Neuroprotective effects of serotonin 5-HT1A 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 (5HT1A 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-HT1A 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.