Heme Oxygenase-1 Dysregulation in the Brain: Implications for HIVAssociated Neurocognitive Disorders
Surendra S. Ambegaokar and Dennis L. Kolson
Affiliation: Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 280 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA 19104, USA.
Keywords: Dimethyl fumarate, heme oxygenase, HIV associated neurocognitive disorders, HO-1, oxidative stress,
Heme oxygenase-1 (HO-1) is a highly inducible and ubiquitous cellular enzyme that subserves cytoprotective
responses to toxic insults, including inflammation and oxidative stress. In neurodegenerative diseases such as Alzheimer’s
disease, Parkinson’s disease and multiple sclerosis, HO-1 expression is increased, presumably reflecting an endogenous
neuroprotective response against ongoing cellular injury. In contrast, we have found that in human immunodeficiency
virus (HIV) infection of the brain, which is also associated with inflammation, oxidative stress and neurodegeneration,
HO-1 expression is decreased, likely reflecting a unique role for HO-1 deficiency in neurodegeneration pathways
activated by HIV infection. We have also shown that HO-1 expression is significantly suppressed by HIV replication in
cultured macrophages which represent the primary cellular reservoir for HIV in the brain. HO-1 deficiency is associated
with release of neurotoxic levels of glutamate from both HIV-infected and immune-activated macrophages; this
glutamate-mediated neurotoxicity is suppressed by pharmacological induction of HO-1 expression in the macrophages.
Thus, HO-1 induction could be a therapeutic strategy for neuroprotection against HIV infection and other
neuroinflammatory brain diseases. Here, we review various stimuli and signaling pathways regulating HO-1 expression in
macrophages, which could promote neuronal survival through HO-1-modulation of endogenous antioxidant and immune
modulatory pathways, thus limiting the oxidative stress that can promote HIV disease progression in the CNS. The use of
pharmacological inducers of endogenous HO-1 expression as potential adjunctive neuroprotective therapeutics in HIV
infection is also discussed.
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