we estimated the minimum required TCO concentration to achieve a suitable contrast between the high and low binding regions. The estimation was carried out using pretargeted autoradiography on brain sections of an Alzheimer’s disease mouse model. Biodistribution studies in wild-type (WT) mice were used to correlate how different TCO/Ab ratios alter the brain uptake. Pretargeted autoradiography showed that increasing the number of TCOs as well as increasing the TCO-Ab concentration increased the imaging contrast. A minimum brain concentration of TCOs for pretargeting purposes was determined to be 10.7 pmol/g in vitro. Biodistribution studies in WT mice showed a brain uptake of 1.1% ID/g using TCO-3D6scFv8D3 with 6.8 TCO/Ab. According to our estimations using the optimal parameters, pretargeted imaging beyond the BBB is not a utopia. Necessary brain TCO concentrations can be reached and are in the same order of magnitude as required to achieve sufficient contrast. This work gives a first estimate that pretargeted imaging is indeed possible with antibodies. This could allow the imaging of currently ‘undruggable’ targets and therefore be crucial to monitor (e.g., therapies for intractable neurodegenerative diseases).

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Stolp, H. B., and K. M. Dziegielewska. "Review: Role of developmental inflammation and blood-brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases." Neuropathology and Applied Neurobiology 35, no. 2 (April 2009): 132–46. http://dx.doi.org/10.1111/j.1365-2990.2008.01005.x.

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Vorbrodt, A. W., and D. H. Dobrogowska. "153 Blood-Brain Barrier (BBB) to endogenous albumin in experimental and naturally occurring neurodegenerative diseases." Neurobiology of Aging 17, no. 4 (January 1996): S39. http://dx.doi.org/10.1016/s0197-4580(96)80155-2.

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Gilgun-Sherki, Yossi, Eldad Melamed, and Daniel Offen. "Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier." Neuropharmacology 40, no. 8 (June 2001): 959–75. http://dx.doi.org/10.1016/s0028-3908(01)00019-3.

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Lee, David, and Tamara Minko. "Nanotherapeutics for Nose-to-Brain Drug Delivery: An Approach to Bypass the Blood Brain Barrier." Pharmaceutics 13, no. 12 (November 30, 2021): 2049. http://dx.doi.org/10.3390/pharmaceutics13122049.

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Treatment of neurodegenerative diseases or other central nervous system (CNS) disorders has always been a significant challenge. The nature of the blood-brain barrier (BBB) limits the penetration of therapeutic molecules to the brain after oral or parenteral administration, which, in combination with hepatic metabolism and drug elimination and inactivation during its journey in the systemic circulation, decreases the efficacy of the treatment, requires high drug doses and often induces adverse side effects. Nose-to-brain drug delivery allows the direct transport of therapeutic molecules by bypassing the BBB and increases drug concentration in the brain. The present review describes mechanisms of nose-to-brain drug delivery and discusses recent advances in this area with especial emphasis on nanotechnology-based approaches.

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Furutama, Daisuke, Shinji Matsuda, Yosuke Yamawaki, Saki Hatano, Ai Okanobu, Takumi Memida, Hiroshi Oue, et al. "IL-6 Induced by Periodontal Inflammation Causes Neuroinflammation and Disrupts the Blood–Brain Barrier." Brain Sciences 10, no. 10 (September 27, 2020): 679. http://dx.doi.org/10.3390/brainsci10100679.

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Background: Periodontal disease (PD) is a risk factor for systemic diseases, including neurodegenerative diseases. The role of the local and systemic inflammation induced by PD in neuroinflammation currently remains unclear. The present study investigated the involvement of periodontal inflammation in neuroinflammation and blood–brain barrier (BBB) disruption. Methods: To induce PD in mice (c57/BL6), a ligature was placed around the second maxillary molar. Periodontal, systemic, and neuroinflammation were assessed based on the inflammatory cytokine mRNA or protein levels using qPCR and ELISA. The BBB permeability was evaluated by the mRNA levels and protein levels of tight junction-related proteins in the hippocampus using qPCR and immunofluorescence. Dextran tracing in the hippocampus was also conducted to examine the role of periodontal inflammation in BBB disruption. Results: The TNF-α, IL-1β, and IL-6 levels markedly increased in gingival tissue 1 week after ligation. The IL-6 serum levels were also increased by ligature-induced PD. In the hippocampus, the IL-1β mRNA expression levels were significantly increased by ligature-induced PD through serum IL-6. The ligature-induced PD decreased the claudin 5 expression levels in the hippocampus, and the neutralization of IL-6 restored its levels. The extravascular 3-kDa dextran levels were increased by ligature-induced PD. Conclusions: These results suggest that the periodontal inflammation-induced expression of IL-6 is related to neuroinflammation and BBB disruption in the hippocampus, ultimately leading to cognitive impairment. Periodontal therapy may protect against neurodegenerative diseases.

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Maan, Gagandeep, Biplab Sikdar, Ashish Kumar, Rahul Shukla, and Awanish Mishra. "Role of Flavonoids in Neurodegenerative Diseases: Limitations and Future Perspectives." Current Topics in Medicinal Chemistry 20, no. 13 (June 9, 2020): 1169–94. http://dx.doi.org/10.2174/1568026620666200416085330.

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Background: Flavonoids, a group of natural dietary polyphenols, are known for their beneficial effects on human health. By virtue of their various pharmacological effects, like anti-oxidative, antiinflammatory, anti-carcinogenic and neuroprotective effects, flavonoids have now become an important component of herbal supplements, pharmaceuticals, medicinals and cosmetics. There has been enormous literature supporting neuroprotective effect of flavonoids. Recently their efficacy in various neurodegenerative diseases, like Alzheimer’s disease and Parkinson diseases, has received particular attention. Objective: The mechanism of flavanoids neuroprotection might include antioxidant, antiapoptotic, antineuroinflammatory and modulation of various cellular and intracellular targets. In in-vivo systems, before reaching to brain, they have to cross barriers like extensive first pass metabolism, intestinal barrier and ultimately blood brain barrier. Different flavonoids have varied pharmacokinetic characteristics, which affect their pharmacodynamic profile. Therefore, brain accessibility of flavonoids is still debatable. Methods: This review emphasized on current trends of research and development on flavonoids, especially in neurodegenerative diseases, possible challenges and strategies to encounter using novel drug delivery system. Results: Various flavonoids have elicited their therapeutic potential against neurodegenerative diseases, however by using nanotechnology and novel drug delivery systems, the bioavailability of favonoids could be enhanced. Conclusion: This study bridges a significant opinion on medicinal chemistry, ethanopharmacology and new drug delivery research regarding use of flavonoids in management of neurodegeneration.

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Kalyan, Manjunath, Ahmed Hediyal Tousif, Sharma Sonali, Chandrasekaran Vichitra, Tuladhar Sunanda, Sankar Simla Praveenraj, Bipul Ray, et al. "Role of Endogenous Lipopolysaccharides in Neurological Disorders." Cells 11, no. 24 (December 14, 2022): 4038. http://dx.doi.org/10.3390/cells11244038.

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Lipopolysaccharide (LPS) is a cell-wall immunostimulatory endotoxin component of Gram-negative bacteria. A growing body of evidence reveals that alterations in the bacterial composition of the intestinal microbiota (gut dysbiosis) disrupt host immune homeostasis and the intestinal barrier function. Microbial dysbiosis leads to a proinflammatory milieu and systemic endotoxemia, which contribute to the development of neurodegenerative diseases and metabolic disorders. Two important pathophysiological hallmarks of neurodegenerative diseases (NDDs) are oxidative/nitrative stress and inflammation, which can be initiated by elevated intestinal permeability, with increased abundance of pathobionts. These changes lead to excessive release of LPS and other bacterial products into blood, which in turn induce chronic systemic inflammation, which damages the blood–brain barrier (BBB). An impaired BBB allows the translocation of potentially harmful bacterial products, including LPS, and activated neutrophils/leucocytes into the brain, which results in neuroinflammation and apoptosis. Chronic neuroinflammation causes neuronal damage and synaptic loss, leading to memory impairment. LPS-induced inflammation causes inappropriate activation of microglia, astrocytes, and dendritic cells. Consequently, these alterations negatively affect mitochondrial function and lead to increases in oxidative/nitrative stress and neuronal senescence. These cellular changes in the brain give rise to specific clinical symptoms, such as impairment of locomotor function, muscle weakness, paralysis, learning deficits, and dementia. This review summarizes the contributing role of LPS in the development of neuroinflammation and neuronal cell death in various neurodegenerative diseases.

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Padmanabhan, Parasuraman, Mathangi Palanivel, Ajay Kumar, Domokos Máthé, George K. Radda, Kah-Leong Lim, and Balázs Gulyás. "Nanotheranostic agents for neurodegenerative diseases." Emerging Topics in Life Sciences 4, no. 6 (December 15, 2020): 645–75. http://dx.doi.org/10.1042/etls20190141.

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Анотація:

Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), affect the ageing population worldwide and while severely impairing the quality of life of millions, they also cause a massive economic burden to countries with progressively ageing populations. Parallel with the search for biomarkers for early detection and prediction, the pursuit for therapeutic approaches has become growingly intensive in recent years. Various prospective therapeutic approaches have been explored with an emphasis on early prevention and protection, including, but not limited to, gene therapy, stem cell therapy, immunotherapy and radiotherapy. Many pharmacological interventions have proved to be promising novel avenues, but successful applications are often hampered by the poor delivery of the therapeutics across the blood-brain-barrier (BBB). To overcome this challenge, nanoparticle (NP)-mediated drug delivery has been considered as a promising option, as NP-based drug delivery systems can be functionalized to target specific cell surface receptors and to achieve controlled and long-term release of therapeutics to the target tissue. The usefulness of NPs for loading and delivering of drugs has been extensively studied in the context of NDDs, and their biological efficacy has been demonstrated in numerous preclinical animal models. Efforts have also been made towards the development of NPs which can be used for targeting the BBB and various cell types in the brain. The main focus of this review is to briefly discuss the advantages of functionalized NPs as promising theranostic agents for the diagnosis and therapy of NDDs. We also summarize the results of diverse studies that specifically investigated the usage of different NPs for the treatment of NDDs, with a specific emphasis on AD and PD, and the associated pathophysiological changes. Finally, we offer perspectives on the existing challenges of using NPs as theranostic agents and possible futuristic approaches to improve them.

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I, Rodriguez-Izquierdo, Serramia MJ, Gomez R, De La Mata FJ, Bullido MJ та Muñoz-Fernández MA. "Gold Nanoparticles Crossing Blood-Brain Barrier Prevent HSV-1 Infection and Reduce Herpes Associated Amyloid-βsecretion". Journal of Clinical Medicine 9, № 1 (7 січня 2020): 155. http://dx.doi.org/10.3390/jcm9010155.

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Infections caused by HSV-1 and their typical outbreaks invading the nervous system have been related to neurodegenerative diseases. HSV-1 infection may deregulate the balance between the amyloidogenic and non-amyloidogenic pathways, raising the accumulation of amyloid-β peptides, one of the hallmarks in the neurodegenerative diseases. An effective treatment against both, HSV-1 infections and neurodegeneration, is a major therapeutic target. Therefore, gold nanoparticles (NPAus) have been previously studied in immunotherapy, cancer and cellular disruptions with very promising results. Our study demonstrates that a new NPAus family inhibits the HSV-1 infection in a neural-derived SK-N-MC cell line model and that this new NPAus reduces the HSV-1-induced β-secretase activity, as well as amyloid-β accumulation in SK-APP-D1 modifies cell line. We demonstrated that NPAuG3-S8 crosses the blood-brain barrier (BBB) and does not generate cerebral damage to in vivo CD1 mice model. The NPAuG3-S8 could be a promising treatment against neuronal HSV-1 infections and neuronal disorders related to the Aβ peptides.

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Hafezi-Moghadam, Ali, Kennard L. Thomas, and Denisa D. Wagner. "ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage." American Journal of Physiology-Cell Physiology 292, no. 4 (April 2007): C1256—C1262. http://dx.doi.org/10.1152/ajpcell.00563.2005.

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Previously, we reported a defect in the blood-brain barrier (BBB) of apolipoprotein E-deficient (apoE−/−) mice ( 24 ). Here, we investigate BBB permeability in wild-type (WT) and apoE−/− mice as a function of age. Both WT and apoE−/− mice showed significantly increased cortical BBB leakage with age. However, in apoE−/− mice, the leakage increased at a 3.7× higher rate compared with WT mice. Surprisingly, the cerebellum showed significantly more leakage than other brain regions across age, while there was no difference between the two hemispheres. To determine the contribution of tissue- vs. blood-borne apoE to vascular permeability, we generated chimeric mice by bone marrow transplantation and measured their BBB leakage. These experiments suggest that both blood- and tissue-derived apoE are equally important for BBB function. In sum, we find an age-dependent defect in the BBB that is exacerbated in apoE−/− mice. Since vascular defects are found in patients with age-related neurodegenerative diseases, such as Alzheimer's, age-related BBB leakage could underlie these defects and may thus be an important contributor to the cumulative neuronal damage of these diseases.

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Cano, Amanda, Álvaro Muñoz-Morales, Elena Sánchez-López, Miren Ettcheto, Eliana B. Souto, Antonio Camins, Mercè Boada, and Agustín Ruíz. "Exosomes-Based Nanomedicine for Neurodegenerative Diseases: Current Insights and Future Challenges." Pharmaceutics 15, no. 1 (January 16, 2023): 298. http://dx.doi.org/10.3390/pharmaceutics15010298.

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Neurodegenerative diseases constitute a group of pathologies whose etiology remains unknown in many cases, and there are no treatments that stop the progression of such diseases. Moreover, the existence of the blood–brain barrier is an impediment to the penetration of exogenous molecules, including those found in many drugs. Exosomes are extracellular vesicles secreted by a wide variety of cells, and their primary functions include intercellular communication, immune responses, human reproduction, and synaptic plasticity. Due to their natural origin and molecular similarities with most cell types, exosomes have emerged as promising therapeutic tools for numerous diseases. Specifically, neurodegenerative diseases have shown to be a potential target for this nanomedicine strategy due to the difficult access to the brain and the strategy’s pathophysiological complexity. In this regard, this review explores the most important biological-origin drug delivery systems, innovative isolation methods of exosomes, their physicochemical characterization, drug loading, cutting-edge functionalization strategies to target them within the brain, the latest research studies in neurodegenerative diseases, and the future challenges of exosomes as nanomedicine-based therapeutic tools.

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Cuadrado, Antonio. "Brain-Protective Mechanisms of Transcription Factor NRF2: Toward a Common Strategy for Neurodegenerative Diseases." Annual Review of Pharmacology and Toxicology 62, no. 1 (January 6, 2022): 255–77. http://dx.doi.org/10.1146/annurev-pharmtox-052220-103416.

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Neurodegenerative diseases are characterized by the loss of homeostatic functions that control redox and energy metabolism, neuroinflammation, and proteostasis. The transcription factor nuclear factor erythroid 2–related factor 2 (NRF2) is a master controller of these functions, and its overall activity is compromised during aging and in these diseases. However, NRF2 can be activated pharmacologically and is now being considered a common therapeutic target. Many gaps still exist in our knowledge of the specific role that NRF2 plays in specialized brain cell functions or how these cells respond to the hallmarks of these diseases. This review discusses the relevance of NRF2 to several hallmark features of neurodegenerative diseases and the current status of pharmacological activators that might pass through the blood-brain barrier and provide a disease-modifying effect.

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Charrière, Karine, Imen Ghzaiel, Gérard Lizard, and Anne Vejux. "Involvement of Microglia in Neurodegenerative Diseases: Beneficial Effects of Docosahexahenoic Acid (DHA) Supplied by Food or Combined with Nanoparticles." International Journal of Molecular Sciences 22, no. 19 (September 30, 2021): 10639. http://dx.doi.org/10.3390/ijms221910639.

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Neurodegenerative diseases represent a major public health issue and require better therapeutic management. The treatments developed mainly target neuronal activity. However, an inflammatory component must be considered, and microglia may constitute an important therapeutic target. Given the difficulty in developing molecules that can cross the blood–brain barrier, the use of food-derived molecules may be an interesting therapeutic avenue. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (22:6 omega-3), has an inhibitory action on cell death and oxidative stress induced in the microglia. It also acts on the inflammatory activity of microglia. These data obtained in vitro or on animal models are corroborated by clinical trials showing a protective effect of DHA. Whereas DHA crosses the blood–brain barrier, nutritional intake lacks specificity at both the tissue and cellular level. Nanomedicine offers new tools which favor the delivery of DHA at the cerebral level, especially in microglial cells. Because of the biological activities of DHA and the associated nanotargeting techniques, DHA represents a therapeutic molecule of interest for the treatment of neurodegenerative diseases.

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