Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants
1RS Dow Neurobiology Laboratories, Legacy Research, Portland, OR, USA and 2Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn and Hertie Foundation, Bonn, Germany
Correspondence to: Detlev Boison, PhD, R.S. Dow Neurobiology Laboratories, Legacy Research, 1225 NE 2nd Ave, Portland, OR 97232, USA E-mail: dboison{at}downeurobiology.org
Epilepsy therapy is largely symptomatic and no effective therapy is available to prevent epileptogenesis. We therefore analysed the potential of stem cell-derived brain implants and of paracrine adenosine release to suppress the progressive development of seizures in the rat kindling-model. Embryonic stem (ES) cells, engineered to release the inhibitory neuromodulator adenosine by biallelic genetic disruption of the adenosine kinase gene (Adk–/–), and respective wild-type (wt) cells, were differentiated into neural precursor cells (NPs) and injected into the hippocampus of rats prior to kindling. Therapeutic effects of NP-derived brain implants were compared with those of wt baby hamster kidney cells (BHK) and adenosine releasing BHK cell implants (BHK-AK2), which were previously shown to suppress seizures by paracrine adenosine release. Wild-type NP-graft recipients were characterized by an initial delay of seizure development, while recipients of adenosine releasing NPs displayed sustained protection from developing generalized seizures. In contrast, recipients of wt BHK cells failed to display any effects on kindling development, while recipients of BHK-AK2 cells were only moderately protected from seizure development. The therapeutic effect of Adk–/–-NPs was due to graft-mediated adenosine release, since seizures could transiently be provoked after blocking adenosine A1 receptors. Histological analysis of NP-implants at day 26 revealed cell clusters within the infrahippocampal cleft as well as intrahippocampal location of graft-derived cells expressing mature neuronal markers. In contrast, BHK and BHK-AK2 cell implants only formed cell clusters within the infrahippocampal cleft. We conclude that ES cell-derived adenosine releasing brain implants are superior to paracrine adenosine release from BHK-AK2 cell implants in suppressing seizure progression in the rat kindling-model. These findings may indicate a potential antiepileptogenic function of stem cell-mediated adenosine delivery.
Key Words: adenosine; adenosine kinase; epileptogenesis; stem cells; cell therapy
Abbreviations: ADD, afterdischarge duration; ADK, adenosine kinase; BHK cells, baby hamster kidney cells; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; EGFP, enhanced green fluorescent protein; ES cell, embryonic stem cell; FGF-2, basic fibroblast growth factor; NP, neural precursor.
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Received July 13, 2006. Revised January 25, 2007. Accepted March 5, 2007.
* These authors contributed equally to this work.
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