Neuroprotective effects of serotonin 5-HT 1A receptor activation against ischemic cell damage in gerbil hippocampus: Involvement of NMDA receptor NR1 subunit and BDNF.
It is known that the activation of 5-hydroxytryptamine receptor type 1A (5HT(1A) receptor) may protect against brain damage induced by transient global ischemia. The biochemical mechanisms that underlie this neuroprotective effect remain however to be fully elucidated. Given that serotonergic drugs may regulate N-methyl-d-aspartate (NMDA) receptor function, which is implicated in events leading to ischemia-induced neuronal cell death, and also stimulate the expression of brain-derived neurotrophic factor (BDNF), which is down-regulated in cerebral ischemia, we sought to determine the effects of the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on the levels of NMDA receptor NR1 subunit and BDNF in gerbil hippocampus after transient global cerebral ischemia. Pretreatment with 8-OH-DPAT (1 mg/kg) prevented the neuronal loss in CA1 subfield 72 h after ischemia and also the dramatic decrease in BDNF immunoreactivity observed in this area at an earlier time. NMDA receptor NR1 levels in whole hippocampus were not affected 24 h after ischemia, but the levels of the subunit phosphorylated at the protein kinase A (PKA) site, pNR1(Ser897), were significantly increased, and this increase was prevented by the same 8-OH-DPAT dose, a probable consequence of the increased phosphatase 1 (PP1) enzyme activity found in ischemic gerbils pretreated with the 5-HT(1A) receptor agonist. The results indicate that both NR1 subunit phosphorylation and the neurotrophin BDNF account, at least in part, for the neuroprotective effect of 8-OH-DPAT on cell damage induced by global ischemia in the gerbil hippocampus and support the potential interest of 5-HT1A receptor activation in the search for neuroprotective strategies.
Salazar-Colocho
Pablo
P
Division of Neuroscience, CIMA, University of Navarra, Av. Pío XII 55, 31008, Pamplona, Spain. pscolocho@alumni.unav.es
Del Río
Joaquín
J
Frechilla
Diana
D
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage; D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects; D005849:Gerbillinae; D006624:Hippocampus / Q000473:pathology*; D002546:Ischemic Attack, Transient / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C089504:polyphosphoinositide phosphatase; D010744:Phosphoric Monoester Hydrolases; D010751:Phosphopyruvate Hydratase