Abstract
Cholinergic deficits and oxido-nitrosative stress are consistently associated with Alzheimer’s disease (AD). Previous findings indicate that acetylcholine subdues Ca2+ current in the brain. Cholinergic antagonists (e.g., scopolamine) can instigate Ca2+-induced redox imbalance, inflammation, and cell-death pathways leading to AD-type memory impairment. Earlier, several Ca2+-channel blockers (CCB, e.g., dihydropyridine type) or cholinergic enhancers showed promising results in animal models of AD. In the present research, pretreatment effects of lacidipine (L-type CCB) on learning and memory functions were investigated using the scopolamine mouse model of AD. Swiss albino mice (20–25 g) were administered lacidipine (1 and 3 mg/kg) for 14 days. Scopolamine, an anti-muscarinic drug, was given (1 mg/kg) from days 8 to 14. The mice were subjected to elevated plus maze (EPM) and passive-avoidance (PA) paradigms. Bay-K8644 (a Ca2+-channel agonist) was administered before behavioral studies on days 13 and 14. Biochemical parameters of oxidative stress and acetylcholinesterase (AChE) activity were quantified using the whole brain. Behavioral studies showed an increase in transfer latency (TL) in the EPM test and a decrease in step-through latency (STL) in the PA test in scopolamine-administered mice. Scopolamine enhanced the AChE activity and oxidative stress in the brain of mice which resulted in memory impairment. Lacidipine prevented the amnesia against scopolamine and reduced the oxidative stress and AChE activity in the brain of mice. Bay-K8644 attenuated the lacidipine-induced improvement in memory and redox balance in scopolamine-administered mice. Lacidipine can prevent the oxidative stress and improve the cholinergic function in the brain. These properties of lacidipine can mitigate the pathogenesis of AD-type dementia.
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Data Availability
The data can be made available on request.
Abbreviations
- ACh:
-
Acetylcholine
- AChE:
-
Acetylcholinesterase
- AD:
-
Alzheimer’s disease
- AIF:
-
Apoptosis-inducing factor
- AMPA:
-
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- ANOVA:
-
Analysis of variance
- AThCh:
-
Acetylthiocholine
- Aβ :
-
Amyloid-β
- Bad:
-
BCL2-associated agonist of cell death
- Bax:
-
Bcl-2-associated X protein
- Bcl-xL:
-
B-cell lymphoma-extra large
- Ca2 + :
-
Calcium
- CAT:
-
Catalase
- CCB:
-
Calcium channel blocker
- CDK-5:
-
Cyclin-dependent kinase 5
- CPCSEA:
-
Committee for the Purpose of Control and Supervision of Experiments on Animals
- DMSO:
-
Dimethyl sulfoxide
- EPM:
-
Elevated plus maze
- GABA:
-
γ-Amino butyric acid
- GSH:
-
Glutathione
- GSK-3β :
-
Glycogen synthase kinase
- H2O2 :
-
Hydrogen peroxide
- i.p. :
-
Intraperitoneal
- iNOS:
-
Inducible nitric oxide synthase
- LCD:
-
Lacidipine
- LTP:
-
Long-term potentiation
- mA:
-
Milliampere
- MCI:
-
Mild cognitive impairment
- MDA:
-
Malondialdehyde
- nbM:
-
Nucleus basalis of Meynert
- NFTs:
-
Neurofibrillary tangles
- NFκB:
-
Nuclear factor kappa-light-chain-enhancer of activated B cells
- NMDA:
-
N-Methyl D-aspartate
- NO:
-
Nitric oxide
- PA:
-
Passive avoidance
- ROS:
-
Reactive oxygen species
- SOD:
-
Superoxide dismutase
- STL:
-
Step-through latency
- TL:
-
Transfer latency
- UPS:
-
Ubiquitin–proteasome system
- W:
-
Watt
- λ max :
-
Maximum wavelength
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The authors are thankful to I. K. Gujral Punjab Technical University, Kapurthala (Punjab), and the management of A.S.B.A.S.J.S.M. College of Pharmacy, Bela (Ropar), for providing the necessary research facilities.
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Prof. (Dr.) Nitin Bansal designed the protocol of this study and arranged for the drugs and chemicals. Kunal Khurana (Ph. D. Research Scholar) conducted the research. Dr. Manish Kumar analyzed and interpreted the data. All authors drafted and revised the manuscript, and approved the final draft.
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Khurana, K., Kumar, M. & Bansal, N. Lacidipine Prevents Scopolamine-Induced Memory Impairment by Reducing Brain Oxido-nitrosative Stress in Mice. Neurotox Res 39, 1087–1102 (2021). https://doi.org/10.1007/s12640-021-00346-w
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DOI: https://doi.org/10.1007/s12640-021-00346-w