Silk polymer-based adenosine release: Therapeutic potential for epilepsy

Abstract Adenosine augmentation therapies (AAT) make rational use of the brain's own adenosine-based seizure control system and hold promise for the therapy of refractory epilepsy. In an effort to develop an AAT compatible with future clinical application, we developed a novel silk protein-base...

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Bibliographic Details
Published in:Biomaterials 2008-09, Vol.29 (26), p.3609-3616
Main Authors: Wilz, Andrew, Pritchard, Eleanor M, Li, Tianfu, Lan, Jing-Quan, Kaplan, David L, Boison, Detlev
Format: Article
Language:English
Subjects:
Adenosine
Adenosine - therapeutic use
Advanced Basic Science
Animals
Biocompatible Materials - chemistry
Biocompatible Materials - therapeutic use
Biomaterials
Brain
Controlled drug release
Dentistry
Drug Carriers - chemistry
Drug delivery
Drug Delivery Systems
Epilepsy
Epilepsy - drug therapy
Epilepsy - physiopathology
Fibroins - chemistry
Hippocampus - surgery
Humans
Kindling, Neurologic
Male
Materials Testing
Microspheres
Polymers - chemistry
Prostheses and Implants
Rats
Rats, Sprague-Dawley
Silk
Silk - chemistry
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Summary:Abstract Adenosine augmentation therapies (AAT) make rational use of the brain's own adenosine-based seizure control system and hold promise for the therapy of refractory epilepsy. In an effort to develop an AAT compatible with future clinical application, we developed a novel silk protein-based release system for adenosine. Adenosine releasing brain implants with target release doses of 0, 40, 200, and 1000 ng adenosine per day were prepared by embedding adenosine containing microspheres into nanofilm-coated silk fibroin scaffolds. In vitro , the respective polymers released 0, 33.4, 170.5, and 819.0 ng adenosine per day over 14 days. The therapeutic potential of the implants was validated in a dose-response study in the rat model of kindling epileptogenesis. Four days prior to the onset of kindling, adenosine releasing polymers were implanted into the infrahippocampal cleft and progressive acquisition of kindled seizures was monitored over a total of 48 stimulations. We document a dose-dependent retardation of seizure acquisition. In recipients of polymers releasing 819 ng adenosine per day, kindling epileptogenesis was delayed by one week corresponding to 18 kindling stimulations. Histological analysis of brain samples confirmed the correct location of implants and electrodes. We conclude that silk-based delivery of around 1000 ng adenosine per day is a safe and efficient strategy to suppress seizures.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2008.05.010