Grafts of adenosine-releasing cells suppress seizures in kindling epilepsy

^*Institute of Pharmacology and Toxicology, Eidgenössische Technische Hochschule and University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland; ^†Division of Surgical Research and Gene Therapy Center, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland; and ^‡Swiss Federal Institute of Technology, Bâtiment CE, Ecublens, CH-1014 Lausanne, Switzerland

Edited by Eugene Roberts, Beckman Research Institute of the City of Hope, Duarte, CA, and approved May 3, 2001 (received for review March 2, 2001)

Abstract

Adenosine is an inhibitor of neuronal activity in the brain. The local release of adenosine from grafted cells was evaluated as an ex vivo gene therapy approach to suppress synchronous discharges and epileptic seizures. Fibroblasts were engineered to release adenosine by inactivating the adenosine-metabolizing enzymes adenosine kinase and adenosine deaminase. After encapsulation into semipermeable polymers, the cells were grafted into the brain ventricles of electrically kindled rats, a model of partial epilepsy. Grafted rats provided a nearly complete protection from behavioral seizures and a near-complete suppression of afterdischarges in electroencephalogram recordings, whereas the full tonic–clonic convulsions in control rats remained unaltered. Thus, the local release of adenosine resulting in adenosine concentrations <25 nM at the site of action is sufficient to suppress seizure activity and, therefore, provides a potential therapeutic principle for the treatment of drug-resistant partial epilepsies.

Footnotes

↵ § To whom reprint requests should be addressed. E-mail: boison{at}pharma.unizh.ch.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

ADA,

adenosine deaminase;

ADK,

adenosine kinase;

DPCPX,

8-cyclopentyl-1,3-dipropylxanthine;

BHK,

baby hamster kidney;

araA,

adenine 9-β-d-arabinofuranoside;

EEG,

electroencephalogram;

WT,

wild type