Encapsulated galanin-producing cells attenuate focal epileptic seizures in the hippocampus.
OBJECTIVE
Encapsulated cell biodelivery (ECB) is a relatively safe approach, since the devices can be removed in the event of adverse effects. The main objectives of the present study were to evaluate whether ECB could be a viable alternative of cell therapy for epilepsy. We therefore developed a human cell line producing galanin, a neuropeptide that has been shown to exert inhibitory effects on seizures, most likely acting via decreasing glutamate release from excitatory synapses. To explore whether ECB of genetically modified galanin-producing human cell line could provide seizure-suppressant effects, and test possible translational prospect for clinical application, we implanted ECB devices bilaterally into the hippocampus of rats subjected to rapid kindling, a model for recurrent temporal lobe seizures.


METHODS
Two clones from a genetically modified human cell line secreting different levels of galanin were tested. Electroencephalography (EEG) recordings and stimulations were performed by electrodes implanted into the hippocampus at the same surgical session as ECB devices. One week after the surgery, rapid kindling stimulations were initiated.


RESULTS
Enzyme-linked immunosorbent assay (ELISA) measurements prior to device implantation showed a release of galanin on average of 8.3 ng/mL/24 h per device for the low-releasing clone and 12.6 ng/mL/24 h per device for the high-releasing clone. High-releasing galanin-producing ECB devices moderately decreased stimulation-induced focal afterdischarge duration, whereas low-releasing ECB devices had no significant effect.


CONCLUSIONS
Our study shows that galanin-releasing ECB devices moderately suppress focal stimulation-induced recurrent seizures. Despite this moderate effect, the study provides conceptual proof that ECB could be a viable alternative approach to cell therapy in humans, with the advantage that the treatment could be terminated by removing these devices from the brain. Thereby, this strategy provides a higher level of safety for future therapeutic applications, in which genetically modified human cell lines that are optimized to produce and release antiepileptic compounds could be clinically evaluated for their seizure-suppressant effects.
Experimental Epilepsy Group, Wallenberg Neuroscience Center, BMC A-11, Lund University Hospital, Lund, Sweden.
Litsa
L
Nikitidou
Malene
M
Torp
Lone
L
Fjord-Larsen
Philip
P
Kusk
Lars U
LU
Wahlberg
Mérab
M
Kokaia
D000818:Animals; D002460:Cell Line; D017690:Cell Transplantation / Q000379:methods*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage; D004569:Electroencephalography; D004797:Enzyme-Linked Immunosorbent Assay; D004828:Epilepsies, Partial / Q000188:drug therapy* / Q000503:physiopathology; D019004:Galanin / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use*; D006026:Glycoside Hydrolases; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D008297:Male; D009044:Motor Cortex / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004337:Drug Carriers; D019004:Galanin; D006026:Glycoside Hydrolases; C022562:capsular-polysaccharide galactohydrolase
ECB device; Encapsulated cells; Epilepsy; Galanin; Hippocampus; Kindling