title: HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a.
abstract: Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite the extensive research, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. Loss of GABAergic tone may have an important role in the neuropathic pain state. Glutamic acid decarboxylase 67 (GAD67) is one of the isoforms that catalyze GABA synthesis. Here, we used recombinant herpes simplex virus (HSV-1) vectors that encode gad1 gene to evaluate the therapeutic potential of GAD67 in peripheral HIV gp120-induced neuropathic pain in rats. We found that (1) subcutaneous inoculation of the HSV vectors expressing GAD67 attenuated mechanical allodynia in the model of HIV gp120-induced neuropathic pain, (2) the anti-allodynic effect of GAD67 was reduced by GABA-A and-B receptors antagonists, (3) HSV vectors expressing GAD67 reversed the lowered GABA-IR expression and (4) the HSV vectors expressing GAD67 suppressed the upregulated mitochondrial superoxide and Wnt5a in the spinal dorsal horn. Taken together, our studies support the concept that recovering GABAergic tone by the HSV vectors may reverse HIV-associated neuropathic pain through suppressing mitochondrial superoxide and Wnt5a. Our studies provide validation of HSV-mediated GAD67 gene therapy in the treatment of HIV-related neuropathic pain.
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Anesthesiology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kanda
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Anesthesiology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kanao
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yi
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Anesthesiology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Iida
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.|Hussman Institute of Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.|Veterans Affairs Medical Center, Miami, FL, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Levitt
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Candiotti
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Lubarsky
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hao
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000008:administration & dosage / Q000633:toxicity*; D015658:HIV Infections / Q000821:virology; D006801:Humans; D008297:Male; D009437:Neuralgia / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D000071818:Wnt-5a Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D015699:HIV Envelope Protein gp120; D017382:Reactive Oxygen Species; D000071818:Wnt-5a Protein; C491837:Wnt5a protein, rat; D013481:Superoxides; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1