| Summary: | 博士 === 國防醫學院 === 醫學科學研究所 === 97 === Status epilepticus (SE) is more common in children than in adults, with almost 40 ~ 50 % of the cases occurring in children younger than 2 years of age. In the immature stage, it has been shown that SE can cause neuroadaptation which might result in brain disorders in adulthood. Neonatal seizure may alter the developing neurocircuitry and cause behavioral, memory abnormalities in adulthood.
Studies focus on the hippocampus indicated that SE in immature brain can cause long-term abnormal neuronal connectivity in the hippocampus. Whether similar neuropathology occurs in other brain regions has been less studied. Previous studies indicate that LiPC-induced SE causes less brain damage in the neonatal stage, such as on the postnatal day 10 (P10) in pup rats. When SE is induced at P10, which is roughly equivalent to a human newborn, rats do not become epileptic nor develop neuronal loss or cognitive deficits. While the immature brain appears to be less vulnerable to prolonged seizures than the mature brain, seizures early in life can be associated with later behavioral and memory disturbances.
The purpose of this study was to determine the effects of early-life SE following adolescent methamphetamine (MA) administration on behavioral sensitization and spatial memory.
SE was induced at postnatal day 10 (P10) by pilocarpine in rats pretreated with lithium (LiPC-treated). At P43 (adolescence) both groups (saline- or LiPC-treated) of rats were further divided into saline- (Sal/Sal and LiPC/Sal) or MA-treated (Sal/MA and LiPC/MA) groups. MA (5 mg/kg, i.p) or saline was injected twice daily for 5 consecutive days. After 7 days withdrawal (P48~P54), the rats underwent MA challenge (5 mg/kg, i.p) or water maze task. At P60, brain tissues were evaluated for the content of dopamine (including its metabolites), glutamate and malondialdehyde (MDA) and the gene expression of regulators of G-protein signaling-4 (RGS4), tissue plasminogen activator (tPA), serum- and glucose-regulated kinase 1 (SGK1) and superoxide dismutase 2 (SOD2) immediately following completion of MA challenge or the water maze. The brains were also analyzed with Timm stain for mossy fiber sprouting.
In the first study behavioral sensitization to repeated MA administrations in adolescence was augmented in rats with neonatal SE induced by LiPC. We focused on the dopaminergic and glutamateric neurotransmission of the prefrontal-striatal circuitry in adolescence and found decreased prefrontal cortex (PFC) dopamine levels in neonatal SE (LiPC/Sal) group, increased striatal dopamine and its metabolites in LiPC/MA group, and increased levels of glutamate in PFC and striatum in Sal/MA and LiPC/MA groups with the magnitude of increase the highest in LiPC/MA group. Gene expression of regulators of G-protein signaling-4 (RGS4) in PFC as well as in striatum was also the lowest in the LiPC/MA group. These findings suggest neonatal SE results in prefrontal-striatal dopaminergic and glutamatergic neuroadaptation, which may account for augmented behavioral sensitization to MA in adolescence.
In the second study we found rats previously subjected to early-life SE exhibited memory deficit to MA administration in adolescence by water maze. Levels of mRNA of tPA and SGK1 were markedly lower in hippocampus in LiPC/MA than Sal/Sal group, while hippocampal level of MDA and gene expression of SOD2 were significantly elevated in LiPC/MA group. More sprouting of Mossy fiber were found in LiPC/MA rats by Timm staining. Results from this study suggest that adolescent MA administration exacerbates spatial memory deficit in rats subjected to early-life SE, possibly through the oxidative stress in hippocampus.
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