Glycogen synthase kinase 3 beta (GSK-3 beta) as a therapeutic target in neuroAIDS.
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-3beta). 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-3beta 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-3beta blockade.
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Stephen
S
Dewhurst
Sanjay B
SB
Maggirwar
Giovanni
G
Schifitto
Howard E
HE
Gendelman
Harris A
HA
Gelbard
D015526:AIDS Dementia Complex / Q000188:drug therapy / Q000201:enzymology*; D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000201:enzymology*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
D019380:Anti-HIV Agents; D047428:Protein Kinase Inhibitors; D014635:Valproic Acid; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3