Fluoxetine attenuates kainic acid-induced neuronal cell death in the mouse hippocampus

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 μg) 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-1β, and TNF-α) inductions were also suppressed by fluoxetine administration. It is interesting to note here that fluoxetine treatment suppressed NF-κB 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.

Introduction

The administration of the excitatory amino acid l-glutamate analog, kainic acid (KA), in animals elicits characteristic patterns of epileptic behavior in a dose-dependent manner (Coyle, 1983, Sperk et al., 1985). KA-induced neuronal over-excitation triggers acute neuronal cell death in limbic structures, such as, CA1 and CA3 regions of the hippocampus (Frederickson et al., 1989, Choi, 1990, Weiss et al., 2000). This process is followed by the activation of glial cells, and an insidious progress of cell death may occur over several days to weeks (Weise et al., 2005). Thus, this in vivo cell death model shows the features of both acute and delayed cell death within relatively limited areas in the brain. A number of recent studies have shown that the KA-induced delayed cell death is associated with the activation of microglia and astrocytes in the hippocampus, and with enhanced reactive oxygen species (ROS) production and cytokine expression (Cho et al., 2003, Kim et al., 2004, Penkowa et al., 2005).

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI), and is commonly prescribed for treating major depression due to its tolerability and safety. Furthermore, it has been reported that chronically administered fluoxetine enhances the anticonvulsant effects of conventional antiepileptic drugs in a mouse maximal electroshock model (Borowicz et al., 2007), and that dietary fluoxetine supplementation abolishes handling-induced seizure susceptibility in epileptic mice via neural remodeling (Richman and Heinrichs, 2007). However, despite the fact that depression is one of the most common comorbidities in patients with epilepsy, the antidepressive effect of fluoxetine during post-state epilepticus is controversial. Recently, Mazarati et al. (2008) reported that fluoxetine failed to affect depressive behavior following status epilepticus, whereas Qi et al. (2008) concluded that fluoxetine alleviates depression-like behavior in rats exposed to chronic forced swim stress.

In our previous report, we reported that fluoxetine strongly protects against delayed cerebral ischemic injury (Lim et al., 2009). In this study, we explored the neuroprotective effects of fluoxetine in a murine KA-induced epilepsy model. Intraperitoneal (i.p.) administration of fluoxetine was found to remarkably suppress hippocampal cell death, and its neuroprotective effects were found to be accompanied by reductions in memory impairment. Furthermore, microglia activation and proinflammatory marker expressions were found to be markedly repressed in KA-treated brains by fluoxetine administration.