Effectiveness of Muscimol‐containing Microparticles against Pilocarpine‐induced Focal Seizures

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Abstract
Summary: Purpose: To investigate the efficacy of in situ lipid–protein–sugar particles (LPSPs) in mitigating the epileptogenic and histologic effects of intrahippocampal pilocarpine in rats. Methods: LPSPs with and without muscimol were produced by spray‐drying, sized by Coulter counter, and muscimol content determined by high‐pressure liquid chromatography (HLPC). Particles, free muscimol or saline, were injected into the hippocampi of Sprague–Dawley rats before 40 mM pilocarpine, and seizure activity was scored. The trajectories of behavioral scores between groups were compared with two‐way repeated measures analysis of variance. Animals were killed after 2 weeks. Brain sections were stained (Timm and thionin) and scored. Results: LPSPs were 4 to 5 μm in diameter, and contained 0 or 2% (wt/wt) muscimol. In vitro, muscimol was released over a 5‐day period. Intrahippocampal injections of normal saline and blank LPSPs did not deter seizure activity from pilocarpine. The rise of the trajectory in behavior scores in animals given LPSPs containing 5 μg muscimol was significantly slower than in those receiving saline, blank particles, or 5 μg of unencapsulated muscimol. There was less apparent neuronal injury and CA3 and supragranular mossy fiber sprouting in hippocampi of animals receiving muscimol‐containing particles than in animals that did not receive muscimol. Hippocampi of animals that received 5 μg of encapsulated muscimol showed less supragranular sprouting than did those receiving 5 μg of unencapsulated muscimol, but showed no difference in cell loss or CA3 sprouting. Conclusions: Focally delivered biodegradable microparticles loaded with muscimol are effective in reducing seizure activity from pilocarpine in animals and mitigate the histologic effects.