The therapeutic promise of positive allosteric modulation of nicotinic receptors

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

In the central nervous system, deficits in cholinergic neurotransmission correlate with decreased attention and cognitive impairment, while stimulation of neuronal nicotinic acetylcholine receptors improves attention, cognitive performance and neuronal resistance to injury as well as produces robust analgesic and anti-inflammatory effects. The rational basis for the therapeutic use of orthosteric agonists and positive allosteric modulators (PAMs) of nicotinic receptors arises from the finding that functional nicotinic receptors are ubiquitously expressed in neuronal and non-neuronal tissues including brain regions highly vulnerable to traumatic and ischemic types of injury (e.g., cortex and hippocampus). Moreover, functional nicotinic receptors do not vanish in age-, disease- and trauma-related neuropathologies, but their expression and/or activation levels decline in a subunit- and brain region-specific manner. Therefore, augmenting the endogenous cholinergic tone by nicotinic agents is possible and may offset neurological impairments associated with cholinergic hypofunction. Importantly, because neuronal damage elevates extracellular levels of choline (a selective agonist of α7 nicotinic acetylcholine receptors) near the site of injury, α7-PAM-based treatments may augment pathology-activated α7-dependent auto-therapies where and when they are most needed (i.e., in the penumbra, post-injury). Thus, nicotinic-PAM-based treatments are expected to augment the endogenous cholinergic tone in a spatially and temporally restricted manner creating the potential for differential efficacy and improved safety as compared to exogenous orthosteric nicotinic agonists that activate nicotinic receptors indiscriminately. In this review, I will summarize the existing trends in therapeutic applications of nicotinic PAMs.

Original languageEnglish
Pages (from-to)181-185
Number of pages5
JournalEuropean Journal of Pharmacology
Volume727
Issue number1
DOIs
StatePublished - 15 Mar 2014

Keywords

  • Analgesia
  • Cerebral ischemia
  • Choline
  • Nicotinic acetylcholine receptor
  • PNU-120596
  • Positive allosteric modulator

Fingerprint Dive into the research topics of 'The therapeutic promise of positive allosteric modulation of nicotinic receptors'. Together they form a unique fingerprint.

  • Cite this