Selective activation of central subtypes of the nicotinic acetylcholine receptor has opposite effects on neonatal excitotoxic brain injuries.
The incidence of neurological disabilities ascribable to perinatal injury is rising in Western countries, raising ethical and financial problems. No curative treatments are available. The pathophysiology of brain lesions of hypoxic-ischemic or inflammatory origin involves various neurotransmitters or neuromodulators. Among these, glutamate plays a key role. By overactivating N-methyl-D-aspartate receptors, it triggers the excitotoxic cascade. Although addictive, nicotine prevents excitotoxic neuronal death in adult animals. Its potential neuroprotective effects have not been evaluated in neonates. We found that nicotine is neuroprotective in vivo, in a murine model of neonatal excitotoxic brain injury, and in vitro, in primary cultures of cortical neurons. We investigated the respective roles in nicotine-related neuroprotection of the two dominant nicotinic acetylcholine receptor (nAChR) isoforms, namely, alpha4beta2 (heteropentameric) and alpha7 (homopentameric). Inhibition of alpha4beta2, either pharmacological (i.e., an alpha4beta2 nAChR antagonist) or molecular (beta2-/- knockout mice), abolished the protective effect of nicotine in vivo and in vitro, suggesting the involvement of alpha4beta2 nAChR in neonatal nicotine-related neuroprotection. In contrast, activation of alpha7 nAChR, which is protective in adult animals, was deleterious in our neonatal model, whereas its blockade, either pharmacological or molecular (alpha7-/- knockout mice) provided neuroprotection. Neuroprotective strategies must consider these opposite properties of distinct nAChR isoforms in neonates.
Laudenbach
Vincent
V
Laboratoire de Neurologie du Développement, INSERM E9935, Hôpital Robert Debré, Paris, France. vlaudenb@infobiogen.fr
Medja
Fadia
F
Zoli
Michele
M
Rossi
Francesco M
FM
Evrard
Philippe
P
Changeux
Jean-Pierre
JP
Gressens
Pierre
P
D000818:Animals; D000831:Animals, Newborn; D001345:Autoradiography; D001927:Brain Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology; D007051:Ibotenic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D007267:Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008959:Models, Neurological; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579166:Chrna7 protein, mouse; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D007051:Ibotenic Acid; D016202:N-Methylaspartate; D009538:Nicotine