Seizure suppression in kindled rats by intraventricular grafting of an adenosine releasing synthetic polymer.
Adenosine, an endogenous inhibitory neuromodulator in the central nervous system, exerts anticonvulsant activity that is largely based on the inhibition of the release of excitatory amino acids. As a novel approach to treat pharmacoresistant partial epilepsies, the grafting of adenosine-releasing cells is foreseen to provide a local and sustained source of adenosine. The feasibility of this cell-based therapy was investigated in the present study by the intraventricular implantation of synthetic polymers that release adenosine. Kindled rats with a ventricular implant of an adenosine-releasing polymer showed a profound reduction of seizure activity. This was demonstrated not only by a 75% reduction of grade 5 seizures but also by a reduction of the amplitude and duration of afterdischarges in electroencephalographic (EEG) recordings. Kindled control rats that were implanted with bovine serum albumin (BSA)-containing polymers or were sham operated, continued to show their presurgery seizure pattern. Adenosine displayed antiepileptic activity when released in an amount of 20-50 ng per day. This finding sets the target for the required amount of adenosine to be released from future adenosine-releasing cells for antiepileptic therapy. The present results clearly support the feasibility of a novel therapy for epilepsy based on adenosine-releasing cells.
Boison
D
D
Institute of Pharmacology, ETH, Zurich, Switzerland.
Scheurer
L
L
Tseng
J L
JL
Aebischer
P
P
Mohler
H
H
D000241:Adenosine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001672:Biocompatible Materials; D002417:Cattle; D002552:Cerebral Ventricles; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004343:Drug Implants; D004569:Electroencephalography / Q000187:drug effects; D004833:Epilepsy, Temporal Lobe; D005240:Feasibility Studies; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011145:Polyvinyls; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000517:prevention & control*; D012710:Serum Albumin, Bovine
D000927:Anticonvulsants; D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D004343:Drug Implants; D018696:Neuroprotective Agents; D011145:Polyvinyls; C016438:ethylenevinylacetate copolymer; D012710:Serum Albumin, Bovine; D000241:Adenosine