Prolonged seizure suppression by a single implantable polymeric-TRH microdisk preparation

Thyrotropin-releasing hormone (TRH; Protirelin) is an endogenous neuropeptide known to have anticonvulsant effects in several seizure models and in intractable epileptic patients. Like most neuropeptides, its duration of action may be limited by a lack of sustained site-specific bioavailability. To attempt to provide long-term delivery, we attached TRH to a biodegradable polyanhydride copolymer as a sustained-release carrier. Utilizing the rat kindling model of temporal lobe epilepsy, a single TRH microdisk implanted stereotaxically into the seizure focus (amygdala) significantly suppressed kindling expression when assessed by the number of stimulations required to reach each behavioral stage and to become fully kindled (8.63 ± 0.92 vs. 16.17 ± 1.37; Mean ± S.E.M.). Two indices of seizure severity, afterdischarge duration (Mean ± S.E.M., sec.) (stimulated amygdala [87.40 ± 5.47 vs. 51.80 ± 15.65] and unstimulated amygdala [89.60 ± 5.55 vs. 48.67 ± 15.8] and clonus duration (71.2 ± 5.94 vs. 29.40 ± 8.87; Mean ± S.E.M., sec.), were also significantly reduced by a single polymeric-TRH implant. Fifty days after initiation of the study a significant reduction in clonus duration (53.90 ± 3.27 vs. 40.09 ± 4.14) still remained in the TRH-implanted groups. This report is the first to provide evidence in support of in situ microdisk pharmacotherapy for potential neuropeptide delivery in intractable epilepsy and possibly other neurological disorders.