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Abstract
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and one of the commonly
prescribed antidepressants. Numerous clinical observations and animal studies indicate
that fluoxetine enhances the anticonvulsant potencies of several antiepileptic drugs.
In the previous report, we showed that fluoxetine strongly protects against delayed
cerebral ischemic injury. In the present study, the authors investigated whether fluoxetine
has a beneficial effect on KA-induced neuronal cell death. An intracerebroventricular
(i.c.v.) injection of 0.94 nmol (0.2 microg) of KA produced typical neuronal cell
death both in CA1 and CA3 regions of the hippocampus. Although, there was no significant
difference in the time course or severity of epileptic behavior, the systemic administration
of fluoxetine 30 min before KA administration significantly attenuated this neuronal
cell death. Fluoxetine was found to suppress neuronal cell loss when injected at 10
mg/kg and the effect was enhanced at 50 mg/kg. Furthermore, this fluoxetine-induced
neuroprotection was accompanied by marked improvements in memory impairment, as determined
by passive avoidance tests. KA-induced gliosis and proinflammatory marker (COX-2,
IL-1beta, and TNF-alpha) inductions were also suppressed by fluoxetine administration.
It is interesting to note here that fluoxetine treatment suppressed NF-kappaB activity
dose-dependently in KA-treated mouse brains, suggesting that this explains in part
its anti-inflammatory effect. Together, these results suggest that fluoxetine has
therapeutic potential in terms of suppressing KA-induced pathogenesis in the brain,
and that these neuroprotective effects are associated with its anti-inflammatory effects.