And HIVAssociated Dementia

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Marcus Kaul, PhD and Stuart A. Lipton, MD, PhD

1. INTRODUCTION

Neuronal injury and apoptosis may account, at least in part, for neurological complications associated with human immunodeficiency virus (HIV)-1 infection ranging from mild cognitive and motor impairment to dementia. The primary cell types infected in the brain are macrophages and microglia. These cells have been found in vivo and in vitro to release neurotoxic factors. Evidence has accumulated that neuronal apoptosis in HIV-related insults occurs predominantly via an indirect pathway comprising a complex cooperation of cytokines, reactive oxygen species and reactive nitrogen species, lipid mediators, and excitotoxins. These molecules lead to excessive stimulation of the N-methyl-d-aspartate subtype of glutamate receptor (NMDAR). Of note, chemokine receptors, which, in conjunction with CD4, mediate HIV infection of macrophages/microglia, are present on neurons and astrocytes in addition to macrophages/microglia. Thus, these receptors potentially allow direct interaction between the virus and neurons (Fig. 2). The fact that specific chemokines ameliorate HIV/gp120-induced neuronal apoptosis that is mediated by NMDARs suggests a functional connection between the receptors for chemokines and NMDA. Accordingly, here we review the role of the NMDAR in HIV-1-related and excitotoxic neuronal cell death.

2. GLUTAMATE RECEPTORS, EXCITOTOXICITY, AND NEURONAL CELL DEATH

NMDAR belongs to a large and heterogeneous family of membrane proteins, the glutamate receptors. These glutamate receptors recognize the major excitatory neurotransmitter in the central nervous system (CNS), (S)-glutamic acid (Glu), and other related excitatory amino acids (EAAs) (1-3). To date, four classes of EAA receptors have been identified and many member subunits cloned. These include three "ionotropic" receptor classes [iGluRs, comprised of ligand-gated ion channels termed (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), kainic acid (KA), and NMDA receptors] and a G-protein-coupled or "metabotropic" EAA receptor class (mGluRs) (1,2,4). Both iGluRs and mGluRs are considered to play important roles in the CNS under normal physiological and pathophysiological conditions. Under physiological conditions, activation of iGluRs in neurons initiates transient depolarization and excitation. AMPARs mediate the fast component of excitatory postsynaptic currents and NMDARs underlie a slower component. Presynaptic release of Glu and consequent depolarization of the postsynaptic neuronal membrane via AMPAR-coupled channels relieve the Mg2+ block of the ion channel associated with the NMDAR under resting conditions. This effect allows subsequent controlled Ca2+ influx through the NMDAR-coupled ion channel.

From: Contemporary Clinical Neuroscience: Glutamate and Addiction Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ

Fig. 1. Current model of NMDA receptor-associated neuronal injury. Schematic illustration of NMDAR-related signaling pathways that lead to neuronal apoptosis and may contribute to neurodegenerative disease, including HIV-associated dementia. These pathways can be interrupted to prevent neuronal apoptosis; thus, their study affords the opportunity to develop potential treatments for various neurologic diseases. Drug or molecular therapies are being developed to (1) antagonize NMDA receptors (NMDA-Rc), (2) modulate activation of the p38 mitogen-activated kinase (MAPK)-MEF2C (transcription factor) pathway, (3) prevent toxic reactions of free radicals such as nitric oxide (NO) and reactive oxygen species (ROS) that form peroxynitrite (ONOO-), and (4) inhibit apoptosis-inducing factors, including caspases. Activation of the p38 MAPK-MEF2C pathway appears to occur upstream of the effector caspases (not illustrated here). (Color illustration in insert following p. 142.)

Fig. 1. Current model of NMDA receptor-associated neuronal injury. Schematic illustration of NMDAR-related signaling pathways that lead to neuronal apoptosis and may contribute to neurodegenerative disease, including HIV-associated dementia. These pathways can be interrupted to prevent neuronal apoptosis; thus, their study affords the opportunity to develop potential treatments for various neurologic diseases. Drug or molecular therapies are being developed to (1) antagonize NMDA receptors (NMDA-Rc), (2) modulate activation of the p38 mitogen-activated kinase (MAPK)-MEF2C (transcription factor) pathway, (3) prevent toxic reactions of free radicals such as nitric oxide (NO) and reactive oxygen species (ROS) that form peroxynitrite (ONOO-), and (4) inhibit apoptosis-inducing factors, including caspases. Activation of the p38 MAPK-MEF2C pathway appears to occur upstream of the effector caspases (not illustrated here). (Color illustration in insert following p. 142.)

This voltage-dependent modulation of the NMDAR results in activity-driven synaptic modulation (2,5). However, extended and/or excessive NMDAR activation and consequent overexcitation can damage neurons and eventually cause cell death. This process is called excitotoxicity and appears to be favored by sustained elevation of the intracellular Ca2+ concentration and/or compromised cellular energy metabolism (5,6).

A role for Glu excitotoxicity in brain disorders was first suggested by the work of Olney following the pioneering work of Lucas and Newhouse in the retina (6). Subsequently, several lines of evidence indicated that excessive stimulation of glutamate receptors contributes to the neuropathological processes in stroke, head and spinal cord injury, Huntington's disease, Parkinson's disease, possibly Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, and HIV-1 associated dementia (1,5,7). Indeed, excitotoxicity seems to represent a common final pathway in a wide variety of neurodegenerative disorders (8).

NMDAR has attracted particular interest as a major player in excitotoxicity because this receptor, in contrast to most non-NMDARs (AMPA and KA receptors), is highly permeable to Ca2+, and excessive Ca2+ influx can trigger excitotoxic neuronal injury (3,9). In addition, NMDAR antagonists effectively prevent glutamate neurotoxicity, both in vitro and in vivo in animal studies, as well as in recent phase III clinical trials with the NMDAR open-channel blocker, memantine (2,5,10). However, AMPA and KA receptors can also mediate excitotoxicity and contribute to neuronal damage under certain conditions (2,5). For example, a subpopulation of Ca2+- or Zn2+-permeable AMPA receptor-coupled channels have been implicated in selective neurodegenerative disorders, such as ischemia, epilepsy, Alzheimer's disease, and amyotrophic lateral sclerosis (3). Also, transgenic mice overexpressing AMPARs display increased damage subsequent to ischemia when compared to control animals (11).

Excessive stimulation of the NMDAR induces several detrimental intracellular signals that contribute to neuronal cell death by apoptosis or necrosis, depending on the intensity of the initial insult (12). Excessive Ca2+ influx through NMDAR-coupled ion channels leads to an elevation of the intracellular free-Ca2+ concentration to a point that results in Ca2+ overload of mitochondria, depolarization of the mitochondrial membrane potential, and a decrease in ATP synthesis. Additionally, excessive intracellular Ca2+ stimulates protein kinase cascades and the generation of free radicals, including reactive oxygen species (ROS) and nitric oxide (NO) (12). NO can react with ROS to form cytotoxic peroxynitrite (OONO) (12), and in alternative redox states, NO can also activate p21ras by S-nitrosy-lation (transfer of the NO group to a critical cysteine thiol) (13). However, the NO group can also inhibit caspases in cerebrocortical neurons via S-nitrosylation, thereby attenuating apoptosis (14). The scaffolding protein PSD-95 (postsynaptic density-95) links the principal subunit of the NMDAR (NR1) with neuronal nitric oxide synthase (nNOS), a Ca2+-activated enzyme, and thus brings nNOS into close proximity to Ca2+ via the NMDAR-operated ion channel (15) (see Fig. 1).

Importantly, excessive Ca2+ influx also activates the stress-related p38 mitogen-activated protein kinase (p38 MAPK)/myocyte enhancer factor 2C (MEF2C transcription factor) pathway and c-Jun N-terminal kinase (JNK) pathways in cerebrocortical or hippocampal neurons. Activation of these pathways has been implicated in neuronal apoptosis (16,17). As stated above, excessive intracellular Ca2+ accumulation after NMDAR stimulation leads to depolarization of the mitochondrial membrane potential (A¥m) and a drop in the cellular ATP concentration. If the initial excitotoxic insult is fulminant, the cells do not recover their ATP levels and die at this point because of the loss of ionic home-ostasis, resulting in acute swelling and lysis (necrosis). If the insult is milder, ATP levels recover, and the cells enter a delayed death pathway requiring energy, known as apoptosis (12).

It has been reported that NMDAR-mediated excitotoxicity leading to neuronal apoptosis also involves activation of the Ca2+/calmodulin-regulated protein phosphatase calcineurin, release of cytochrome c from mitochondria, activation of caspase-3, lipid peroxidation, and cytoskeletal breakdown (12,18,19). Inhibition of calcineurin or caspase-3 with FK506 caspase inhibitors, respectively, can attenuate this form of excitotoxicity (12,19). It has been proposed that the adenine nucleotide translocator (ANT) is a part of the mitochondrial permeability transition pore (PTP) and participates in mitochondrial depolarization. Indeed, our group has found that pharmacologic blockade of the ANT with bongkrekic acid prevented collapse of the mitochondrial membrane potential (A¥m), as well as subsequent caspase-3 activation and NMDA-induced neuronal apoptosis. However, treatment with bongkrekic acid failed to inhibit the transient drop in ATP concentration (although it hastened the recovery of ATP levels) and did not prevent the liberation of cytochrome c into the cytosol. Thus, initiation of caspase-3 activation and resultant neuronal apoptosis after NMDAR activation require a fac-tor(s) in addition to cytochrome c release (18).

Interestingly, stimulation of specific subtypes of the G-protein-coupled mGluRs interferes with excitotoxic NMDAR-mediated activation of MAPKs and can attenuate subsequent neuronal cell death

(16). Additionally, glial cells, including astrocytes, microglia, and oligodendrocytes, may possess some types of glutamate receptor (4). Both AMPA and KA receptor subtypes as well as mGluRs have been reported on microglia, and functional NMDARs have been reported to exist in some cases on astrocytes and oligodendrocytes (although these latter findings of NMDARs need to be verified). Glial glutamate receptors appear to be involved in interactions between neuronal and glial cells and, hence, may conceivably contribute to synaptic efficacy. Furthermore, under certain pathologic circumstances, such as cerebral hypoxia-ischemia and possibly HIV-1 infection of the brain, astrocytes and oligodendrocytes may undergo glutamate-mediated excitotoxic cell death (4).

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