Neuroprotective activities of sodium valproate in a murine model of human immunodeficiency virus-1 encephalitis.
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 beta-catenin through inhibiting glycogen synthase kinase 3beta 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-1ADA infected monocyte-derived macrophages (MDMs). In SCID mice with HIV-1 MDM-induced encephalitis, VPA treatment significantly reduced neuronal phosphorylatedbeta-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 beta-catenin. The use of VPA as an adjuvant in treatment of human HAD is being pursued.
Dou
Huanyu
H
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198-5215, USA.
Birusingh
Kevin
K
Faraci
Jill
J
Gorantla
Santhi
S
Poluektova
Larisa Y
LY
Maggirwar
Sanjay B
SB
Dewhurst
Stephen
S
Gelbard
Harris A
HA
Gendelman
Howard E
HE
D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001479:Basal Ganglia / Q000473:pathology / Q000821:virology; D015415:Biomarkers / Q000032:analysis; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D016655:HIV Core Protein p24 / Q000032:analysis / Q000096:biosynthesis; D015699:HIV Envelope Protein gp120 / Q000633:toxicity; D015497:HIV-1 / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification; D006801:Humans; D008264:Macrophages / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D012367:RNA, Viral / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000627:therapeutic use*; D016875:tau Proteins / Q000378:metabolism
D015415:Biomarkers; D016655:HIV Core Protein p24; D015699:HIV Envelope Protein gp120; D018696:Neuroprotective Agents; D012367:RNA, Viral; D016875:tau Proteins; D014635:Valproic Acid