Effectiveness of muscimol-containing microparticles against pilocarpine-induced focal seizures.
OBJECTIVE
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 microm 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 microg muscimol was significantly slower than in those receiving saline, blank particles, or 5 microg 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 microg of encapsulated muscimol showed less supragranular sprouting than did those receiving 5 microg 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.
Kohane
Daniel S
DS
Pediatric Intensive Care Unit, MassGeneral Hospital for Children, Boston, Massachusetts, USA. dkohane@partners.org
Holmes
Gregory L
GL
Chau
Ying
Y
Zurakowski
David
D
Langer
Robert
R
Cha
Byung Ho
BH
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D004337:Drug Carriers; D004343:Drug Implants; D004828:Epilepsies, Partial / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D058785:GABA-A Receptor Agonists; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007267:Injections; D008081:Liposomes; D008855:Microscopy, Electron, Scanning; D009118:Muscimol / Q000008:administration & dosage / Q000494:pharmacology*; D010316:Particle Size; D010862:Pilocarpine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D000927:Anticonvulsants; D004337:Drug Carriers; D004343:Drug Implants; D058785:GABA-A Receptor Agonists; D008081:Liposomes; D010862:Pilocarpine; D009118:Muscimol