Prolonged infusion of inhibitors of calcineurin or L-type calcium channels does not block mossy fiber sprouting in a model of temporal lobe epilepsy

Abstract

Purpose: It would be useful to selectively block granule cell axon (mossy fiber) sprouting to test its functional role in temporal lobe epileptogenesis. Targeting axonal growth cones may be an effective strategy to block mossy fiber sprouting. L-type calcium channels and calcineurin, a calcium-activated phosphatase, are critical for normal growth cone function. Previous studies have provided encouraging evidence that blocking L-type calcium channels or inhibiting calcineurin during epileptogenic treatments suppresses mossy fiber sprouting. Methods: Rats were treated systemically with pilocarpine to induce status epilepticus, which lasted at least 2 h. Then, osmotic pumps and cannulae were implanted to infuse calcineurin inhibitors (FK506 or cyclosporin A) or an L-type calcium channel blocker (nicardipine) into the dorsal dentate gyrus. After 28 days of continuous infusion, extent of mossy fiber sprouting was evaluated with Timm staining and stereological methods. Results: Percentages of volumes of the granule cell layer plus molecular layer that were Timm-positive were similar in infused and noninfused hippocampi. Conclusions: These findings suggest inhibiting calcineurin or L-type calcium channels does not block mossy fiber sprouting in the pilocarpine-treated rat model of temporal lobe epilepsy. © 2008 International League Against Epilepsy.