Expression and regulation of the two cyclooxygenase isoforms in rhesus macaque brain during lentivirus infection: differentiation of reversible inflammatory and irreversible neuronal sequelae

Abstract

The regulation of cyclooxygenase type-1 and type-2 (COX-1, COX-2), key enzymes in the conversion of arachidonic acid to prostanoids and mediators of inflammation, was investigated in the brain of simian immunodeficiency virus (SIV)-infected rhesus macaques. COX-1 and COX-2 were constitutively expressed in hippocampal and cortical neurons. COX-1 was additionally found to be expressed in cholinergic basal forebrain neurons (septum, diagonal band of Broca and nucleus basalis of Meynert). This expression was highly species-specific, as COX-1 was coexpressed with specific cholinergic markers choline acetyl transeferase, vesicular acetyl choline transporter (VAChT) and high affinity choline transporter in these neurons, in both the rhesus macaque and human, but was absent from basal forebrain cholinergic neurons in rat, mouse and guinea pig brain. COX-1 immunoreactivity was decreased more than 50% in cholinergic projection neurons of the basal forebrain in AIDS-diseased monkeys. Decreased COX-1 expression was accompanied by a decrease of VAChT-positive fibers and terminals in parietal and frontal cortex, and hippocampus. Additionally, COX-1 and COX-2 were downregulated in frontal cortex neurons in AIDS. Nonneuronally, only COX-1 was expressed constitutively in microglia and endothelial cells, and was not changed in early SIV infection. Late stage of disease was characterized by upregulation of COX-1 in scattered microglia/macrophages, macrophage nodules and multinucleated giant cells. Endothelial COX-1 expression was unchanged during SIV infection. In AIDS-symptomatic monkey brains COX-2 was induced focally in nodule and syncytium forming macrophages and in endothelial cells in areas of viral burden and inflammatory cell infiltrates. Treatment with the antiretroviral brain-permeant 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG) substantially reduced focal expression of COX-1 and COX-2 in AIDS, but diffuse COX-1 microgliosis was not. 6-Cl-ddG did not decrease COX-1 immunoreactivity in cortical and cholinergic basal forebrain neurons and cortical cholinergic fiber loss. We conclude that COX-1 coexpression is a feature of the cholinergic basal forebrain telecephalic projection system specific to primates, and may be important in primate-specific functions of this system, and in the cholinergic dysregulation that accompanies primate lentiviral encephalitis. Nonneuronal COX-2 induction is associated with reversible overt inflammatory events to areas of active viral replication. Treatment with cyclooxygenase-inhibitors and central cholinomimetica might be beneficial beside highly active antiretroviral therapy in immunodeficiency virus-induced encephalopathy and encephalitis.