Attenuation of Kindled Seizures by Intranasal Delivery of Neuropeptide-Loaded Nanoparticles

Michael J. Kubek, Abraham J. Domb, Michael C. Veronesi

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

Thyrotropin-releasing hormone (TRH; Protirelin), an endogenous neuropeptide, is known to have anticonvulsant effects in animal seizure models and certain intractable epileptic patients. Its duration of action, however, is limited by rapid tissue metabolism and the blood-brain barrier. Direct nose-to-brain delivery of neuropeptides in sustained-release biodegradable nanoparticles (NPs) is a promising mode of therapy for enhancing CNS neuropeptide bioavailability. To provide proof of principle for this delivery approach, we used the kindling model of temporal lobe epilepsy to show that 1) TRH-loaded copolymer microdisks implanted in a seizure focus can attenuate kindling development in terms of behavioral stage, afterdischarge duration (ADD), and clonus duration; 2) intranasal administration of an unprotected TRH analog can acutely suppress fully kindled seizures in a concentration-dependent manner in terms of ADD and seizure stage; and 3) intranasal administration of polylactide nanoparticles (PLA-NPs) containing TRH (TRH-NPs) can impede kindling development in terms of behavioral stage, ADD, and clonus duration. Additionally, we used intranasal delivery of fluorescent dye-loaded PLA-NPs in rats and application of dye-loaded or dye-attached NPs to cortical neurons in culture to demonstrate NP uptake and distribution over time in vivo and in vitro respectively. Also, a nanoparticle immunostaining method was developed as a procedure for directly visualizing the tissue level and distribution of neuropeptide-loaded nanoparticles. Collectively, the data provide proof of concept for intranasal delivery of TRH-NPs as a viable means to 1) suppress seizures and perhaps epileptogenesis and 2) become the lead compound for intranasal anticonvulsant nanoparticle therapeutics.

Original languageEnglish
Pages (from-to)359-371
Number of pages13
JournalNeurotherapeutics
Volume6
Issue number2
DOIs
StatePublished - Apr 2009
Externally publishedYes

Bibliographical note

Funding Information:
This work was sponsored in part by grants from Citizens United for Research in Epilepsy (CURE) (M.J.K.), Indiana University–Purdue University Indianapolis IUPUI Research Venture Award (M.J.K.) and the Bi-national Science Foundation (Israel and United States) (M.J.K., A.J.D.). The authors thank Dr. William Truitt, Mr. Dan Kubek, Ms. Amanda Weinert, Ms. Amy Dietrich, and Mr. Yanir Aldouby for their expert technical assistance; Ms. Cynthia Cally, Division of Biostatistics, for statistical advice; and Dr. Debomoy Lahiri, Departments of Psychiatry and Medical & Molecular Genetics, for expert assistance in the preparation of this manuscript.

Funding

This work was sponsored in part by grants from Citizens United for Research in Epilepsy (CURE) (M.J.K.), Indiana University–Purdue University Indianapolis IUPUI Research Venture Award (M.J.K.) and the Bi-national Science Foundation (Israel and United States) (M.J.K., A.J.D.). The authors thank Dr. William Truitt, Mr. Dan Kubek, Ms. Amanda Weinert, Ms. Amy Dietrich, and Mr. Yanir Aldouby for their expert technical assistance; Ms. Cynthia Cally, Division of Biostatistics, for statistical advice; and Dr. Debomoy Lahiri, Departments of Psychiatry and Medical & Molecular Genetics, for expert assistance in the preparation of this manuscript.

FundersFunder number
Bi-national Science Foundation
Citizens United for Research in Epilepsy
Indiana University-Purdue University Indianapolis

    Keywords

    • TRH
    • drug delivery
    • epilepsy therapy
    • intranasal
    • kindling
    • thyrotropin-releasing hormone

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