Adeno-associated viral vector-mediated preprosomatostatin expression suppresses induced seizures in kindled rats

Gowri Natarajan; Jeffrey A Leibowitz; Junli Zhou; Yang Zhao; Jessica A McElroy; Michael A King; Brandi K Ormerod; Paul R Carney

doi:10.1016/j.eplepsyres.2017.01.002

Adeno-associated viral vector-mediated preprosomatostatin expression suppresses induced seizures in kindled rats

Epilepsy Res. 2017 Feb:130:81-92. doi: 10.1016/j.eplepsyres.2017.01.002. Epub 2017 Jan 7.

Authors

Gowri Natarajan¹, Jeffrey A Leibowitz², Junli Zhou³, Yang Zhao⁴, Jessica A McElroy⁵, Michael A King⁶, Brandi K Ormerod⁷, Paul R Carney⁸

Affiliations

¹ 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.
² J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA.
³ 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.
⁴ Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32611, USA.
⁵ Wilder Center of Excellence for Epilepsy Research, University of Florida, Gainesville, FL 32611, USA; Department of Pediatrics, University of Florida, Gainesville, FL 32611, USA.
⁶ 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.
⁷ 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.
⁸ 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.

PMID: 28167431
DOI: 10.1016/j.eplepsyres.2017.01.002

Abstract

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.

Keywords: Adeno-associated viral vectors; Gene therapy; Hippocampus; Kindling; Neuropeptides; Somatostatin.

MeSH terms

Animals
Dependovirus
Disease Models, Animal
Genetic Therapy*
Genetic Vectors
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Hippocampus / pathology
Hippocampus / physiopathology*
Implantable Neurostimulators
Kindling, Neurologic
Male
Neurons / pathology
Neurons / physiology
Parvovirinae / genetics
Protein Precursors / administration & dosage
Protein Precursors / genetics
Protein Precursors / metabolism*
Random Allocation
Rats, Sprague-Dawley
Seizures / pathology
Seizures / physiopathology*
Seizures / therapy*
Somatostatin / administration & dosage
Somatostatin / genetics
Somatostatin / metabolism*

Substances

Protein Precursors
enhanced green fluorescent protein
Green Fluorescent Proteins
Somatostatin

Supplementary concepts

Adeno-associated virus-5