Cotinine and 6-Hydroxy-L-Nicotine Reverses Memory Deficits and Reduces Oxidative Stress in Aβ25-35-Induced Rat Model of Alzheimer's Disease.

Razvan Stefan Boiangiu,Bogdan Alexandru Stache,Bogdan Alexandru Stache,Brindusa Alina Petre,Brindusa Alina Petre,Dragos Lucian Gorgan,Lucian Hritcu,Marius Mihasan

doi:10.3390/antiox9080768

Razvan Stefan Boiangiu, Bogdan Alexandru Stache + Show 6 more

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https://doi.org/10.3390/antiox9080768

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Abstract

The nicotinic derivatives, cotinine (COT), and 6-hydroxy-L-nicotine (6HLN), showed promising cognitive-improving effects without exhibiting the nicotine’s side-effects. Here, we investigated the impact of COT and 6HLN on memory impairment and the oxidative stress in the Aβ25-35-induced rat model of Alzheimer’s disease (AD). COT and 6HLN were chronically administered to Aβ25-35-treated rats, and their memory performances were assessed using in vivo tasks (Y-maze, novel object recognition, and radial arm maze). By using in silico tools, we attempted to associate the behavioral outcomes with the calculated binding potential of these nicotinic compounds in the allosteric sites of α7 and α4β2 subtypes of the nicotinic acetylcholine receptors (nAChRs). The oxidative status and acetylcholinesterase (AChE) activity were determined from the hippocampal tissues. RT-qPCR assessed bdnf, arc, and il-1β mRNA levels. Our data revealed that COT and 6HLN could bind to α7 and α4β2 nAChRs with similar or even higher affinity than nicotine. Consequently, the treatment exhibited a pro-cognitive, antioxidant, and anti-AChE profile in the Aβ25-35-induced rat model of AD. Finally, RT-qPCR analysis revealed that COT and 6HLN positively modulated the bdnf, arc, and il-1β genes expression. Therefore, these nicotinic derivatives that act on the cholinergic system might represent a promising choice to ameliorate AD conditions.

Highlights

Alzheimer’s disease (AD) is a progressive, unremitting neurodegenerative disease and represents the most typical cause of dementia in the elderly population
The α7 subtype of nicotinic acetylcholine receptors (nAChRs) is highly expressed in the hippocampus and is involved in cognitive functions of the central nervous system (CNS), such as memory formation, and its modulation is emerging as a therapeutic approach for cognitive disorders, including AD [64]
In the AD brain, the ACh level is limited, and the loss of α7 nAChRs in the hippocampus was correlated with progressive loss of cognitive functions [64,65]

Summary

Introduction

Alzheimer’s disease (AD) is a progressive, unremitting neurodegenerative disease and represents the most typical cause of dementia in the elderly population. AD manifests by a severe and gradual memory loss, which is accompanied by several pathologic hallmarks such as the formation of extra- and intracellular senile plaques of beta-amyloid (Aβ), the intraneuronal formation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein and death of cholinergic neurons in the hippocampus with a reduction in acetylcholine (ACh) levels [3,4,5]. The cholinergic hypothesis states that the cognitive decline observed in AD is caused by the loss of cholinergic function in the central nervous system (CNS) [9]. It is considered that the deterioration of cognitive function observed in AD patients is caused by the degeneration of the cholinergic neurons in the basal forebrain and associated loss of cholinergic neurotransmission in the cerebral cortex and hippocampus [10]

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