Research ReportFluoxetine attenuates kainic acid-induced neuronal cell death in the mouse hippocampus
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.
Section snippets
Systemic administration of fluoxetine attenuated kainic acid (KA)-induced cell death in the hippocampus
Characteristic epileptic behaviors in KA (0.2 μg, i.c.v.)-administered mice were observed as early as 5 min after the drug treatment. These stereotypic epileptic responses were augmented rapidly, reaching the highest level approximately 120 min after KA administration (Fig. 1). The temporal seizure progression was scored according to Sperk et al.'s (1985) seizure rating scale. To examine the neuroprotective effect of fluoxetine, it was administered (i.p.) at 10 or 50 mg/kg 30 min before KA
Discussion
This study demonstrates that fluoxetine inhibits hippocampal cell death and memory impairment in KA-treated mice. Inhibition of microglial and astroglial activation by fluoxetine and the concomitant suppressions of inflammatory marker expressions suggest that fluoxetine exerts its neuroprotective effects via an anti-inflammatory mechanism in this murine model of hippocampal cell death. Accumulating evidence suggests that inflammation contributes substantially to later brain damage occurring
Kainic acid and evaluation of seizure behavior
Intracerebroventricular (i.c.v.) injections of KA into the brain were previously described (Cho et al., 2003). Male BALB/c mice (22–28 g) were anaesthetized with an intraperitoneal (i.p.) injection of a 3.5:1 mixture (1.5 μl/g body weight) of ketamine (50 mg/ml) and xylazine hydrochloride (23.3 mg/ml), and placed on a stereotaxic apparatus (Stoelting Co, Wood Dale, USA). Mice were then injected with 4 μl of saline containing 0.94 nmol (0.2 μg) of KA at 0.5 μl/min into the right lateral
Acknowledgments
This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MOST) (2005-01096) for J-K Lee.
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