SUMMARYObjective: To characterize the changes in microglial proinflammatory M1 and antiinflammatory M2 marker expression during epileptogenesis in the chronic pilocarpine and intrahippocampal kainate models. Methods: M1-activated microglia express proinflammatory cytokines driving infiltration of cells, whereas M2-activated microglia are more reparative, promoting phagocytosis of debris and expression of proteins associated with cellular stability and repair. Microglial markers were characterized as acute (3 days , and interleukin-10 (IL-10)) markers in both models. Video-electroencephalography (EEG) recordings were used to quantify late chronic seizure frequency. Results: Three days post-SE microglia in the pilocarpine model expressed M1 and M2 markers, but only M1 markers were upregulated after kainate-induced SE. After 3 weeks, M1/M2 marker expression was largely ablated in the hippocampal formation of both models. Small mRNA level increases of CD11b, glial fibrillary acidic protein (GFAP), and IL-1b were found in the pilocarpine model, consistent with IL-1b contributing to spontaneous seizures, whereas mRNA levels of TNFa and Ym1 were decreased. In the late chronic phase, some M1/M2 markers, IL-1b, TNFa, Arg1, Ym1, and CD206, resurged in the kainate, but not pilocarpine model, which may reflect and/ or contribute to highly frequent seizures in kainate-SE mice. Significance: The common M1 upregulation acutely post-SE may signal a role early in epileptogenesis, with a more pure "inflamed" central nervous system state after kainate-SE, potentially contributing to the development of more frequent seizures. The difference may also be due to the contribution of peripheral inflammation after pilocarpine injection. In summary, the microglial inflammatory response during epileptogenesis is complex, varies between models, and appears to correlate with chronic seizure frequency.
We hypothesized that in epileptic brains citric acid cycle intermediate levels may be deficient leading to hyperexcitability. Anaplerosis is the metabolic refilling of deficient metabolites. Our goal was to determine the anticonvulsant effects of feeding triheptanoin, the triglyceride of anaplerotic heptanoate. CF1 mice were fed 0-35% calories from triheptanoin. Body weights and dietary intake were similar in mice fed triheptanoin vs. standard diet. Triheptanoin feeding increased blood propionyl-carnitine levels, signifying its metabolism. 35%, but not 20%, triheptanoin delayed development of corneal kindled seizures. After pilocarpine-induced status epilepticus (SE), triheptanoin feeding increased the pentylenetetrazole tonic seizure threshold during the chronically epileptic stage. Mice in the chronically epileptic stage showed various changes in brain metabolite levels, including a reduction in malate. Triheptanoin feeding largely restored a reduction in propionyl-CoA levels and increased methylmalonyl-CoA levels in SE mice. In summary, triheptanoin was anticonvulsant in two chronic mouse models and increased levels of anaplerotic precursor metabolites in epileptic mouse brains. The mechanisms of triheptanoin's effects and its efficacy in humans suffering from epilepsy remain to be determined.
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