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

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.

Anxiolytic, Promnesic, Anti-Acetylcholinesterase and Antioxidant Effects of Cotinine and 6-Hydroxy-L-Nicotine in Scopolamine-Induced Zebrafish (Danio rerio) Model of Alzheimer’s Disease

“…Similarly, due to structural resemblance with NIC, the anxiolytic properties of COT and 6HLN showed in this study could be associated with the binding to α4β2 and α7 nAChRs. In a recent study, we showed, using in silico tools, that these nicotinic derivatives might bind to α4β2 and α7 nAChRs with similar or higher affinity than NIC [ 33 ]. The COT effects on anxiety-like behavior were investigated in a mouse model of post-traumatic stress disorder (PTSD) induced by fear conditioning [ 75 ].…”

“…Recently, we demonstrated that both COT and 6HLN ameliorated the cognitive deficits in a rat model of AD induced by intracerebroventricular (i.c.v.) infusion of Aβ 25–35 peptide, and this effect might be related to the binding of α7 and α4β2 nAChRs [ 33 ]. Our group also evaluated the effects of chronic administration of 6HLN on spatial memory in normal Wistar rats using specific hippocampus-dependent tasks, such as Y-maze or radial arm maze [ 89 ].…”

“…The npy , bdnf , egr1 , and nrf2a genes expression in the zebrafish brain was investigated using an RT-qPCR procedure as formerly described by Ionita et al [ 64 ] and Boiangiu et al [ 33 ]. For this, total RNA was purified from ~5 mg brain tissue using the Maxwell ® 16 Tissue Lev Total RNA Purification kit (Promega, Madison, WI, USA) according to the manufacturer instructions and the automatic purification system Maxwell ® 16 Instrument AS2000 (Promega, Madison, WI, USA).…”

“…We have previously shown that 6HLN attenuates the cognitive deficits and recovered the antioxidant capacity in the hippocampus of several rodent models of AD [ 31 , 32 , 33 ]. Furthermore, it was demonstrated that COT ameliorates the memory impairments and decrease the Aβ load in AD mice [ 34 , 35 ].…”

Beneficial Effects of Citrus-Derived Polymethoxylated Flavones for Central Nervous System Disorders

“…The Aβ fragment 25–35 (Aβ25–35) is also involved in the pathogenesis of AD [ 112 , 113 ]. Researchers have investigated the neuroprotective effect of nobiletin against Aβ25-35-induced neuronal cell damage [ 114 ].…”