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The Journal of Neuroscience, October 8, 2003, 23(27):9162-9170

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Cellular/Molecular
Neuroprotective Activities of Sodium Valproate in a Murine Model of Human Immunodeficiency Virus-1 Encephalitis

Huanyu Dou,^1,2 Kevin Birusingh,^1,2 Jill Faraci,^1,2 Santhi Gorantla,^1,2 Larisa Y. Poluektova,^1,2 Sanjay B. Maggirwar,⁵ Stephen Dewhurst,⁵ Harris A. Gelbard,^4,5 and Howard E. Gendelman^1,2,3

¹Center for Neurovirology and Neurodegenerative Disorders, ²Department of Pathology and Microbiology, and ³Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-5215, ⁴Center for Aging and Developmental Biology, and ⁵Department of Neurology, Pediatrics, and Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642

Human immunodeficiency virus-1 (HIV-1) infection of the nervous system can result in neuroinflammatory events leading first to neuronal dysfunction then to cognitive and behavioral impairments in infected people. The multifaceted nature of the disease process, commonly called HIV-1-associated dementia (HAD), provides a number of adjunctive therapeutic opportunities. One proposed adjunctive therapy is sodium valproate (VPA), an anticonvulsant known to promote neurite outgrowth and increase -catenin through inhibiting glycogen synthase kinase 3 activity and tau phosphorylation. We now show that VPA treatment of rat cortical neurons exposed to HIV-1 gp120 prevents resultant neurotoxic activities. This includes the induction of significant neurite outgrowth and microtubule-associated protein 2 (MAP-2) and neuron-specific nuclear protein (NeuN) antigens in affected neuronal cell bodies and processes. Similarly, VPA protects severe combined immunodeficient (SCID) mice against the neurodegeneration of HIV-1_ADA infected monocyte-derived macrophages (MDMs). In SCID mice with HIV-1 MDM-induced encephalitis, VPA treatment significantly reduced neuronal phosphorylated-catenin and tau without affecting HIV-1 replication or glial activation. We conclude that VPA protects neurons against HIV-1 infected MDM neurotoxicity, possibly through its effects on the phosphorylation of tau and -catenin. The use of VPA as an adjuvant in treatment of human HAD is being pursued.

Key words: HIV-1 associated dementia; HIV-1 encephalitis; monocyte-derived macrophages; sodium valproate; neuroprotection; severe combined immunodeficient mice

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Received July 9, 2003; revised August 8, 2003; accepted August 22, 2003.

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