TY - JOUR
T1 - Neuroprotective activities of sodium valproate in a murine model of human immunodeficiency virus-1 encephalitis
AU - Dou, Huanyu
AU - Birusingh, Kevin
AU - Faraci, Jill
AU - Gorantla, Santhi
AU - Poluektova, Larisa Y.
AU - Maggirwar, Sanjay B.
AU - Dewhurst, Stephen
AU - Gelbard, Harris A.
AU - Gendelman, Howard E.
PY - 2003/10/8
Y1 - 2003/10/8
N2 - 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 β-catenin through inhibiting glycogen synthase kinase 3β 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 phosphorylated β-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 β-catenin. The use of VPA as an adjuvant in treatment of human HAD is being pursued.
AB - 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 β-catenin through inhibiting glycogen synthase kinase 3β 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 phosphorylated β-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 β-catenin. The use of VPA as an adjuvant in treatment of human HAD is being pursued.
KW - HIV-1 associated dementia
KW - HIV-1 encephalitis
KW - Monocyte-derived macrophages
KW - Neuroprotection
KW - Severe combined immunodeficient mice
KW - Sodium valproate
UR - http://www.scopus.com/inward/record.url?scp=0141988725&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0141988725&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.23-27-09162.2003
DO - 10.1523/jneurosci.23-27-09162.2003
M3 - Article
C2 - 14534250
AN - SCOPUS:0141988725
SN - 0270-6474
VL - 23
SP - 9162
EP - 9170
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 27
ER -