Nicotinic receptors in neurodegeneration

Abstract

Many studies have focused on expanding our knowledge of the structure and diversity of peripheral and central nicotinic receptors. Nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily of pentameric ligand-gated ion channels, which include GABA (A and C), serotonin, and glycine receptors. Currently, 9 alpha (α2-α10) and 3 beta (β2-β4) subunits have been identified in the central nervous system (CNS), and these subunits assemble to form a variety of functional nAChRs. The pentameric combination of several alpha and beta subunits leads to a great number of nicotinic receptors that vary in their properties, including their sensitivity to nicotine, permeability to calcium and propensity to desensitize. In the CNS, nAChRs play crucial roles in modulating presynaptic, postsynaptic, and extrasynaptic signaling, and have been found to be involved in a complex range of CNS disorders including Alzheimer's disease (AD), Parkinson's disease (PD), schizophrenia, Tourette´s syndrome, anxiety, depression and epilepsy. Therefore, there is growing interest in the development of drugs that modulate nAChR functions with optimal benefits and minimal adverse effects. The present review describes the main characteristics of nAChRs in the CNS and focuses on the various compounds that have been tested and are currently in phase I and phase II trials for the treatment of neurodegenerative diseases including PD, AD and age-associated memory and mild cognitive impairment.

Keywords: Alzheimer disease; Parkinson disease; neurodegeneration; nicotinic receptors; pharmacology; subunit composition..

Fig. (1)

Structure and composition of neuronal nAChR. A) nAChR are transmembrane oligomers consisting of five subunits where each one is composed of a large amino-terminal extracellular domain, three hydrophobic transmembrane domains (M1-M3), a large intracellular loop and four hydrophobic transmembrane domains (M4). B) Pentameric arrangement of nAChR subunits in the neuronal α4β2 heteromeric and homomeric α7 subtypes. The localization of the ACh binding site is represented with a yellow circle.

Fig. (2)

Regional distribution of the nAChR subunits in the rodent brain. The nAChR subunits predominantly expressed in selected CNS regions are specifically shown in the table below. The brain regions involved in Parkinson and Alzheimer diseases are indicated in the figure. Summary of the data is primarily based on references , and .

Fig. (3)

Chemical structures of nicotine, acetylcholine and its products of metabolism. Cotinine is one of the main products of nicotine metabolism. Choline is produced during the hydrolysis of ACh by acetylcholinesterase. JAY2-22-33 and JWB1-84-1 are two choline analogs. Citicholine is a choline donor.

Fig. (4)

Chemical structure of the main acetylcholinesterase inhibitors. Galantamine and Donepezil are also described to modulate nAChRs whereas Rivastigmine seems to be active only by inhibiting acetylcholinesterase activity.

Fig. (5)

Chemical structure of several nAChRs. All of them produce beneficial effects on locomotor activity, learning and behavior in vivo.

Fig. (6)

Chemical structure of several nAChRs. All of them produce beneficial effects on locomotor activity, learning and behavior in vivo.