Blood-Brain Barrier Therapeutics for Neurological Diseases
DOI:
https://doi.org/10.47611/jsrhs.v10i3.1735Keywords:
Neurodiseases, Alzheimer's Disease, Parkinson's Disease, Neurotherapeutics, Blood-Brain Barrier, Amyloid-B, Neurofibrillary Tangles, A-synucleinAbstract
The Blood-Brain Barrier (BBB) is a highly selective filter responsible for allowing certain gases such as oxygen and lipid-soluble molecules to pass (Anand 2014). Its selectiveness makes it challenging for many therapeutics to combat Alzheimer’s and Parkinson’s disease with external drug therapies. Large-molecule drug therapies never pass the BBB while small-molecule drugs pass only about 5% of the time (Pardridge 2005). In Alzheimer’s disease, tight junctions between endothelial cells degrade, causing an unregulated accumulation of amyloid-β (Aβ) protein (Ramanathan 2015). Consequently, this leads to the formation of neurofibrillary tangles that cut off the nutrient supply to the brain cells and kill neurons (Ramanathan 2015). In Parkinson’s disease, astrocyte mutations cause a build-up of α-synuclein (αSyn) which affects the neuroinflammatory response and causes dysfunction in dopaminergic neurons (Booth 2017; Meade 2019). New drug therapies for Alzheimer’s and Parkinson’s continue to undergo trials; some such as FPS-ZM1 and tilavonemab for Alzheimer’s and Ravicti for Parkinson’s have shown promising results. In addition, similarities in dysfunction for both diseases and some types of cancer have sparked possibilities in retargeting cancer drugs to improve Alzheimer's and Parkinson’s pathologies. This review will summarize current therapeutic advancements for Alzheimer’s and Parkinson’s disease and their possible future contributions.
Downloads
References or Bibliography
Anand, R., Gill, K. D., & Mahdi, A. A. (2014). Therapeutics of Alzheimer’s disease: Past, present and future. Neuropharmacology, 76 Pt A, 27–50.
Angelopoulou, E., Paudel, Y. N., Shaikh, M. F., & Piperi, C. (2020). Flotillin: A Promising Biomarker for Alzheimer’s Disease. Journal of Personalized Medicine, 10(2). https://doi.org/10.3390/jpm10020020
Axon Presented Positive Phase II Trial Results of AADvac1 at AAT-AD/PD 2020. (n.d.). Retrieved January 25, 2021, from https://www.biospace.com/article/axon-presented-positive-phase-ii-trial-results-of-aadvac1-at-aat-ad-pd-2020/
Azeliragon. (n.d.). Retrieved January 28, 2021, from https://www.alzforum.org/therapeutics/azeliragon
Bednarczyk, J., & Lukasiuk, K. (2011). Tight junctions in neurological diseases. Acta Neurobiologiae Experimentalis, 71(4), 393–408.
Bittar, A., Bhatt, N., & Kayed, R. (2020). Advances and considerations in AD tau-targeted immunotherapy. Neurobiology of Disease, 134, 104707.
Booth, H. D. E., Hirst, W. D., & Wade-Martins, R. (2017). The Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis. Trends in Neurosciences, 40(6), 358.
Brahmachari, S., Karuppagounder, S. S., Ge, P., Lee, S., Dawson, V. L., Dawson, T. M., & Ko, H. S. (2017). c-Abl and Parkinson’s Disease: Mechanisms and Therapeutic Potential. In Journal of Parkinson’s Disease (Vol. 7, Issue 4, pp. 589–601). https://doi.org/10.3233/jpd-171191
Burstein, A. H., Grimes, I., Galasko, D. R., Aisen, P. S., Sabbagh, M., & Mjalli, A. M. M. (2014). Effect of TTP488 in patients with mild to moderate Alzheimer’s disease. BMC Neurology, 14, 12.
Campanella, C., Pace, A., Caruso Bavisotto, C., Marzullo, P., Marino Gammazza, A., Buscemi, S., & Palumbo Piccionello, A. (2018). Heat Shock Proteins in Alzheimer’s Disease: Role and Targeting. International Journal of Molecular Sciences, 19(9). https://doi.org/10.3390/ijms19092603
Carter, J., & Lippa, C. F. (2001). Beta-amyloid, neuronal death and Alzheimer’s disease. Current Molecular Medicine, 1(6), 733–737.
Cerebrospinal Fluid (CSF). (n.d.). Retrieved February 26, 2021, from https://www.nationalmssociety.org/Symptoms-Diagnosis/Diagnosing-Tools/Cerebrospinal-Fluid-(CSF)
Deane, R., Singh, I., Sagare, A. P., Bell, R. D., Ross, N. T., LaRue, B., Love, R., Perry, S., Paquette, N., Deane, R. J., Thiyagarajan, M., Zarcone, T., Fritz, G., Friedman, A. E., Miller, B. L., & Zlokovic, B. V. (2012). A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease. The Journal of Clinical Investigation, 122(4), 1377.
Deepa Dash, V. G. (2019). Anticancer Drugs for Parkinson’s Disease: Is It a Ray of Hope or Only Hype? Annals of Indian Academy of Neurology, 22(1), 13.
Desai, B. S., Monahan, A. J., Carvey, P. M., & Hendey, B. (2007). Blood-brain barrier pathology in Alzheimer’s and Parkinson's disease: implications for drug therapy. Cell Transplantation, 16(3), 285–299.
Dotiwala, A. K., McCausland, C., & Samra, N. S. (2020). Anatomy, Head and Neck, Blood Brain Barrier. In StatPearls. StatPearls Publishing.
Drug Approvals - From Invention to Market...12 Years! (n.d.). Retrieved April 25, 2021, from https://www.medicinenet.com/script/main/art.asp?articlekey=9877
Drummond, E., & Wisniewski, T. (2017). Alzheimer’s disease: experimental models and reality. Acta Neuropathologica, 133(2), 155–175.
Exploring the Link Between Dopamine and Parkinson’s Disease. (n.d.). Retrieved February 25, 2021, from https://www.cedars-sinai.org/blog/exploring-the-link-between-dopamine-and-parkinsons-disease.html
Fan, Y.-J., Zhou, Y.-X., Zhang, L.-R., Lin, Q.-F., Gao, P.-Z., Cai, F., Zhu, L.-P., Liu, B., & Xu, J.-H. (2018). C1206, a novel curcumin derivative, potently inhibits Hsp90 and human chronic myeloid leukemia cells in vitro. Acta Pharmacologica Sinica, 39(4), 649.
FEBS Press. (n.d.). Retrieved February 25, 2021, from https://febs.onlinelibrary.wiley.com/doi/full/10.1111/febs.12335
Ferris, H. A., Perry, R. J., Moreira, G. V., Shulman, G. I., Horton, J. D., & Kahn, C. R. (2017). Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proceedings of the National Academy of Sciences of the United States of America, 114(5), 1189–1194.
Genetics and Parkinson’s. (n.d.). Retrieved February 25, 2021, from https://www.parkinson.org/understanding-parkinsons/causes/genetics
Hong, Y., Shen, C., Yin, Q., Sun, M., Ma, Y., & Liu, X. (2016). Effects of RAGE-Specific Inhibitor FPS-ZM1 on Amyloid-β Metabolism and AGEs-Induced Inflammation and Oxidative Stress in Rat Hippocampus. Neurochemical Research, 41(5), 1192–1199.
Jin, U., Park, S. J., & Park, S. M. (2019). Cholesterol Metabolism in the Brain and Its Association with Parkinson’s Disease. 28(5), 554–567.
Kadry, H., Noorani, B., & Cucullo, L. (2020). A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids and Barriers of the CNS, 17(1), 69.
Kang, S.-J., Kim, J. S., & Park, A. S. M. (2018). Ubiquitin C-terminal Hydrolase L1 Regulates Lipid Raft-dependent Endocytosis. Experimental Neurobiology, 27(5), 377–386.
Karim, M. R., Liao, E. E., Kim, J., Meints, J., Martinez, H. M., Pletnikova, O., Troncoso, J. C., & Lee, M. K. (2020). α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment. Molecular Neurodegeneration, 15(1), 1–18.
Kong, Y., Liu, C., Zhou, Y., Qi, J., Zhang, C., Sun, B., Wang, J., & Guan, Y. (2020). Progress of RAGE Molecular Imaging in Alzheimer’s Disease. Frontiers in Aging Neuroscience, 12, 227.
Lochhead, J. J., Yang, J., Ronaldson, P. T., & Davis, T. P. (2020). Structure, Function, and Regulation of the Blood-Brain Barrier Tight Junction in Central Nervous System Disorders. Frontiers in Physiology, 11, 914.
Luo, W., Sun, W., Taldone, T., Rodina, A., & Chiosis, G. (2010). Heat shock protein 90 in neurodegenerative diseases. In Molecular Neurodegeneration (Vol. 5, Issue 1, p. 24). https://doi.org/10.1186/1750-1326-5-24
Meade, R. M., Fairlie, D. P., & Mason, J. M. (2019). Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles. Molecular Neurodegeneration, 14(1), 1–14.
Monahan, A. J., Warren, M., & Carvey, P. M. (2008). Neuroinflammation and peripheral immune infiltration in Parkinson’s disease: an autoimmune hypothesis. Cell Transplantation, 17(4), 363–372.
Nilotinib. (n.d.). Retrieved February 25, 2021, from
[No title]. (n.d.). Retrieved February 23, 2021, from https://www.alzdiscovery.org/uploads/cognitive_vitality_media/Azeliragon-Cognitive-Vitality-For-Researchers.pdf
Novak, P., Schmidt, R., Kontsekova, E., Kovacech, B., Smolek, T., Katina, S., Fialova, L., Prcina, M., Parrak, V., Dal-Bianco, P., Brunner, M., Staffen, W., Rainer, M., Ondrus, M., Ropele, S., Smisek, M., Sivak, R., Zilka, N., Winblad, B., & Novak, M. (2018). FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease. Alzheimer’s Research & Therapy, 10(1), 1–16.
Pagan, F. L., Hebron, M. L., Wilmarth, B., Torres-Yaghi, Y., Lawler, A., Mundel, E. E., Yusuf, N., Starr, N. J., Anjum, M., Arellano, J., Howard, H. H., Shi, W., Mulki, S., Kurd-Misto, T., Matar, S., Liu, X., Ahn, J., & Moussa, C. (2020). Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease: A Phase 2 Randomized Clinical Trial. JAMA Neurology, 77(3), 309.
Pardridge, W. M. (2005). The blood-brain barrier: bottleneck in brain drug development. NeuroRx: The Journal of the American Society for Experimental NeuroTherapeutics, 2(1), 3–14.
Phenylbutyrate for Alpha-synuclein Clearance from the Brain. (n.d.). Retrieved February 26, 2021, from https://www.michaeljfox.org/grant/phenylbutyrate-alpha-synuclein-clearance-brain
Phenylbutyrate Response as a Biomarker for Alpha-synuclein Clearance From the Brain. (n.d.). Retrieved February 26, 2021, from https://clinicaltrials.gov/ct2/show/NCT02046434
Ramanathan, A., Nelson, A. R., Sagare, A. P., & Zlokovic, B. V. (2015). Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer’s disease: the role, regulation and restoration of LRP1. In Frontiers in Aging Neuroscience (Vol. 7). https://doi.org/10.3389/fnagi.2015.00136
Ribatti, D., Nico, B., Crivellato, E., & Artico, M. (2006). Development of the blood-brain barrier: a historical point of view. Anatomical Record. Part B, New Anatomist, 289(1), 3–8.
Sabbagh, M. N., Agro, A., Bell, J., Aisen, P. S., Schweizer, E., & Galasko, D. (2011). PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease. Alzheimer Disease and Associated Disorders, 25(3), 206–212.
Sánchez-Wandelmer, J., Dávalos, A., Herrera, E., Giera, M., Cano, S., de la Peña, G., Lasunción, M. A., & Busto, R. (2009). Inhibition of cholesterol biosynthesis disrupts lipid raft/caveolae and affects insulin receptor activation in 3T3-L1 preadipocytes. Biochimica et Biophysica Acta, 1788(9). https://doi.org/10.1016/j.bbamem.2009.05.002
Shytle, R. D., Tan, J., Bickford, P. C., Rezai-Zadeh, K., Hou, L., Zeng, J., Sanberg, P. R., Sanberg, C. D., Alberte, R. S., Fink, R. C., & Roschek, B., Jr. (2012). Optimized turmeric extract reduces β-Amyloid and phosphorylated Tau protein burden in Alzheimer’s transgenic mice. Current Alzheimer Research, 9(4), 500–506.
Sviridov, D., Miller, Y. I., Ballout, R. A., Remaley, A. T., & Bukrinsky, M. (2020). Targeting Lipid Rafts—A Potential Therapy for COVID-19. In Frontiers in Immunology (Vol. 11). https://doi.org/10.3389/fimmu.2020.574508
Tomeh, M. A., Hadianamrei, R., & Zhao, X. (2019). A Review of Curcumin and Its Derivatives as Anticancer Agents. International Journal of Molecular Sciences, 20(5). https://doi.org/10.3390/ijms20051033
Tönnies, E., & Trushina, E. (2017). Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease. In Journal of Alzheimer’s Disease (Vol. 57, Issue 4, pp. 1105–1121). https://doi.org/10.3233/jad-161088
Udovin, L., Quarracino, C., Herrera, M. I., Capani, F., Otero-Losada, M., & Perez-Lloret, S. (2020). Role of Astrocytic Dysfunction in the Pathogenesis of Parkinson’s Disease Animal Models from a Molecular Signaling Perspective. In Neural Plasticity (Vol. 2020, pp. 1–10). https://doi.org/10.1155/2020/1859431
Upadhaya, A. R. (2012). Analysis of Amyloid Beta (Aβ) Protein in Amyloid Precursor Protein (APP) Transgenic Mouse Models of Alzheimer’s Disease (AD) and in Human Brains.
Wake, H., Moorhouse, A. J., & Nabekura, J. (2011). Functions of microglia in the central nervous system--beyond the immune response. Neuron Glia Biology, 7(1), 47–53.
Website. (n.d.). Retrieved February 25, 2021, from Azeliragon. [cited 28 Jan 2021]. Available: https://www.alzforum.org/therapeutics/azeliragon
West, T., Hu, Y., Verghese, P. B., Bateman, R. J., Braunstein, J. B., Fogelman, I., Budur, K., Florian, H., Mendonca, N., & Holtzman, D. M. (2017). Preclinical and Clinical Development of ABBV-8E12, a Humanized Anti-Tau Antibody, for Treatment of Alzheimer’s Disease and Other Tauopathies. The Journal of Prevention of Alzheimer’s Disease, 4(4). https://doi.org/10.14283/jpad.2017.36
World Health Organization. (2006). Neurological Disorders: Public Health Challenges. World Health Organization.
Zhang, J., Lei, W., Chen, X., Wang, S., & Qian, W. (2018). Oxidative stress response induced by chemotherapy in leukemia treatment (Review). In Molecular and Clinical Oncology. https://doi.org/10.3892/mco.2018.1549
Published
How to Cite
Issue
Section
Copyright (c) 2021 Aarushi Sahni; Nicole Katchur
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Copyright holder(s) granted JSR a perpetual, non-exclusive license to distriute & display this article.
