Abstract
Alzheimer’s disease (AD) is a multifactorial disorder where amyloid beta (Aβ) plaques, Ca2+ dysregulation, excessive oxidative stress, mitochondrial dysfunction and synaptic loss operate synergistically to bring about cholinergic deficits and dementia. New therapeutic interventions are gaining prominence as the morbidity and mortality of AD increases exponentially every year. Treating AD with antihypertensive drugs is thought to be a promising intervention; however, its mechanism of action of ameliorating AD needs further investigation. In this context, the present study explores the protective effect of verapamil, an antihypertensive agent of Ca2+ channel blocker (CCB) class against scopolamine-induced in vitro neurotoxicity and in vivo cognitive impairment. Supplementation of verapamil was found to attenuate oxidative stress by preventing mitochondrial injury, and augment the expression of genes involved in the cholinergic function (mACR1), synaptic plasticity (GAP43, SYP) and Ca2+-dependent memory-related genes (CREB1, CREBBP, BDNF). Further, verapamil treatment in mice attenuated the cognitive and behavioural deficits induced by scopolamine as measured by the elevated plus maze and passive avoidance test (P < 0.05). Thus, the present study demonstrates the neuroprotective effect of verapamil against the pathogenesis of AD such as oxidative stress, mitochondrial dysfunction and cognitive decline. These observations emphasize the importance of ‛Ca2+ dysregulation’ and ‛mitochondrial dysfunction’ theories in AD and recommends the supplementation of compounds that regulate Ca2+ homeostasis and mitochondrial function in susceptible AD individuals.
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- Aβ:
-
Amyloid beta
- DMEM:
-
Dulbecco’s modified eagle medium
- DMSO:
-
Dimethyl sulfoxide
- DNPH :
-
2,4-dinitrophenylhydrazine
- DTNB :
-
5,5′-dithiobis-(2-nitrobenzoic acid)
- EDTA :
-
Ethylenediaminetetraacetic acid
- FBS :
-
Fetal bovine serum
- GAPDH :
-
Glyceraldehyde 3-phosphate dehydrogenase
- HBSS :
-
Hank’s balanced salt solution
- Iso-OMPA :
-
tetraisopropyl pyrophosphoramide
- JC1 :
-
5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide
- LTP :
-
Long term potentiation
- MTT :
-
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- NBT :
-
Nitroblue tretazolium
- PBS :
-
Phosphate buffered saline
- VOC :
-
Voltage operated channel
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Acknowledgements
We acknowledge the support from Dr. G. Ariharasivakumar (KMCH College of Pharmacy, Coimbatore, India) and R. Vadivelan (JSS College of Pharmacy, Ooty, India) for animal studies. The authors PS and RKC respectively acknowledge the research fellowships DST-INSPIRE and DST-PURSE, both provided by the Department of Science and Technology, New Delhi.
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Ponne, S., Kumar, C.R. & Boopathy, R. Verapamil attenuates scopolamine induced cognitive deficits by averting oxidative stress and mitochondrial injury – A potential therapeutic agent for Alzheimer’s Disease. Metab Brain Dis 35, 503–515 (2020). https://doi.org/10.1007/s11011-019-00498-x
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DOI: https://doi.org/10.1007/s11011-019-00498-x