Enhancement of nicotinic receptors alleviates cytotoxicity in neurological disease models

Abstract

The common pathological mechanisms among the spectrum of neurodegenerative diseases are supposed to be shared. Multiple lines of evidence, from molecular and cellular to epidemiological, have implicated nicotinic transmission in the pathology of the two most common neurodegenerative disorders, namely Alzheimer's disease (AD) and Parkinson's disease (PD). In this review article we present evidence of nicotinic acetylcholine receptor (nAChR)-mediated protection against neurotoxicity induced by β amyloid (Aβ), glutamate, rotenone, and 6-hydroxydopamine (6-OHDA) and the signal transduction involved in this mechanism. Our studies have clarified that survival signal transduction, the α7 nAChR/Src family/PI3K/AKT pathway and subsequent upregulation of Bcl-2 and Bcl-x, would lead to neuroprotection. In addition to the PI3K/AKT pathway, two other survival pathways, JAK2/STAT3 and MEK/ERK, are proposed by other groups. In rotenone- and 6-OHDA-induced PD models, nAChR-mediated neuroprotection was also observed, and the effect was blocked not only by α7 but also by α4β2 nAChR antagonists. We also document that nAChR stimulation blocks glutamate neurotoxicity in spinal cord motor neurons. These findings suggest that nAChR-mediated neuroprotection is achieved through subtypes of nAChRs and common signal cascades. An early diagnosis and protective therapy with nAChR stimulation could be effective in delaying the progression of neurodegenerative diseases such as AD, PD and amyotrophic lateral sclerosis.

Keywords: Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; glutamate; nAChR; nicotine; β amyloid.

Figure 1.

Composition of two major nicotinic acetylcholine receptors, α4β2 and α7, in the central nervous system.

Figure 2.

Proposed hypothesis for the mechanism of nicotinic acetylcholine receptor (nAChR)-mediated survival signal transduction against glutamate-induced necrosis. AChE, acetylcholinesterase; NMDA, N-methyl-D-aspartate; NO, nitric oxide; SNOC, NO-generating agent.

Figure 3.

Proposed three pathways for the mechanism of nicotinic acetylcholine receptor (nAChR)-mediated survival signal transduction. 1: PI3K/AKT pathway; 2: JAK2/STAT3 pathway; 3: RAS/RAF/MEK/ERK/MAPK pathway.