Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Mini-Review Article

Approaches to Optimizing Dantrolene Neuroprotection for the Treatment of Alzheimer's Disease

Author(s): Matan B. Abou, Liang Sun and Huafeng Wei*

Volume 17, Issue 4, 2020

Page: [324 - 328] Pages: 5

DOI: 10.2174/1567205017666200522204722

Price: $65

Open Access Journals Promotions 2
Abstract

Alzheimer’s Disease (AD), a neurodegenerative disorder with high incidence and mortality, is leading its way to the top of the list of the deadliest diseases without an effective disease-modifying drug. Ca2+ dysregulation, specifically abnormal release of Ca2+ via over activated ryanodine receptor (RyR), has been increasingly considered as an alternative upstream mechanism in AD pathology. Consequently, dantrolene, a RyR antagonist and FDA approved drug to treat malignant hyperthermia and chronic muscle spasms, has been shown to ameliorate memory loss in AD transgenic mice. However, the inefficiency of dantrolene to pass the Blood Brain Barrier (BBB) and penetrate the Central Nervous System needs to be resolved, considering its dose-dependent neuroprotection in AD and other neurodegenerative diseases. In this mini-review, we will discuss the current status of dantrolene neuroprotection in AD treatment and a strategy to maximize its beneficial effects, such as intranasal administration of dantrolene.

Keywords: Alzheimer's disease, dantrolene, treatment, intranasal, calcium, blood brain barrier.

[1]
Rapid growth in neuroscience research: A study of neuroscience papers from 2006-2015 has revealed the most productive journals and contributing countries, and the most popular research topics [Internet]ScienceDaily 2019[cited 23 June 2019] Available from https://www.sciencedaily.com/releases/2017/04/170420093736.htm
[2]
Stocum D. Regenerative medicine of neural tissues. In: Regen Biol Med. 2012; pp. 285-323.
[3]
Schneider LS, Mangialasche F, Andreasen N, et al. Clinical trials and late-stage drug development for Alzheimer’s disease: An appraisal from 1984 to 2014. J Intern Med 2014; 275(3): 251-83.
[http://dx.doi.org/10.1111/joim.12191] [PMID: 24605808]
[4]
Khachaturian ZS. Calcium hypothesis of Alzheimer’s disease and brain aging. Ann N Y Acad Sci 1994; 747(1): 1-11.
[http://dx.doi.org/10.1111/j.1749-6632.1994.tb44398.x] [PMID: 7847664]
[5]
Reitz C. Alzheimer’s disease and the amyloid cascade hypothesis: A critical review. Int J Alzheimers Dis 2012; 2012: 369808.
[http://dx.doi.org/10.1155/2012/369808] [PMID: 22506132]
[6]
Selkoe DJ. Alzheimer disease and aducanumab: Adjusting our approach. Nat Rev Neurol 2019; 15(7): 365-6.
[http://dx.doi.org/10.1038/s41582-019-0205-1] [PMID: 31138932]
[7]
Feuerstein A. Biogen halts studies of closely watched alzheimer’s drug, a blow to hopes for new treatment 2019.https://www.scientificamerican.com/article/biogen-halts-studies-of-closely-watched-alzheimers-drug-a-blow-to-hopes-for-new-treatment/?redirect=1
[8]
Mullane K, Williams M. Alzheimer’s therapeutics: Continued clinical failures question the validity of the amyloid hypothesis-but what lies beyond? Biochem Pharmacol 2013; 85(3): 289-305.
[http://dx.doi.org/10.1016/j.bcp.2012.11.014] [PMID: 23178653]
[9]
Bezprozvanny I, Mattson MP. Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 2008; 31(9): 454-63.
[http://dx.doi.org/10.1016/j.tins.2008.06.005] [PMID: 18675468]
[10]
Henley DB, May PC, Dean RA, Siemers ER. Development of semagacestat (LY450139), a functional γ-secretase inhibitor, for the treatment of Alzheimer’s disease. Expert Opin Pharmacother 2009; 10(10): 1657-64.
[http://dx.doi.org/10.1517/14656560903044982] [PMID: 19527190]
[11]
Coric V, van Dyck CH, Salloway S, et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol 2012; 69(11): 1430-40.
[http://dx.doi.org/10.1001/archneurol.2012.2194] [PMID: 22892585]
[12]
DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2001; 98(15): 8850-5.
[http://dx.doi.org/10.1073/pnas.151261398] [PMID: 11438712]
[13]
Doody RS, Raman R, Farlow M, et al. Alzheimer’s Disease Cooperative Study Steering Committee Semagacestat Study Group. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 2013; 369(4): 341-50.
[http://dx.doi.org/10.1056/NEJMoa1210951] [PMID: 23883379]
[14]
Liang L, Wei H. Dantrolene, a treatment for Alzheimer disease? Alzheimer Dis Assoc Disord 2015; 29(1): 1-5.
[http://dx.doi.org/10.1097/WAD.0000000000000076] [PMID: 25551862]
[15]
Wang Y, Shi Y, Wei H. calcium dysregulation in alzheimer’s disease: A target for new drug development. J Alzheimers Dis Parkinsonism 2017; 7(5): 374.
[http://dx.doi.org/10.4172/2161-0460.1000374] [PMID: 29214114]
[16]
Tong BC, Wu AJ, Li M, Cheung KH. Calcium signaling in Alzheimer’s disease & therapies. Biochim Biophys Acta Mol Cell Res 2018; 1865(11 Pt B): 1745-60.
[http://dx.doi.org/10.1016/j.bbamcr.2018.07.018] [PMID: 30059692]
[17]
Choi RH, Koenig X, Launikonis BS. Dantrolene requires Mg2+ to arrest malignant hyperthermia. Proc Natl Acad Sci USA 2017; 114(18): 4811-5.
[http://dx.doi.org/10.1073/pnas.1619835114] [PMID: 28373535]
[18]
Copenhaver PF, Anekonda TS, Musashe D, et al. A translational continuum of model systems for evaluating treatment strategies in Alzheimer’s disease: Isradipine as a candidate drug. Dis Model Mech 2011; 4(5): 634-48.
[http://dx.doi.org/10.1242/dmm.006841] [PMID: 21596710]
[19]
Berridge MJ. Calcium hypothesis of Alzheimer’s disease. J Physiol 2009; 459(3): 441-9.
[20]
Wang J, Ono K, Dickstein DL, et al. Carvedilol as a potential novel agent for the treatment of Alzheimer’s disease. Neurobiol Aging 2011; 32(12): 2321.e1-2321.e12.
[http://dx.doi.org/10.1016/j.neurobiolaging.2010.05.004] [PMID: 20579773]
[21]
Bloss EB, Hunter RG, Waters EM, Munoz C, Bernard K, McEwen BS. Behavioral and biological effects of chronic S18986, a positive AMPA receptor modulator, during aging. Exp Neurol 2008; 210(1): 109-17.
[http://dx.doi.org/10.1016/j.expneurol.2007.10.007] [PMID: 18035355]
[22]
Salomone S, Caraci F, Leggio GM, Fedotova J, Drago F. New pharmacological strategies for treatment of Alzheimer’s disease: Focus on disease modifying drugs. Br J Clin Pharmacol 2012; 73(4): 504-17.
[http://dx.doi.org/10.1111/j.1365-2125.2011.04134.x] [PMID: 22035455]
[23]
Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F. Dantrolene--a review of its pharmacology, therapeutic use and new developments. Anaesthesia 2004; 59(4): 364-73.
[http://dx.doi.org/10.1111/j.1365-2044.2004.03658.x] [PMID: 15023108]
[24]
Oulès B, Del Prete D, Greco B, et al. Ryanodine receptor blockade reduces amyloid-β load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci 2012; 32(34): 11820-34.
[http://dx.doi.org/10.1523/JNEUROSCI.0875-12.2012] [PMID: 22915123]
[25]
Peng J, Liang G, Inan S, et al. Dantrolene ameliorates cognitive decline and neuropathology in Alzheimer triple transgenic mice. Neurosci Lett 2012; 516(2): 274-9.
[http://dx.doi.org/10.1016/j.neulet.2012.04.008] [PMID: 22516463]
[26]
Zhang H, Sun S, Herreman A, De Strooper B, Bezprozvanny I. Role of presenilins in neuronal calcium homeostasis. J Neurosci 2010; 30(25): 8566-80.
[http://dx.doi.org/10.1523/JNEUROSCI.1554-10.2010] [PMID: 20573903]
[27]
Wu Z, Yang B, Liu C, et al. Long-term dantrolene treatment reduced intraneuronal amyloid in aged Alzheimer triple transgenic mice. Alzheimer Dis Assoc Disord 2015; 29(3): 184-91.
[http://dx.doi.org/10.1097/WAD.0000000000000075] [PMID: 25650693]
[28]
Chakroborty S, Briggs C, Miller MB, et al. Stabilizing ER Ca2+ channel function as an early preventative strategy for Alzheimer’s disease. PLoS One 2012; 7(12): e52056
[http://dx.doi.org/10.1371/journal.pone.0052056] [PMID: 23284867]
[29]
Muehlschlegel S, Sims JR. Dantrolene: Mechanisms of neuroprotection and possible clinical applications in the neurointensive care unit. Neurocrit Care 2009; 10(1): 103-15.
[http://dx.doi.org/10.1007/s12028-008-9133-4] [PMID: 18696266]
[30]
Hanson LR, Frey WH II. Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci 2008; 9(3): S5.
[http://dx.doi.org/10.1186/1471-2202-9-S3-S5] [PMID: 19091002]
[31]
Zhang L, Andou Y, Masuda S, Mitani A, Kataoka K. Dantrolene protects against ischemic, delayed neuronal death in gerbil brain. Neurosci Lett 1993; 158(1): 105-8.
[http://dx.doi.org/10.1016/0304-3940(93)90623-S] [PMID: 8233063]
[32]
Shi Y, Zhang L, Gao X, et al. Intranasal dantrolene as a disease-modifying drug in Alzheimer 5XFAD mice. Alzheimers & Dementia 2019; 15(7): 597.
[33]
Xiao C, Davis FJ, Chauhan BC, et al. Brain transit and ameliorative effects of intranasally delivered anti-amyloid-β oligomer antibody in 5XFAD mice. J Alzheimers Dis 2013; 35(4): 777-88.
[http://dx.doi.org/10.3233/JAD-122419] [PMID: 23542865]
[34]
Haraschak JL, Langston VC, Wang R, et al. Pharmacokinetic evaluation of oral dantrolene in the dog. J Vet Pharmacol Ther 2014; 37(3): 286-94.
[http://dx.doi.org/10.1111/jvp.12089] [PMID: 24219828]
[35]
Meredith ME, Salameh TS, Banks WA. Intranasal delivery of proteins and peptides in the treatment of neurodegenerative diseases. AAPS J 2015; 17(4): 780-7.
[http://dx.doi.org/10.1208/s12248-015-9719-7] [PMID: 25801717]
[36]
Wang J, Shi Y, Yu S, et al. Intranasal administration of dantrolene increased brain concentration and duration. PLoS One 2020; 15 e0229156.
[PMID: 32160210]
[37]
Lacampagne A, Liu X, Reiken S, et al. Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits. Acta Neuropathol 2017; 134(5): 749-67.
[PMID: 28631094]
[38]
Schrank S, McDaid J, Briggs CA, et al. Human-induced neurons from presenilin 1 mutant patients model aspects of Alzheimer’s disease pathology. Int J Mol Sci 2020; 21(3): 1030.
[PMID: 32033164]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy