Thyrotropin-releasing hormone (TRH) is reported to have anticonvulsant effects in animal seizure models and certain intractable epileptic patients. However, its duration of action is limited by rapid tissue metabolism and the blood brain barrier. Direct nose-brain delivery of neuropeptides in sustained-release biodegradable nanoparticles (NPs) is a promising mode of therapy for enhancing CNS bioavailability. Bioactivity/neuroprotection of d,l polylactide nanoparticles containing TRH was assessed against glutamate toxicity in cultured rat fetal hippocampal neurons. Subsequently, we utilized the kindling model of temporal lobe epilepsy to determine if intranasal administration of nanoparticles containing TRH (TRH-NPs) could inhibit kindling development. Animals received daily treatments of either blank (control) or TRH-NPs for 7 days before initiation of kindling. On day 8 and each day thereafter until either fully kindled or until day 20, the animals received daily treatments before receiving a kindling stimulus 3 h later. Afterdischarge duration (ADD) was assessed via electroencephalographs recorded from electrodes in the basolateral amygdalae and behavioral seizure stereotypy was simultaneously recorded digitally. Intranasal application of TRH-NPs resulted in a significant reduction in seizure ADD as kindling progressed, while the number of stimulations required to reach stage V seizures and to become permanently kindled was significantly greater in TRH-NP-treated subjects. Additionally, delay to clonus was significantly prolonged while clonus duration was reduced indicating a less severe seizure in TRH-NP-treated subjects. Our results provide proof of principle that intranasal delivery of sustained-release TRH-NPs may be neuroprotective and can be utilized to suppress seizures and perhaps epileptogenesis.
|Number of pages||10|
|State||Published - 25 Nov 2009|
Bibliographical noteFunding Information:
This work was sponsored by a grant from Citizens United for Research in Epilepsy (CURE) . The authors would like to thank Mr. Daniel Kubek, Miss Amanda Weinert, Dr. William Truitt and Ms. Amy Kostrewza for their expert technical assistance. Dr. Vincent Gattone and Ms. Caroline Miller of the Indiana University School of Medicine Electron Microscopy Center were instrumental in helping us characterize the TRH-NPs. We thank Ms. Cynthia Cally, Division of Biostatistics, Department of Medicine for statistical advice. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.