title: γ-Aminobutyric acid type A receptor inhibition triggers a nicotinic neuroprotective mechanism.
abstract: Nicotinic acetylcholine receptor (nAChR)-mediated neuroprotection has been implicated in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases and hypoxic ischemic events as well as other diseases hallmarked by excitotoxic and apoptotic neuronal death. Several modalities of nicotinic neuroprotection have been reported. However, although this process generally involves α4β2 and α7 subtypes, the underlying mechanisms are largely unknown. Interestingly, both activation and inhibition of α7 nAChRs have been reported to be neuroprotective. We have shown that inhibition of α7 nAChRs protects the function of acute hippocampal slices against excitotoxicity in an α4β2-dependent manner. Neuroprotection was assessed as the prevention of the N-methyl-D-aspartate-dependent loss of the area of population spikes (PSs) in the CA1 area of acute hippocampal slices. Our results support a model in which α7 AChRs control the release of γ-aminobutyric acid (GABA). Blocking either α7 or GABA(A) receptors reduces the inhibitory tone on cholinergic terminals, thereby promoting α4β2 activation, which in turn mediates neuroprotection. These results shed light on how α7 nAChR inhibition can be neuroprotective through a mechanism mediated by activation of α4β2 nAChRs.
authors.affiliation: School of Medicine, Universidad Central del Caribe, Bayamón, Puerto Rico. ferchmin@gmail.com
authors.forename: P A
authors.initials: PA
authors.lastname: Ferchmin
authors.forename: Dinely
authors.initials: D
authors.lastname: Pérez
authors.forename: William
authors.initials: W
authors.lastname: Castro Alvarez
authors.forename: Mario A
authors.initials: MA
authors.lastname: Penzo
authors.forename: Héctor M
authors.initials: HM
authors.lastname: Maldonado
authors.forename: Vesna A
authors.initials: VA
authors.lastname: Eterovic
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism* / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D018756:GABA Antagonists; D018696:Neuroprotective Agents; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2