Nicotinic acetylcholine receptors and learning and memory deficits in Neuroinflammatory diseases

Abstract

Animal survival depends on cognitive abilities such as learning and memory to adapt to environmental changes. Memory functions require an enhanced activity and connectivity of a particular arrangement of engram neurons, supported by the concerted action of neurons, glia, and vascular cells. The deterioration of the cholinergic system is a common occurrence in neurological conditions exacerbated by aging such as traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), Alzheimer’s disease (AD), and Parkinson’s disease (PD). Cotinine is a cholinergic modulator with neuroprotective, antidepressant, anti-inflammatory, antioxidant, and memory-enhancing effects. Current evidence suggests Cotinine’s beneficial effects on cognition results from the positive modulation of the α7-nicotinic acetylcholine receptors (nAChRs) and the inhibition of the toll-like receptors (TLRs). The α7nAChR affects brain functions by modulating the function of neurons, glia, endothelial, immune, and dendritic cells and regulates inhibitory and excitatory neurotransmission throughout the GABA interneurons. In addition, Cotinine acting on the α7 nAChRs and TLR reduces neuroinflammation by inhibiting the release of pro-inflammatory cytokines by the immune cells. Also, α7nAChRs stimulate signaling pathways supporting structural, biochemical, electrochemical, and cellular changes in the Central nervous system during the cognitive processes, including Neurogenesis. Here, the mechanisms of memory formation as well as potential mechanisms of action of Cotinine on memory preservation in aging and neurological diseases are discussed.

Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

“…This contention is further strengthened by the findings that nicotine may modulate the release of inflammatory cytokines and the expression of TLRs [225,226]. Indeed, recent findings indicate the inhibition of TLRs by cotinine, a metabolite of nicotine via α7nAChR [35]. As our understanding of the intricate interactions between GM, microglia, and, specifically, the role of nAChRs in these scenarios expands, more therapeutic targets may become available.…”

“…Due to the limited efficacy and/or complications of current interventions, extensive effort, particularly towards the prevention of neurodegeneration, has been expended. In this regard, neuronal nAChRs have emerged as a viable target [ 4 , 34 , 35 ]. Interestingly, a mutation in RIC3, a chaperone of neuronal nicotinic acetylcholine receptor subunit α-7 (CHRNA7), was implicated in PD [ 7 ].…”

“…Further nicotinic receptor subtype distinctions are evident in their physiological roles and central distribution. Thus, alpha7 or the low-affinity subtype, which are most abundant in the hippocampus, play a prominent role in neuronal survival and growth and are involved in various cognitive functions, including attentional processes [ 35 ]. These receptors are also implicated in pain modulation [ 149 ].…”

The complexities of ligand/receptor interactions: Exploring the role of molecular vibrations and quantum tunnelling

“…In fact, because of the much longer half-life of cotinine in mammals, many of the non-addictive cholinergic effects, as well as most of the beneficial effects traditionally usually attributed to nicotine, are currently thought to be caused by cotinine instead. [80][81][82][83] That said, there are inconsistencies in the reports of cotinine effects, particularly to nAChRs; this is likely due to the considerable heterogeneity of nicotinic receptors and the variety of model organisms tested. Even though cotinine is part of nicotine metabolism in certain invertebrate species, [22] there are no published systematic studies about cotinine in invertebrates at the time of this writing.…”

Insights into Pharmacological Activities of Nicotine and 6-Hydroxy-L-nicotine, a Bacterial Nicotine Derivative: A Systematic Review

“…Research on the relationship between cotinine, the primary metabolite of NIC, and memory is an area of interest, particularly in the context of cognitive function and neurological disorders. Some studies suggest that cotinine may have cognition-enhancing effects, potentially improving memory and cognitive function [8][9][10]. Cotinine has been investigated for its potential neuroprotective effects, and such protection may contribute to improved cognitive outcomes [11,12].…”