Excitotoxicity in HIV associated neurocognitive disorders

Abstract

HAND (HIV associated neurocognitive disorders) represents a group of disorders, encompassing HIV associated asymptomatic neurocognitive impairment (ANI), HIV-associated mild neurocognitive disorders (MND), and HIV associated dementia (HAD). Even in the era of highly-active antiretroviral therapy, the prevalence of HAND is thought to be around 40 %, with milder forms making up a greater proportion of cases. HAND are clinically manifest as subcortical dementing processes; correlating with the preferential involvement of the basal ganglia, subcortical white matter, frontal lobe and hippocampus in neuropathological studies. A central mechanism leading to synaptic dysfunction and loss, neuronal dysfunction and apoptosis in HAND is excitotoxicity mediated through the excessive activation of neuronal (and probably astrocytic) NMDA receptors (NMDAR). There is direct and indirect evidence that in HAND, increased neuronal NMDAR activation occurs due to elevated extracellular glutamate; a result of both increased presynaptic release and impaired clearance from the synaptic space. In addition, high levels of quinolinic acid (QUIN) (an NMDAR agonist) released by activated macrophages (and to a lesser extent microglia) lead to excessive NMDAR activation and excitotoxicity. Furthermore, HIV related proteins (particularly gp120 and Tat) can both activate the NMDAR, and augment receptor activation by glutamate and other agonists. In vitro evidence supports the role of NMDAR antagonists in the prevention of neuronal loss induced by HIV related proteins. Clinical studies have demonstrated that the NMDAR antagonist memantine is safe and tolerable in HAND patients; so far clinical trials have failed to demonstrate a clinically beneficial effect of this therapy on neurocognitive function in HAND patients, however trials are ongoing.