Biomedical subjects

Avindra Nath

Publications and source records attributed to Avindra Nath.

At least 73 records · Page 4Linked to original sources

PubMed2004

Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: Differential involvement of caspase-3 and endonuclease G.

Human immunodeficiency virus-1 (HIV-1) infection affects the striatum, resulting in gliosis and neuronal losses. To determine whether HIV-1 proteins induce striatal neurotoxicity through an apoptotic mechanism, mouse striatal neurons isolated on embryonic day 15 and the effects of HIV-1 Tat(1-72) and gp120 on survival were assessed in vitro. Mitochondrial release of cytochrome c, caspase-3 activation, and neuron survival, as well as an alternative apoptotic pathway involving endonuclease G (endo G), were assessed at 4 h, 24 h, 48 h, and/or 72 h using enzyme assays and immunoblotting. Both HIV-1 Tat and gp120 significantly increased caspase-3 activation in a concentration-dependent manner in striatal neurons at 4 h following continuous exposure in vitro. Tat(1-72) and gp120 caused significant neuronal losses at 48 h and/or 72 h. Tat(1-72) increased cytochrome c release, and caspase-3 and endo G activation at 4 h, 24 h, and/or 72 h. By contrast, gp120 increased caspase-3 activation, but failed to increase cytochrome c or endo G levels in the cytoplasm at 4 h, 24 h, and/or 72 h. The cell permeant caspase inhibitor Z-DEVD-FMK significantly attenuated gp120-induced, but not Tat(1-72)-induced, neuronal death, suggesting that gp120 acts in large part through the activation of caspase(s), whereas Tat(1-72)-induced neurotoxicity was accompanied by activating an alternative pathway involving endo G. Thus, although Tat(1-72) and gp120 induced significant neurotoxicity, the nature of the apoptotic events preceding death differed. Collectively, our findings suggest that HIV-1 proteins are intrinsically toxic to striatal neurons and the pathogenesis is mediated through separate actions involving both caspase-3 and endo G.

Animals↗

PubMed2004

Inflammatory changes and breakdown of microvascular integrity in early human immunodeficiency virus dementia.

Increased postcontrast enhancement in contrast-enhanced magnetic resonance imaging (CE-MRI) of the central nervous system (CNS) is a predictor of human immunodeficiency virus (HIV) dementia severity in HIV-infected subjects. The present study confirms this earlier finding in a mildly impaired patient cohort, and demonstrates that the increased postcontrast enhancement is correlated with increased cerebrospinal fluid (CSF) levels of monocyte chemoattractant protein (MCP)-1, an inflammatory chemokine, and increased CNS levels of mI, a microglial marker. These results suggest that early CNS inflammation may underlie the microvascular changes observed, and may be a factor in the development of HIV dementia.

AIDS Dementia Complex↗

PubMed2004

Gene transfer of baculoviral p35 by adenoviral vector protects human cerebral neurons from apoptosis.

Apoptosis plays an important role in neuronal cell death in both chronic and acute human neurological diseases, including ALS, Huntington's disease, cerebral ischemia, and HIV encephalopathy. We evaluated the ability of an extremely powerful antiapoptotic agent, baculoviral p35, to prevent apoptosis and cell death of human cerebral neurons that undergo severe neurotoxic changes in a culture system when treated with agents that are implicated in human neurological disorders, that is, tumor necrosis factor (TNFalpha) and the HIV proteins Tat and gp120. P35 is a potent broad-spectrum antiapoptotic protein derived from baculovirus, that inhibits nearly all caspases, and has other antiapoptotic actions as well. Adenoviral vectors expressing p35 (Ad. p35) or a control gene (lacZ) efficiently transduced human neurons. Treatment of control cultures with the toxic agents TNFalpha, TNFalpha plus Actinomycin D, or Tat and gp120, induced neurotoxicity and death of neurons. Transduction of neurons with Ad. p35 blocked apoptosis, and eliminated cell death due to TNFalpha, or Tat and gp120. Viral vector transfer of the p35 gene efficiently protects human neurons from TNFalpha, or Tat and gp120-induced apoptosis and cell death. These results suggest that p35 transduction of neurons by viral vectors could be therapeutically useful in the treatment of human neurodegenerative diseases.

Aborted Fetus↗

PubMed2004

Cytotoxic effects of exposure to the human immunodeficiency virus type 1 protein Tat in the hippocampus are enhanced by prior ethanol treatment.

BACKGROUND: Long-term ethanol exposure leads to increases in the expression and/or sensitivity of NMDA-type glutamate receptors, effects that may contribute to the development of cytotoxicity in the brain. The human immunodeficiency virus 1 (HIV-1) transcription factor Tat is one of many viral proteins that may contribute to the development of HIV-associated dementia (HAD) by indirectly or directly promoting excess function of NMDA receptors. Thus, these studies examined the hypothesis that long-term ethanol pre-exposure would sensitize the hippocampus to Tat-induced cytotoxicity in an NMDA receptor-dependent manner. METHODS: Organotypic slice cultures of rat hippocampus were exposed to a recombinant 86-amino acid form of Tat (Tat1-86) or a Tat deletion mutant devoid of amino acids 31 to 61 (TatDelta31-61; 0.1-100 nM) for 24 hr alone or during withdrawal from 10 days of ethanol exposure (50 mM in culture medium). Additional cultures were exposed to NMDA (5 microM) or the NMDA receptor channel blocker MK-801 (1 microM) during these treatments. Cellular injury in the CA1, CA3, and dentate gyrus regions of slice cultures was assessed by microscopy of propidium iodide fluorescence. RESULTS: Twenty-four hours of withdrawal from ethanol exposure did not produce overt cellular injury in any region of slice cultures. However, NMDA-induced toxicity was markedly increased in ethanol-pre-exposed cultures, an effect prevented by MK-801 (1 microM) coexposure. Treatment of cultures with Tat1-86 alone (> or = 0.1 nM) produced modest toxicity in each region of hippocampal cultures that was also blocked by MK-801 coexposure. In contrast, exposure to TatDelta31-61 did not alter propidium iodide fluorescence. Exposure of cultures to Tat1-86 (> or = 0.1 nM) during ethanol withdrawal resulted in a marked potentiation of Tat's toxic effects in each region of slice cultures, particularly the CA1 region. This potentiation of Tat neurotoxicity was significantly attenuated by coexposure of cultures to MK-801 (1 microM). CONCLUSIONS: These results indicate that long-term ethanol exposure sensitizes the hippocampus to the cytotoxic effects of Tat in an NMDA receptor-dependent manner. This may suggest that HIV-1-positive individuals who are alcohol dependent possess a heightened risk for the development of HAD. Furthermore, the NMDA receptor, particularly allosteric modulatory sites such as polyamine-sensitive sites, may be a therapeutic target to be investigated in the treatment of HAD.

Animals↗

PubMed2004

Preferential vulnerability of astroglia and glial precursors to combined opioid and HIV-1 Tat exposure in vitro.

Human immunodeficiency virus (HIV)-1 infection can cause characteristic neural defects such as progressive motor dysfunction, striatal pathology and gliosis. Recent evidence suggests that HIV-induced pathogenesis is exacerbated by heroin abuse and that the synergistic neurotoxicity is a direct effect of heroin on the CNS, an alarming observation considering the high incidence of HIV infection with injection drug abuse. Although HIV infection results in neurodegeneration, neurons themselves are not directly infected. Instead, HIV affects microglia and astroglia, which subsequently contributes to the neurodegenerative changes. Opioid receptors are widely expressed by macroglia and macroglial precursors, and the activation of mu-opioid receptors can modulate programmed cell death, as well as the response of neural cells to cytotoxic insults. For this reason, we questioned whether opioid drugs might modify the vulnerability of macroglia and macroglial precursors to HIV-1 Tat protein. To address this problem, the effects of morphine and/or HIV Tat(1-72) on the viability of macroglia and macroglial precursors were assessed in mixed-glial cultures derived from mouse striatum. Our findings indicate that sustained exposure to morphine and Tat(1-72) viral protein induces the preferential death of glial precursors and some astrocytes. Moreover, the increased cell death is mediated by mu-opioid receptors and accompanied by the activation of caspase-3. Our results imply that opiates can enhance the cytotoxicity of HIV-1 Tat through direct actions on glial precursors and/or astroglia, suggesting novel cellular targets for HIV-opiate interactions.

Animals↗

PubMed2004

CD4-independent infection of astrocytes by human immunodeficiency virus type 1: requirement for the human mannose receptor.

Human immunodeficiency virus type 1 (HIV-1) infection occurs in the central nervous system and causes a variety of neurobehavioral and neuropathological disorders. Both microglia, the residential macrophages in the brain, and astrocytes are susceptible to HIV-1 infection. Unlike microglia that express and utilize CD4 and chemokine coreceptors CCR5 and CCR3 for HIV-1 infection, astrocytes fail to express CD4. Astrocytes express several chemokine coreceptors; however, the involvement of these receptors in astrocyte HIV-1 infection appears to be insignificant. In the present study using an expression cloning strategy, the cDNA for the human mannose receptor (hMR) was found to be essential for CD4-independent HIV-1 infectivity. Ectopic expression of functional hMR rendered U87.MG astrocytic cells susceptible to HIV-1 infection, whereas anti-hMR serum and hMR-specific siRNA blocked HIV-1 infection in human primary astrocytes. In agreement with these findings, hMR bound to HIV-1 virions via the abundant and highly mannosylated sugar moieties of HIV-1 envelope glycoprotein gp120 in a Ca(2+)-dependent fashion. Moreover, hMR-mediated HIV-1 infection was dependent upon endocytic trafficking as assessed by transmission electron microscopy, as well as inhibition of viral entry by endosomo- and lysosomotropic drugs. Taken together, these results demonstrate the direct involvement of hMR in HIV-1 infection of astrocytes and suggest that HIV-1 interaction with hMR plays an important role in HIV-1 neuropathogenesis.

Animals↗

PubMed2003

Matrix metalloproteinase 1 interacts with neuronal integrins and stimulates dephosphorylation of Akt.

Several studies have demonstrated that matrix metalloproteinases (MMPs) are cytotoxic. The responsible mechanisms, however, are not well understood. MMPs may promote cytotoxicity through their ability to disrupt or degrade matrix proteins that support cell survival, and MMPs may also cleave substrates to generate molecules that stimulate cell death. In addition, MMPs may themselves act on cell surface receptors that affect cell survival. Among such receptors is the alpha(2)beta(1) integrin, a complex that has previously been linked to leukocyte death. In the present study we show that human neurons express alpha(2)beta(1) and that pro-MMP-1 interacts with this integrin complex. We also show that stimulation of neuronal cultures with MMP-1 is associated with a rapid reduction in the phosphorylation of Akt, a kinase that can influence caspase activity and cell survival. Moreover, MMP-1-associated dephosphorylation of Akt is inhibited by a blocking antibody to the alpha(2) integrin, but not by batimastat, an inhibitor of MMP-1 enzymatic activity. Such dephosphorylation is also stimulated by a catalytic mutant of pro-MMP-1. Additional studies show that MMP-1 causes neuronal death, which is significantly diminished by both a general caspase inhibitor and anti-alpha(2) but not by batimastat. Together, these results suggest that MMP-1 can stimulate dephosphorylation of Akt and neuronal death through a non-proteolytic mechanism that involves changes in integrin signaling.

Antibodies↗

PubMed2003

HIV-1 Tat protein alters tight junction protein expression and distribution in cultured brain endothelial cells.

Disruption of the blood-brain barrier (BBB) is widely believed to be the main route of human immunodeficiency virus (HIV) entry into the central nervous system (CNS). Although mechanisms of this process are not fully understood, alterations of tight junction protein expression can contribute, at least in part, to this phenomenon. Tight junctions are critical structural and functional elements of cerebral microvascular endothelial cells and the BBB. The aim of the present study was to examine the effects of HIV-1 Tat protein on expression of tight junction proteins. Primary cultures of brain microvascular endothelial cells (BMEC) were employed in these experiments. A 24-hr exposure of BMEC to Tat(1-72) resulted in a decrease of claudin-1, claudin-5, and zonula occludens (ZO)-2 expression, whereas total levels of occludin and ZO-1 remained unchanged. In addition, a short (3-hr) exposure of BMEC to Tat(1-72) induced cellular redistribution of claudin-5 immunoreactivity. Tat(1-72)-induced alterations of claudin-5 expression also were confirmed in vivo where Tat(1-72) was injected into the right hippocampus of mice. These findings indicate that HIV-1 Tat protein can markedly affect expression and distribution of specific tight junction proteins in brain endothelium. Alterations of only distinct tight junction proteins suggest a finely tuned effect of Tat(1-72) on the BBB. Because tight junction proteins are critical for the barrier function of the BBB, such alterations can lead to disturbances of the BBB integrity and contribute to HIV trafficking into the brain.

AIDS Dementia Complex↗

PubMed2003

Temporal relationships between HIV-1 Tat-induced neuronal degeneration, OX-42 immunoreactivity, reactive astrocytosis, and protein oxidation in the rat striatum.

HIV-1 transactivating protein Tat is neurotoxic and is believed to play a role in the development of AIDS-associated dementia complex. Neurotoxicity of Tat may be associated with oxidative stress. In this study we examined temporal progression of histopathological changes induced by a single microinjection of Tat 1-72 into the rat striatum. Degenerating neural cells, detected by Fluoro-Jade B staining and increased protein oxidation, determined by protein carbonyl immunostaining, were observed in the striatum as soon as 2 h following the microinjection. Further progression of neuronal degeneration was associated with pronounced infiltration of the area surrounding Tat 1-72 injection site by OX-42 positive macrophages/microglia, which was evident at the 24 h time point. Signs of reactive astrocytosis were found in the striatum of Tat 1-72 injected animals as late as 7 days following the single microinjection. Increased GFAP immunoreactivity and changes in the morphology of astrocytes coincided with a second phase of increased protein carbonyl formation, but not with neuronal degeneration. Control polypeptide, nontoxic Tat delta 31-61, did not cause any cell death, inflammatory reaction or oxidative damage. Results of our study support the hypothesis that oxidative stress may be an early step in the mechanism of Tat neurotoxicity.

Acetyltransferases↗

PubMed2003

HIV-1 protein Tat potentiation of methamphetamine-induced decreases in evoked overflow of dopamine in the striatum of the rat.

HIV-1 infection of the brain can lead to the development of clinical syndromes reminiscent of Parkinson's disease, suggesting that HIV infection may damage nigrostriatal dopamine (DA) neurons. Although the responsible mechanisms have not been well defined, neurotoxic viral proteins, such as Tat, released from infected cells may be involved. Drug abuse is a major risk factor for contracting HIV infection. Methamphetamine (METH), a psychostimulant with high abuse potential, may also be toxic to brain DA neurons. Thus, the combination of METH abuse and HIV infection may lead to substantial alterations in DA neuron functioning. The present experiments examined how Tat, alone and with METH, affects DA release in the striatum. Male rats were given an intrastriatal injection of Tat (25 micro g) or vehicle 24 h before treatment with saline or neurotoxic doses of METH. Seven days later microdialysis studies were carried out to measure potassium- and amphetamine-evoked overflow of DA from the striatum. The Tat treatment alone led to no change in potassium-evoked overflow of DA, a 20% decrease in amphetamine-evoked overflow of DA, and a 16% decrease in striatal DA content. The METH alone led to a 37-42% decrease in striatal DA overflow and content. The combined treatment with Tat and METH led to significantly greater 70-78% decreases in striatal DA overflow and content. These results indicate that Tat enhances METH-induced reductions in striatal DA release and content, possibly in a synergistic manner, and suggest that METH abusers infected with HIV may be at increased risk for basal ganglia dysfunction.

Animals↗

PubMed2003

Synaptic transport of human immunodeficiency virus-Tat protein causes neurotoxicity and gliosis in rat brain.

Neurodegeneration, synaptic alterations, and gliosis are prominent features of human immunodeficiency virus (HIV) encephalitis, but HIV encephalitis is distinct from other viral encephalitides because neurodegeneration occurs in uninfected neurons at anatomical sites that are often distant from the site of viral replication. The HIV protein Tat is both neurotoxic and proinflammatory; however, its contribution to HIV-related synaptic dysfunction remains unknown. To determine the consequences of continuous Tat production in brain, we genetically engineered rat C6 glioma cells to stably produce Tat and stereotaxically infused these cells into the rat striatum or hippocampus. We discovered that HIV-Tat protein could be transported along anatomical pathways from the dentate gyrus to the CA3/4 region and from the striatum to the substantia nigra, resulting in behavioral abnormalities, neurotoxicity, and reactive gliosis. This demonstrates a unique neuronal transport property of a viral protein and establishes a mechanism for neuroglial dysfunction at sites distant from that of viral replication. Tat may thus be an important participant in brain dysfunction in HIV dementia.

AIDS Dementia Complex↗

PubMed2003

Intracellular human immunodeficiency virus Tat expression in astrocytes promotes astrocyte survival but induces potent neurotoxicity at distant sites via axonal transport.

The human immunodeficiency virus (HIV)-Tat protein has been implicated in the neuropathogenesis of HIV infection. However, its role in modulating astroglial-neuronal relationships is poorly understood. Astrocyte infection with HIV has been associated with rapid progression of dementia. We thus initially transfected astrocytes with HIV proviral DNA and confirmed Tat production in these cells. Subsequently, using stably Tat-producing asytocyte cell lines, we observed that Tat promoted astrocyte survival by causing a prominent antioxidant effect and resistance to cell injury in these cells. Tat was released extracellularly where it could be taken up by other cells. Tat remained functionally active following uptake and caused long terminal repeat (LTR) transactivation in lymphocytic and astrocytic cell lines. Tat released from astrocytes caused mitochondrial dysfunction, trimming of neurites, and cell death in neurons. Tat neurotoxicity was attenuated by anti-Tat antibodies, kynurenate or heparan sulfate. The neurotoxic effects of Tat were caused at concentrations lower than that needed to cause LTR transactivation. When Tat-expressing cells were injected into the rat dentate gyrus, Tat was taken up by granule cells and transported along neuronal pathways to the CA3 region where it caused glial cell activation and neurotoxicity. The arginine-rich domain of Tat was essential for both the LTR transactivation and the neurotoxic properties of Tat. Thus HIV-Tat is a potent neurotoxin that may act at distant sites while at the same time it assures its production by preventing cell death in astrocytes where it is produced.

Astrocytes↗

PubMed2003

Methamphetamine potentiates HIV-1 Tat protein-mediated activation of redox-sensitive pathways in discrete regions of the brain.

Tat is a major regulatory protein encoded by human immunodeficiency viral genome, which has been implicated in the pathogenesis of HIV infection, including neurologic complications associated with this disease. In addition, drug abuse has been identified as a major risk factor of HIV infection. We hypothesize that abusive drugs, such as methamphetamine (METH), can directly influence specific molecular processes that can further contribute to toxic effects of Tat. To elucidate the molecular signaling pathways of Tat- and/or METH-induced toxicity, we investigated the effects of a single injection of Tat (25 microg/microl into the right hippocampus) and/or METH (10 mg/kg, intraperitoneally) on the generation of cellular oxidative stress, DNA-binding activity of specific redox-responsive transcription factors, and expression of inflammatory genes. Administration of Tat or METH resulted in stimulation of cellular oxidative stress and activation of redox-regulated transcription factors in the cortical, striatal, and hippocampal regions of the mouse brain. In addition, DNA-binding activities of NF-kappaB, AP-1, and CREB in the frontal cortex and hippocampus were more pronounced in mice injected with Tat plus METH compared to the effects of Tat or METH alone. Intercellular adhesion molecule-1 gene expression also was upregulated in a synergistic manner in cortical, striatal, and hippocampal regions in mice which received injections of Tat combined with METH compared to the effects of these agents alone. Moreover, synergistic effects of Tat plus METH on the tumor necrosis factor-alpha and interleukin-1beta mRNA levels were observed in the striatal region. These results indicate that Tat and METH can cross-amplify their cellular effects, leading to alterations of redox-regulated inflammatory pathways in the brain. Such synergistic proinflammatory stimulation may have significant implications in HIV-infected patients who abuse drugs.

Animals↗

PubMed2003

Cerebral Toxoplasmosis.

The choice of drugs for treating cerebral toxoplasmosis is limited. There are only three drugs available, and, of these, pyrimethamine and sulfonamide are invariably used in combination. Clindamycin is an alternative choice. Another drug, spiramycin, has poor central nervous system penetration, but achieves high concentrations in the placenta, and it is useful for treatment of toxoplasmosis during pregnancy. Because long-term maintenance therapy is often necessary, particularly in patients with AIDS, a wider choice of antibiotics is urgently necessary, because of potential problems with drug resistance and side effects. Treatment may be started empirically in any patient with HIV infection and multiple brain lesions. The drugs of choice are a combination of sulfadiazine and pyrimethamine. Folinic acid should be added to prevent pyrimethamine-induced bone marrow suppression. Repeated neuroimaging, 2 weeks after initiating therapy, is needed to assess efficacy of treatment. If CD4 cell counts remain below 100 cells per mm(3), lifelong therapy is needed. Tissue diagnosis should be established in patients who do not respond to treatment, who have solitary lesions, or in patients without AIDS. Recent breakthroughs in the understanding of the biology of Toxoplasma will result in the development of a range of new therapies in the near future.

Journal Article↗

PubMed2003

HIV-1 Tat protein upregulates inflammatory mediators and induces monocyte invasion into the brain.

Impaired inflammatory functions may be critical factors in the mechanisms by which HIV-1 enters the CNS. Evidence indicates that a viral gene product, the protein Tat, can markedly contribute to these effects. In the present study we tested the hypothesis that Tat can upregulate the expression of inflammatory cytokines and adhesion molecules and facilitate the entry of monocytes into the brain. Expression of inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) was assessed in C57BL/6 mice injected with Tat(1-72) into the right hippocampus. In the Tat(1-72)-injected groups, mRNA and protein levels of MCP-1, TNF-alpha, VCAM-1, and ICAM-1 were markedly elevated compared to those in control animals. The most pronounced changes were observed in and around the injected hippocampus. Double-labeling immunohistochemistry demonstrated that inflammatory proteins were primarily expressed in activated microglial cells and perivascular cells. In addition, astrocytes and endothelial cells were susceptible to Tat(1-72)-induced inflammatory responses. These changes were associated with a substantial infiltration of monocytes into the brain. These data demonstrate that intracerebral administration of Tat can induce profound proinflammatory effects in the brain, leading to monocyte infiltration.

AIDS Dementia Complex↗

PubMed2003

HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium.

Impaired function of the brain vasculature might contribute to the development of HIV-associated dementia. For example, injury or dysfunction of brain microvascular endothelial cells (BMEC) can lead to the breakdown of the blood-brain barrier (BBB) and thus allow accelerated entry of the HIV-1 virus into the CNS. Mechanisms of injury to BMEC during HIV-1 infection are not fully understood, but the viral gene product Tat may be, at least in part, responsible for this effect. Tat can be released from infected perivascular macrophages in the CNS of patients with AIDS, and thus BMEC can be directly exposed to high concentrations of this protein. To study oxidative and inflammatory mechanisms associated with Tat-induced toxicity, BMEC were exposed to increasing doses of Tat1-72, and markers of oxidative stress, as well as redox-responsive transcription factors such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), were measured. Tat1-72 treatment markedly increased cellular oxidative stress, decreased levels of intracellular glutathione and activated DNA binding activity and transactivation of NF-kappaB and AP-1. To determine if Tat1-72 can stimulate inflammatory responses in brain endothelium in vivo, expression of monocyte chemoattractant protein-1 (MCP-1), an NF-kappaB and AP-1-dependent chemokine, was studied in brain tissue in mice injected with Tat1-72 into the right hippocampus. Tat1-72 markedly elevated the MCP-1 mRNA levels in brain tissue. In addition, a double immunohistochemistry study revealed that MCP-1 protein was markedly overexpressed on brain vascular endothelium. These data indicate that Tat1-72 can induce redox-related inflammatory responses both in in vitro and in vivo environments. These changes can directly lead to disruption of the BBB. Thus, Tat can play an important role in the development of detrimental vascular changes in the brains of HIV-infected patients.

Animals↗

PubMed2003

Selective vulnerability of cerebellar granule neuroblasts and their progeny to drugs with abuse liability.

Cerebellar development is shaped by the interplay of genetic and numerous environmental factors. Recent evidence suggests that cerebellar maturation is acutely sensitive to substances with abuse liability including alcohol, opioids, and nicotine. Assuming substance abuse disrupts cerebellar maturation, a central question is: what are the basic mechanisms underlying potential drug-induced developmental defects? Evidence reviewed herein suggests that the maturation of granule neurons and their progeny are intrinsically affected by several classes of substances with abuse liability. Although drug abuse is also likely to target directly other cerebellar neuron and glial types, such as Purkinje cells and Bergmann glia, findings in isolated granule neurons suggest that they are often the principle target for drug actions. Developmental events that are selectively disrupted by drug abuse in granule neurons and/or their neuroblast precursors include proliferation, migration, differentiation (including neurite elaboration and synapse formation), and programmed cell death. Moreover, different classes of drugs act through distinct molecular mechanisms thereby disrupting unique aspects of development. For example, drug-induced perturbations in: (i) neurotransmitter biogenesis; (ii) ligand and ion-gated receptor function and their coupling to intracellular effectors; (iii) neurotrophic factor biogenesis and signaling; and (iv) intercellular adhesion are all likely to have significant effects in shaping developmental outcome. In addition to identifying therapeutic strategies for drug abuse intervention, understanding the mechanisms by which drugs affect cellular maturation is likely to provide a better understanding of the neurochemical events that normally shape central nervous system development.

Alcoholism↗

PubMed2003

SDF-1alpha is expressed in astrocytes and neurons in the AIDS dementia complex: an in vivo and in vitro study.

Recent in vitro studies suggest that the alpha chemokine stromal-derived factor-1alpha (SDF-1alpha) and its receptor CXCR-4 may contribute to neuronal apoptosis in HIV infection of the brain. The cellular and regional expression of this chemokine and its relationship to the AIDS dementia complex (ADC), however, have remained undetermined. Using immunohistochemistry and semiquantitative RT-PCR, we examined the expression of SDF-1alpha in the frontal cortex (FC), the adjacent deep white matter (DWM). and the basal ganglia (BG) of 17 patients with ADC and 5 normal controls, and the FC and temporal cortex of 6 patients with Alzheimer disease (AD). Additionally, SDF-1alpha expression was studied in 3 different neuronal cultures: differentiated SK-N-MC cells, primary human fetal neuronal, and mouse hippocampal cultures. SDF-1alpha staining was predominantly localized to astrocytes in all 3 groups in the gray matter of the FC and the BG, often in the vicinity of cortical and basal ganglia neurons, but was generally absent in the DWM. Further, the number of positive neurons was significantly greater in the BG of AIDS subjects with advanced brain disease compared to subjects with lesser disease (p = 0.029). All cultures showed prominent SDF-1alpha staining of neurons within the cytoplasm and in neurites, whereas preferential expression in GABA-ergic neurons was found in hippocampal cultures. This is the first study to show that SDF-1alpha is constitutively expressed in astrocytes of the deep and cortical gray matter as well as in neurons of the human brain. Its increased expression in basal ganglia neurons of patients with advanced HIV CNS disease suggests it may also contribute to pathogenesis.

AIDS Dementia Complex↗