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.