Glycogen synthase kinase 3 beta (GSK-3β) as a therapeutic target in neuroAIDS

Stephen Dewhurst, Sanjay B. Maggirwar, Giovanni Schifitto, Howard E. Gendelman, Harris A. Gelbard

Research output: Contribution to journalReview article

36 Scopus citations

Abstract

Highly active antiretroviral therapy (HAART) has made a significant impact on the lives of people living with HIV-1 infection. The incidence of neurologic disease associated with HIV-1 infection of the CNS plummeted between 1996-2000, but unfortunately the number of people currently HIV-1 infected (i.e., prevalence) with associated cognitive impairment has been steadily rising. While the reasons for this may be multifactorial, the implication is clear: there is a pressing need for adjunctive therapy directed at reversing or preventing damage to vulnerable pathways in the central nervous system (CNS) from HIV-1 infection. Using a team of preclinical and clinical investigators, we have focused our efforts on defining how proinflammatory mediators and secretory neurotoxins from HIV-1 disrupt signaling of the survival-regulating enzyme, glycogen synthase kinase 3 beta (GSK-3β). In a series of studies initiated using in vitro, then in vivo models of HIV-1-associated dementia (HAD), we have demonstrated the ability of the mood stabilizing and anticonvulsant drug, sodium valproate (VPA), that inhibits GSK-3β activity and other downstream mediators, to reverse HIV-1-induced damage to synaptic pathways in the CNS. Based on these results, we successfully performed pharmacokinetic and safety and tolerability trials with VPA in a cohort of HIV-1-infected patients with neurologic disease. VPA was well tolerated in this population and secondary measures of brain metabolism, as evidenced by an increase in N-acetyl aspartate/creatine (NAA/Cr), further suggested that VPA may improve gray matter integrity in brain regions damaged by HIV-1. These findings highlight the therapeutic potential of GSK-3β blockade.

Original languageEnglish (US)
Pages (from-to)93-96
Number of pages4
JournalJournal of Neuroimmune Pharmacology
Volume2
Issue number1
DOIs
StatePublished - Mar 2007

Keywords

  • Glycogen synthase kinase 3 beta
  • HIV-1 associated dementia
  • Histone deacetylase type 3
  • Human immunodeficiency virus type 1
  • Neuroprotection

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

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