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Glycogen synthase kinase 3 beta (GSK-3 beta) as a therapeutic target in neuroAIDS
Stephen Dewhurst1, Sanjay B Maggirwar, Giovanni Schifitto
1Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Insights
Sodium valproate (VPA) may reverse central nervous system (CNS) damage in HIV-1 patients. This drug, by inhibiting glycogen synthase kinase 3 beta (GSK-3beta), improved brain metabolism and gray matter integrity in clinical trials.
Area of Science:
- Neuroscience
- Virology
- Pharmacology
Background:
- Highly active antiretroviral therapy (HAART) reduced HIV-1 CNS disease incidence but not prevalence of cognitive impairment.
- HIV-1 infection and associated neurotoxins disrupt CNS signaling, particularly glycogen synthase kinase 3 beta (GSK-3beta).
- There is a need for adjunctive therapies to prevent or reverse HIV-1-induced CNS damage.
Purpose of the Study:
- To investigate the therapeutic potential of sodium valproate (VPA) in reversing HIV-1-induced CNS damage.
- To evaluate VPA's effect on GSK-3beta signaling and synaptic pathways affected by HIV-1.
- To assess the safety, tolerability, and efficacy of VPA in HIV-1-infected patients with neurologic disease.
Main Methods:
- In vitro and in vivo models of HIV-1-associated dementia (HAD) were used to study VPA's effects.
- Studies focused on how HIV-1 neurotoxins disrupt GSK-3beta signaling.
- Pharmacokinetic, safety, and tolerability trials of VPA were conducted in HIV-1 patients.
Main Results:
- Sodium valproate (VPA) demonstrated the ability to reverse HIV-1-induced synaptic damage in preclinical models.
- VPA was well tolerated in HIV-1-infected patients with neurologic disease.
- Secondary measures indicated VPA may improve gray matter integrity and brain metabolism (increased N-acetyl aspartate/creatine ratio).
Conclusions:
- GSK-3beta blockade is a promising therapeutic strategy for HIV-1-associated CNS damage.
- Sodium valproate (VPA) shows potential as an adjunctive therapy for cognitive impairment in HIV-1 infection.
- Further research into VPA's neuroprotective effects in HIV-1 is warranted.
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-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.
