Gabapentin Administration Reduces Reactive Gliosis and Neurodegeneration after Pilocarpine-Induced Status Epilepticus

Abstract

The lithium-pilocarpine model of epilepsy reproduces in rodents several features of human temporal lobe epilepsy, by inducing an acute status epilepticus (SE) followed by a latency period. It has been proposed that the neuronal network reorganization that occurs during latency determines the subsequent appearance of spontaneous recurrent seizures. The aim of this study was to evaluate neuronal and glial responses during the latency period that follows SE. Given the potential role of astrocytes in the post-SE network reorganization, through the secretion of synaptogenic molecules such as thrombospondins, we also studied the effect of treatment with the α2δ1 thrombospondin receptor antagonist gabapentin. Adult male Wistar rats received 3 mEq/kg LiCl, and 20 h later 30 mg/kg pilocarpine. Once SE was achieved, seizures were stopped with 20 mg/kg diazepam. Animals then received 400 mg/kg/day gabapentin or saline for either 4 or 14 days. In vitro experiments were performed in dissociated mixed hippocampal cell culture exposed to glutamate, and subsequently treated with gabapentin or vehicle. During the latency period, the hippocampus and pyriform cortex of SE-animals presented a profuse reactive astrogliosis, with increased GFAP and nestin expression. Gliosis intensity was dependent on the Racine stage attained by the animals and peaked 15 days after SE. Microglia was also reactive after SE, and followed the same pattern. Neuronal degeneration was present in SE-animals, and also depended on the Racine stage and the SE duration. Polysialic-acid NCAM (PSA-NCAM) expression was increased in hippocampal CA-1 and dentate gyrus of SE-animals. Gabapentin treatment was able to reduce reactive gliosis, decrease neuronal loss and normalize PSA-NCAM staining in hippocampal CA-1. In vitro, gabapentin treatment partially prevented the dendritic loss and reactive gliosis caused by glutamate excitotoxicity. Our results show that gabapentin treatment during the latency period after SE protects neurons and normalizes PSA-NCAM probably by direct interaction with neurons and glia.

Subacute administration of fluoxetine prevents short-term brain hypometabolism and reduces brain damage markers induced by the lithium-pilocarpine model of epilepsy in rats

“…Neuronal degeneration in the lithium-pilocarpine model has been described, especially during the early silent phase of epileptogenesis (Mello et al, 1993;Wang et al, 2008b;Rossi et al, 2013). Our results indicate that neurodegeneration is not just restricted to the acute phase of the epileptogenesis as reported, but it was detectable even 33 days following the initial SE (Fig.…”

Serotonin Depletion Does not Modify the Short-Term Brain Hypometabolism and Hippocampal Neurodegeneration Induced by the Lithium–Pilocarpine Model of Status Epilepticus in Rats

“…3) was observed in the hippocampus shortly after (on day 4) pilocarpine-induced SE. These signs of hippocampal damage (neurodegeneration and reactive gliosis) have also been reported to show up a few hours after SE (Rossi et al 2013;Wang et al 2008). Unlike glucose metabolism, these brain damage markers remain longer, as they were even detectable 33 days following the SE (Shiha et al 2015).…”

“…hil hilus, dg dentate gyrus. Scale bar 250 lm Cell Mol Neurobiol amygdala, striatum, and septum (Rossi et al 2013;Wang et al 2008). Subacute fluoxetine administration prevented the brain metabolic impairment and reduced damage signs induced by lithium-pilocarpine (Shiha et al 2015).…”

“…It is characterized by a rapid status epilepticus (SE) followed by a latent period in which generalized brain hypometabolism (Goffin et al 2009;Guo et al 2009;Lee et al 2012) and neuronal damage (primarily in hippocampus) appear (Mello et al 1993;Rossi et al 2013;Wang et al 2008). Brain hypometabolism has been described to appear shortly after the SE onset, returning the metabolic activity to baseline values in the subacute period (Lee et al 2012).…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…Pregabalin is also effective as adjunct therapy for partial seizures (French et al, 2003). It is possible that gabapentin also has a protective mechanism against seizure development (Rossi et al, 2013).…”