Adeno-associated viral vector-mediated preprosomatostatin expression suppresses induced seizures in kindled rats.
Somatostatin is expressed widely in the hippocampus and notably in hilar GABAergic neurons that are vulnerable to seizure neuropathology in chronic temporal lobe epilepsy. We previously demonstrated that sustained bilateral preprosomatostatin (preproSST) expression in the hippocampus prevents the development of generalized seizures in the amygdala kindling model of temporal lobe epilepsy. Here we tested whether sustained preproSST expression is anticonvulsant in rats already kindled to high-grade seizures. Rats were kindled until they exhibited 3 consecutive Racine Grade 5 seizures before adeno-associated virus serotype 5 (AAV5) vector driving either eGFP (AAV5-CBa-eGFP) or preproSST and eGFP (AAV5-CBa-preproSST-eGFP) expression was injected bilaterally into the hippocampal dentate gyrus and CA1 region. Retested 3 weeks later, rats that received control vector (AAV5-CBa-eGFP) continued to exhibit high-grade seizures whereas 6/13 rats that received preproSST vector (AAV5-CBa-preproSST-eGFP) were seizure-free. Of these rats, 5/6 remained seizure-free after repeated stimulation sessions and when the stimulation current was increased. These results suggest that vector-mediated expression of preproSST may be a viable therapeutic strategy for temporal lobe epilepsy.
Wilder Center of Excellence for Epilepsy Research, University of Florida, Gainesville, FL 32611, USA; J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA; Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA; Department of Neurology, University of Florida, Gainesville, FL 32611, USA; Department of Neuroscience, University of Florida, Gainesville, FL 32611, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA.
Gowri
G
Natarajan
J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA.
Jeffrey A
JA
Leibowitz
Wilder Center of Excellence for Epilepsy Research, University of Florida, Gainesville, FL 32611, USA; Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA; Department of Neurology, University of Florida, Gainesville, FL 32611, USA.
Junli
J
Zhou
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32611, USA.
Yang
Y
Zhao
Wilder Center of Excellence for Epilepsy Research, University of Florida, Gainesville, FL 32611, USA; Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA.
Jessica A
JA
McElroy
McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32611, USA; NF/SG VA Medical Center, University of Florida, Gainesville, FL 32611, USA.
Michael A
MA
King
J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA; Department of Neuroscience, University of Florida, Gainesville, FL 32611, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA.
Brandi K
BK
Ormerod
Wilder Center of Excellence for Epilepsy Research, University of Florida, Gainesville, FL 32611, USA; J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA; Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA; Department of Neurology, University of Florida, Gainesville, FL 32611, USA; Department of Neuroscience, University of Florida, Gainesville, FL 32611, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA. Electronic address: paulcarney@unc.edu.
Paul R
PR
Carney
D000818:Animals; D000229:Dependovirus; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D058542:Implantable Neurostimulators; D007696:Kindling, Neurologic; D008297:Male; D009474:Neurons / Q000473:pathology / Q000502:physiology; D019219:Parvovirinae / Q000235:genetics; D011498:Protein Precursors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D013004:Somatostatin / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*
D011498:Protein Precursors; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D013004:Somatostatin
Adeno-associated viral vectors; Gene therapy; Hippocampus; Kindling; Neuropeptides; Somatostatin