Title:Multiple Faceted Roles of Cocaine in Potentiation of HAND
Volume: 14
Issue: 5
Author(s): Yu Cai, Lu Yang, Shannon Callen and Shilpa Buch
Affiliation:
Keywords:
HIV-associated neurocognitive disorders (HAND), cocaine, blood-brain barrier (BBB), astrocytes, microglia,
neurons, neural progenitor cells (NPC).
Abstract: Background: While the advancement of highly active antiretroviral
therapy (HAART) has transformed the course of HIV/AIDS from a death sentence
to a manageable chronic condition, the prevalence of a constellation of
neurological disorders collectively termed as HIV-associated neurocognitive
disorders (HAND) continues to persist in these patients. HAND is characterized by
cognitive dysfunction, depression, impaired memory and/or deficits in motor
skills. The underlying factors leading to HAND have been the subject of extensive
research and are thought to be associated with HIV infection in the CNS combined
with robust immune activation of resident cells of the CNS. In addition, there is a
strong correlation between chronic substance abuse and the manifestation of
HAND. Among the various commonly abused drugs, cocaine has been extensively studied for its
ability to exacerbate the neuropathogenesis of HAND. Ample evidence suggests that cocaine not only
facilitates viral replication in macrophages and microglia, but also inflicts deleterious effects on
various other cells of the CNS, thereby contributing to the potentiation of HAND. Cocaine has been
shown to enhance the permeability of the blood-brain barrier (BBB) through various mechanisms
including direct pro-apoptotic effects on brain endothelial cells, systemic induction of inflammatory
factors which have been demonstrated to down-regulate tight junction proteins and via up-regulation
of several endothelial adhesion molecules leading to accelerated breach of the BBB and increased
influx of HIV-infected leukocytes into the CNS. Cocaine also enhances viral replication in CNS
astrocytes and promotes astrogliosis via astrocyte activation and proliferation. Furthermore, cocaine
also exacerbates neuroinflammatory responses by mediating microglial activation and migration. In
addition to cellular injury mediated by inflammatory responses, cocaine also directly affects the brain
reward system by disrupting the homeostasis of neurotransmitters such as dopamine and acetylcholine
and works synergistically with viral proteins such as tat and gp120 to promote neuronal injury.
Conclusion: This review highlights previous studies in the field on the role of cocaine in the
progression of HAND and gives an overview of the major signaling pathways in the CNS that are
involved in this process.
