Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor.

Morphine has been shown to increase the expression of brain-derived neurotrophic factor (BDNF) in the brain. However, little is known about the effect of morphine withdrawal on BDNF and its precursor protein, or proBDNF, which induces neuronal apoptosis. In this work, we examined whether BDNF and proBDNF levels change in rats chronically injected with escalating doses of morphine and those who undergo spontaneous withdrawal for 60 h. We observed, in the frontal cortex and striatum, that the ratio of BDNF to proBDNF changed depending upon the experimental paradigm. Morphine treatment and morphine withdrawal increased both BDNF and proBDNF levels. However, the increase in proBDNF immunoreactivity in withdrawal rats was more robust than that observed in morphine-treated rats. proBDNF is processed either intracellularly by furin or extracellularly by the tissue plasminogen activator (tPA)/plasminogen system or matrix metalloproteases (MMPs). To examine the mechanisms whereby chronic morphine treatment and morphine withdrawal differentially affects BDNF/proBDNF, the levels MMP-3 and MMP-7, furin, and tPA were analyzed. We found that morphine increases tPA levels, whereas withdrawal causes a decrease. To confirm the involvement of tPA in the morphine-mediated effect on BDNF/proBDNF, we exposed cortical neurons to morphine in the presence of the tPA inhibitor plasminogen activator inhibitor-1 (PAI-1). This inhibitor reversed the morphine-mediated decrease in proBDNF, supporting the hypothesis that morphine increases the availability of BDNF by promoting the extracellular processing of proBDNF by tPA. Because proBDNF could negatively influence synaptic repair, preventing withdrawal is crucial for reducing neurotoxic mechanisms associated with opioid abuse.

Endocytic Trafficking of HIV gp120 is Mediated by Dynamin and Plays a Role in gp120 Neurotoxicity.

Neurons that endocytose the human immunodeficiency virus-1 (HIV) protein gp120 exhibit neurite retraction and activation of caspase-3, suggesting that the endocytic process may be crucial for gp120-mediated neuronal injury. The goal of this study is to demonstrate that internalization and accumulation of gp120 play a role in its neurotoxic effects. In mammalian cells, endocytosis is primarily a dynamin-dependent process. To establish whether gp120 is endocytosed in a dynamin-dependent manner, we used fibroblasts in which deletion of dynamins was induced by tamoxifen. We observed a robust reduction of intracellular gp120 immunoreactivity in tamoxifen-treated cells. To examine whether endocytosis of gp120 is crucial for its neurotoxic effect, we blocked gp120 internalization into primary rat cortical neurons by dynasore, an inhibitor of the dynamin GTP-ase activity. We found that dynasore blocks both gp120 internalization and neurotoxicity. We then utilized gp120-loaded mesoporous silica nanoparticles to deliver gp120 intracellularly. We established that once internalized, gp120 is neurotoxic regardless of chemokine receptor activation. Our data suggest that dynamin-dependent endocytosis of gp120 is critical for its neurotoxicity.

The neurotrophin receptor p75 mediates gp120-induced loss of synaptic spines in aging mice.

Human immunodeficiency virus 1 and its envelope protein gp120 reduce synaptodendritic complexity. However, the mechanisms contributing to this pathological feature are still not understood. The proneurotrophin brain-derived neurotrophic factor promotes synaptic simplification through the activation of the p75 neurotrophin receptor (p75NTR). Here, we have used gp120 transgenic (gp120tg) mice to investigate whether p75NTR has a role in gp120-mediated neurotoxicity. Old (∼10 months) gp120tg mice exhibited an increase in proneurotrophin brain-derived neurotrophic factor levels in the hippocampus as well as a decrease in the number of dendritic spines when compared to age-matched wild type. These effects were not observed in 3- or 6-month-old mice. To test if the reduction in spine density and morphology is caused by the activation of p75NTR, we crossed gp120tg mice with p75NTR null mice. We found that deletion of only 1 copy of the p75NTR gene in gp120tg mice is sufficient to normalize the number of hippocampal spines, strongly suggesting that the neurotoxic effect of gp120 is mediated by p75NTR. These data indicate that p75NTR antagonists could provide an adjunct therapy against synaptic simplification caused by human immunodeficiency virus 1.

Expression of gp120 in mice evokes anxiety behavior: Co-occurrence with increased dendritic spines and brain-derived neurotrophic factor in the amygdala.

Human immunodeficiency virus type 1 (HIV) infection of the brain produces cognitive and motor disorders. In addition, HIV positive individuals exhibit behavioral alterations, such as apathy, and a decrease in spontaneity or emotional responses, typically seen in anxiety disorders. Anxiety can lead to psychological stress, which has been shown to influence HIV disease progression. These considerations underscore the importance of determining if anxiety in HIV is purely psychosocial, or if by contrast, there are the molecular cascades associated directly with HIV infection that may mediate anxiety. The present study had two goals: (1) to determine if chronic exposure to viral proteins would induce anxiety-like behavior in an animal model and (2) to determine if this exposure results in anatomical abnormalities that could explain increased anxiety. We have used gp120 transgenic mice, which display behavior and molecular deficiencies similar to HIV positive subjects with cognitive and motor impairments. In comparison to wild type mice, 6 months old gp120 transgenic mice demonstrated an anxiety like behavior measured by open field, light/dark transition task, and prepulse inhibition tests. Moreover, gp120 transgenic mice have an increased number of spines in the amygdala, as well as higher levels of brain-derived neurotrophic factor and tissue plasminogen activator when compared to age-matched wild type. Our data support the hypothesis that HIV, through gp120, may cause structural changes in the amygdala that lead to maladaptive responses to anxiety.

Implementing neuronal plasticity in NeuroAIDS: the experience of brain-derived neurotrophic factor and other neurotrophic factors.

Human immunodeficiency virus type-1 (HIV) causes mild or severe neurological problems, termed HIV-associated neurocognitive disorder (HAND), even when HIV patients receive antiretroviral therapy. Thus, novel adjunctive therapies are necessary to reduce or abolish the neurotoxic effect of HIV. However, new therapies require a better understanding of the molecular and cellular mechanisms of HIV-induced neurotoxicity. HAND subjects are characterized by being profoundly depressed, and they experience deficits in memory, learning and movements. Experimental evidence has also shown that HIV reduces neurogenesis. These deficits resemble those occurring in premature brain aging or in a brain with impaired neural repair properties. Thus, it appears that HIV diminishes neuronal survival, along with reduced neuronal connections. These two phenomena should not occur in the adult and developing brain when synaptic plasticity is promoted by neurotrophic factors, polypeptides that are present in adult synapses. This review will outline experimental evidence as well as present emerging concepts for the use of neurotrophic factors and in particular brain-derived neurotrophic factor as an adjunct therapy to prevent HIV-mediated neuronal degeneration and restore the loss of synaptic connections.

Human immunodeficiency virus-associated dementia: a link between accumulation of viral proteins and neuronal degeneration.

In the late stage of human immunodeficiency virus-1 (HIV) infection, a subset of individuals develops HIV associated neurocognitive disorders (HAND), which in its severe form, is characterized by motor and cognitive dysfunction. Dendritic pruning, synaptic abnormalities and neuronal apoptosis are observed in these patients. There are numerous advances in our understanding of HIV interactions with cells of the central nervous system. However, the underlying causes of neurological symptoms and pathological alterations observed in HIV positive subjects are poorly understood. Moreover, little is still known about the molecular mechanisms by which HIV induces synaptic dysfunction and degeneration. HAND resembles other common neurological diseases such as Alzheimer's and Huntington's diseases. These neurodegenerative disorders are characterized by accumulation of toxic proteins such as tau and huntingtin, respectively, which promote axonal degeneration by impairing axonal transport. Axonal degeneration precedes neuronal death. Therefore, a better understanding of the mechanisms whereby HIV triggers axonal degeneration has potential implications for developing therapeutic compounds to prevent synaptic failure in HAND. This article highlights and reviews evidence showing that neuronal accumulation of viral proteins promotes axonal damage.

Human immunodeficiency virus type 1 alters brain-derived neurotrophic factor processing in neurons.

The molecular mechanisms leading to synaptic simplification and neuronal apoptosis in human immunodeficiency virus type 1 (HIV-1)-positive subjects are unknown. The HIV protein gp120 reduced the length of neuronal processes similarly to the proneurotrophin pro-brain-derived neurotrophic factor (proBDNF). Intriguingly, the effects of both proBDNF and gp120 were blocked by inhibitors of the p75 neurotrophin receptor, suggesting that proBDNF and gp120 share a similar mechanism of neurotoxicity. Therefore, we tested the hypothesis that gp120 affects the release of proBDNF. Using rat primary neurons, we observed that gp120 promotes a time-dependent intracellular and extracellular accumulation of proBDNF concomitantly with a decrease in mature BDNF. A similar imbalance in the ratio proBDNF/mature BDNF was confirmed in postmortem brains of HIV-positive subjects cognitively impaired and motor impaired. Therefore, it is conceivable to formulate the hypothesis that HIV neurotoxicity includes a gp120-mediated alteration of BDNF processing. To determine the cellular mechanism whereby gp120 produces an accumulation of proBDNF, we examined the levels of intracellular and extracellular enzymes that proteolytically cleave proBDNF furin and tissue plasminogen, respectively. In rat neurons exposed to gp120, intracellular furin levels decreased before cell death, whereas tissue plasminogen changed only during apoptosis. Our data suggest that HIV, through gp120, reduces proBDNF processing by affecting furin levels, and therefore causes an altered balance between antiapoptotic and proapoptotic neurotrophins. Our studies identify a new mechanism that may explain how HIV promotes neuronal injury.

Neurotoxicity of human immunodeficiency virus-1: viral proteins and axonal transport.

Human immunodeficiency virus-1 (HIV) infection of the central nervous system may cause a neurological syndrome termed HIV-associated neurocognitive disorder (HAND) which includes minor neurocognitive disorders or a more severe form of motor and cognitive impairments. Although treatment with highly active antiretroviral agents decreases the load of HIV in the brain, the prevalence of mild forms of HAND is actually increased due to longer life. Therefore, adjunctive and combined therapies must be developed to prevent and perhaps reverse the neurologic deficits observed in individuals with HAND. Key to developing effective therapies is a better understanding of the molecular and cellular mechanisms by which the virus causes this disorder. A number of HIV proteins has been shown to be released from HIV-infected cells. Moreover, these proteins have been shown to possess neurotoxic properties. This review describes new evidence of a direct interaction of the HIV protein gp120 with neurons, which might play a role in the etiopathology of HAND.

HIV-1 decreases the levels of neurotrophins in human lymphocytes.

Neurotrophins control cell survival. Therefore, we examined whether HIV-1 reduces neurotrophin levels. Serum of HIV-positive individuals exhibited lower concentrations of brain-derived neurotrophic factor (BDNF), but not of other neurotrophins, than HIV-negative individuals. In addition, R5 and X4 strains of HIV-1 decreased BDNF expression in T cells. Our results support the hypothesis that reduced levels of BDNF may be a risk factor for T-cell apoptosis and for neurological complications associated with HIV-1 infection.

M-tropic HIV envelope protein gp120 exhibits a different neuropathological profile than T-tropic gp120 in rat striatum.

Most early human immunodeficiency virus type 1 (HIV-1) strains are macrophage (M)-tropic HIV variants and use the chemokine receptor CCR5 for infection. Neuronal loss and dementia are less severe among individuals infected with M-tropic strains. However, after several years, the T-cell (T)-tropic HIV strain, which uses the CXCR4 variant, can emerge in conjunction with brain abnormalities, suggesting strain-specific differences in neuropathogenicity. The molecular and cellular mechanisms of such diversity remain under investigation. We have previously demonstrated that HIV envelope protein gp120IIIB, which binds to CXCR4, causes neuronal apoptosis in rodents. Thus, we have used a similar experimental model to examine the neurotoxic effects of M-tropic gp120BaL. gp120BaL was microinjected in the rat striatum and neuronal apoptosis was examined in the striatum, as well as in anatomically connected areas, such as the somatosensory cortex and the substantia nigra. gp120BaL promoted neuronal apoptosis and tissue loss that were confined to the striatum. Apoptosis was associated with microglial activation and increased levels of interleukin-1beta. Intriguingly, gp120BaL increased brain-derived neurotrophic factor in the striatum. Overall, our data show that gp120BaL demonstrates a different neuropathological profile than gp120IIIB. A better understanding of the pathogenic mechanisms mediating HIV neurotoxicity is vital for developing effective neuroprotective therapies against AIDS-associated dementia complex.

M- and T-tropic HIVs promote apoptosis in rat neurons.

Neuronal loss, reactive astrocytes, and other abnormalities are seen in the brain of individuals with acquired immune deficiency syndrome-associated Dementia Complex (ADC). Human immunodeficiency virus-1 (HIV-1) is believed to be the main agent causing ADC. However, little is known about the molecular and cellular mechanisms of HIV-1 neurotoxicity considering that HIV-1 does not infect post-mitotic neurons and that viral load does not necessarily correlate with ADC. Various viral proteins, such as the envelope protein gp120 and the transcription activator Tat, have been shown to induce neuronal apoptosis through direct and indirect mechanisms both in vitro and in vivo. Progeny HIV-1 virions can also cause neuronal death. However, it has not been fully established yet whether HIV-1 promotes neuronal apoptosis by a direct mechanism. To explore the neurotoxic effect of HIV-1, we exposed rat cerebellar granule cells and cortical neurons in culture to two different strains of HIV-1, IIIB and BaL, T- and M-tropic strains that utilize CXCR4 and CCR5 coreceptors, respectively, to infect cells. We observed that both viruses elicit a time-dependent apoptotic cell death in these cultures without inducing a productive infection as determined by the absence of the core protein of HIV-1, p24, in cell lysates. Instead, neurons were gp120 positive, suggesting that the envelope protein is shed by the virus and then subsequently internalized by neurons. The CXCR4 receptor antagonist AMD3100 or the CCR5 receptor inhibitor D-Ala-peptide T-amide blocked HIV IIIB and HIV Bal neurotoxicity, respectively. In contrast, the N-methyl-D-aspartate receptor blocker MK801 failed to protect neurons from HIV-mediated apoptosis, suggesting that HIV-1 neurotoxicity can be initiated by the viral protein gp120 binding to neuronal chemokine receptors.

Chronic antidepressant treatments increase basic fibroblast growth factor and fibroblast growth factor-binding protein in neurons.

One of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic connections and plasticity in the hippocampus and cerebral cortex. Fibroblast growth factor 2 (FGF2) is a growth factor essential for the proper formation of synaptic connections in the cerebral cortex, maturation and survival of catecholamine neurons, and neurogenesis. In this report, we attempted to establish a correlation between antidepressant treatments and FGF2 expression in the cerebral cortex and hippocampus, two brain areas relevant for depression. Desipramine (DMI, 10mg/kg) or fluoxetine (FLU, 5mg/kg) was injected acutely (single injection) or chronically (daily injection for two weeks) in adult rats. Chronic, but not acute, antidepressant treatments increase FGF2 immunoreactivity in neurons of the cerebral cortex and in both astrocytes and neurons of the hippocampus. FGF2 immunoreactivity in the cortex was increased mainly in the cytoplasm of neurons of layer V. Western blot analyses of nuclear and cytosolic extracts from the cortex revealed that both antidepressants increase FGF2 isoforms in the cytosolic extracts and decrease accumulation of FGF2 immunoreactivity in the nucleus. To characterize the anatomical and cellular specificity of antidepressants, we examined FGF-binding protein (FBP), a secreted protein that acts as an extracellular chaperone for FGF2 and enhances its activity. DMI and FLU increased FBP immunoreactivity in both cortical and hippocampal neurons. Our data suggest that FGF2 and FBP may participate in the plastic responses underlying the clinical efficacy of antidepressants.

Chronic unpredictable stress promotes neuronal apoptosis in the cerebral cortex.

Stress-mediated loss of synaptogenesis in the hippocampus appears to play a role in depressive and mood disorders. However, little is known about the effect of stress/depression on the plasticity and survival of cortical neurons. In this report, we have examined whether chronic stress increases the vulnerability of neurons in the rat cortex. We have used a chronic unpredictable mild stress (CMS) as a rat model of depression. CMS (5 weeks treatment) produced anedonia and increased corticosterone levels. These effects were accompanied by a detectable increase in caspase-3 positive neurons in the cerebral cortex, suggesting apoptosis. Desipramine (DMI), a well known antidepressant, reversed the pro-apoptotic effect of CMS. These results suggest that antidepressants may reduce the pathological changes seen in stress-induced depressive disorders.

Chemokine receptors and neurotrophic factors: potential therapy against aids dementia?

Chemokine receptors, in particular, CXCR4 and CCR5, mediate human immunodeficiency virus type 1 (HIV-1) infection of immunocompetent cells and the apoptosis of these cells. However, the virus does not infect neurons. Yet through a variety of mechanisms, HIV promotes glial cell activation, synaptodendritic alterations, and neuronal loss that ultimately lead to motor and cognitive impairment. Chemokines and chemokine receptors are abundant in the adult central nervous system and play a role in neuronal apoptosis evoked by HIV proteins. Thus, reducing the availability of chemokine receptors may prevent the neuronal degeneration seen in HIV-positive patients. In this article, we present and discuss a recent experimental approach aimed at testing effective neuroprotective therapies against HIV-mediated neuronal degeneration.

Brain-derived neurotrophic factor expression in the substantia nigra does not change after lesions of dopaminergic neurons.

Progressive and irreversible loss of specific neuronal cell populations is commonly seen in chronic neurodegenerative diseases such as Parkinson's disease (PD). Evidence is accumulating that apoptosis is a crucial cellular event responsible for the dysfunction and death of neurons in this disease. Thus, limiting apoptosis may prevent disease pathogenesis. Key to reducing apoptosis is the discovery of neuroprotective compounds that can be given to patients to minimize neuronal damage. In this manuscript, we reviewed the rationale of using an experimental strategy to provide neurotrophic support to injured neurons. Such rationale includes the increase of endogenous production of brain-derived neurotrophic factor (BDNF). BDNF is a potent inhibitor of apoptosis-mediated cell death and neurotoxin-induced degeneration of dopaminergic neurons. However, availability of BDNF may be reduced when dopaminergic neurons degenerate. Therefore, in this work, we have used several well-established neurotoxins for dopaminergic neurons, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 6-OH-dopamine (6-OHDA), and the HIV protein gp120, to examine whether degeneration of nigrostriatal fibers alters BDNF expression. Our data show that these neurotoxins do not decrease the levels of BDNF in the substantia nigra, suggesting that up-regulation of BDNF synthesis by pharmacological means may be a viable therapy to slow down the progress of PD and other neurodegenerative diseases.

Intrastriatal administration of human immunodeficiency virus-1 glycoprotein 120 reduces glial cell-line derived neurotrophic factor levels and causes apoptosis in the substantia nigra.

Uninfected neurons of the substantia nigra (SN) degenerate in human immunodeficiency virus (HIV)-positive patients through an unknown etiology. The HIV envelope glycoprotein 120 (gp120) causes apoptotic neuronal cell death in the rodent striatum, but its primary neurotoxic mechanism is still under investigation. Previous studies have shown that gp120 causes neurotoxicity in the rat striatum by reducing brain-derived neurotrophic factor (BDNF). Because glial cell line-derived neurotrophic factor (GDNF) and BDNF are neurotrophic factors crucial for the survival of dopaminergic neurons of the SN, we investigated whether gp120 reduces GDNF and BDNF levels concomitantly to induce apoptosis. Rats received a microinjection of gp120 or vehicle into the striatum and were sacrificed at various time intervals. GDNF but not BDNF immunoreactivity was decreased in the SN by 4 days in gp120-treated rats. In these animals, a significant increase in the number of caspase-3- positive neurons, both tyrosine hydroxylase (TH)-positive and -negative, was observed. Analysis of TH immunoreactivity revealed fewer TH-positive neurons and fibers in a medial and lateral portion of cell group A9 of the SN, an area that projects to the striatum, suggesting that gp120 induces retrograde degeneration of nigrostriatal neurons. We propose that dysfunction of the nigrostriatal dopaminergic system associated with HIV may be caused by a reduction of neurotrophic factor expression by gp120.

Axonal transport of human immunodeficiency virus type 1 envelope protein glycoprotein 120 is found in association with neuronal apoptosis.

Patients infected by human immunodeficiency virus type 1 (HIV-1) develop acquired immune deficiency syndrome-associated dementia complex (ADC), a disorder characterized by a broad spectrum of motor impairments and cognitive deficits. The number of cells in the brain that are productively infected by HIV-1 is relatively small and consists predominantly of macrophages and microglia, yet HIV-1 causes widespread neuronal loss. A better understanding of the pathogenic mechanisms mediating HIV-1 neurotoxicity is crucial for developing effective neuroprotective therapies against ADC. The HIV-1 envelope glycoprotein 120 (gp120), which is shed from the virus, is one of the agents causing neuronal cell death. However, the cellular mechanisms underlying its neurotoxic effect remain unclear. We report that gp120 injected into the rat striatum or hippocampus is sequestered by neurons and subsequently retrogradely transported to distal neurons that project to these brain areas. Cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, hallmarks of apoptosis, were seen in neurons internalizing and transporting gp120. The retrograde transport of gp120 and apoptosis were mediated by the chemokine receptor CXCR4 because AMD3100, a selective CXCR4 inhibitor, blocked both events. Furthermore, colchicine or nocodazole, two inhibitors of intracellular trafficking, abolished gp120-mediated apoptosis in distal areas. These results indicate that axonal transport of gp120 might play a role in HIV-1-mediated widespread neuronal cell death.

Semisynthetic sphingoglycolipid LIGA20 is neuroprotective against human immunodeficiency virus-gp120-mediated apoptosis.

Apoptosis and neuronal atrophy are commonly seen in patients infected with the human immunodeficiency virus type 1 (HIV-1) in the late phase of infection. The HIV-1 envelope glycoprotein gp120 has been suggested to be a causal agent of neuronal loss. Therefore, blocking gp120 neurotoxicity may be an effective way to reduce the neuronal degeneration seen in HIV patients. Brain-derived neurotrophic factor (BDNF) prevents gp120-mediated apoptosis in cerebellar granule cells. However, BDNF poorly crosses the blood-brain barrier and therefore may not be a suitable therapy for HIV patients. LIGA20 is a semisynthetic sphingoglycolipid that may be a valid alternative to BDNF. In fact, it has been shown that LIGA20 mimics the neuroprotective properties of BDNF. The present study was undertaken to characterize the relative potency of LIGA20 to antagonize gp120-mediated apoptosis. Cerebellar granule cells were exposed to gp120IIIB (5 nM) or stromal-cell derived factor-1 (SDF), the natural ligand for the CXCR4 receptor to which gp120 binds, alone or in combination with LIGA20 (5 microM), and cell death/survival was determined 12 and 24 hr later by various markers of apoptosis. LIGA20 blocked the neurotoxic effect of gp120 and SDF. The neurotrophic effect of LIGA20 was reversed by K252a, a tyrosine kinase inhibitor used to block TrkB signaling, suggesting the involvement of TrkB activation. These findings provide the rationale for exploring the ability of compounds that mimic BDNF activity to reduce neuronal cell death in HIV-1-positive patients.

The nitrosteroid NCX 1015, a prednisolone derivative, improves recovery of function in rats after spinal cord injury.

Glucocorticoids, given at high-doses, improve recovery of function after spinal cord injury (SCI) in animals. However, side effects combined with a limited efficacy in clinical trials have restricted their usefulness for treatment of SCI patients. Recent studies have shown that incorporation of the nitric oxide releasing moiety into the glucocorticoid structure enhances anti-inflammatory properties and reduces side effects. One compound, a derivative of prednisolone (PRE), (NCX 1015, prednisolone 21 [(4'nitrooxymethyl)benzoate]), has interesting pharmacological properties. Therefore, we investigated its effects on apoptosis and recovery of function in rats after SCI. Rats received subcutaneously vehicle, NCX 1015 or PRE (37 micromol/kg, each) 3.5 h after a standardized thoracic lesion. The treatment was continued once a day for 3 days and the effect of both steroids on apoptosis was examined by immunohistochemistry 24 h after the last injection. NCX 1015 but not PRE reduced TUNEL and activated caspase 3 in both white and ventral gray matter as well as tumor necrosis factor immunoreactivity in ventral horn motorneurons, suggesting that NCX 1015 reduces SCI-induced apoptosis. The effect of NCX 1015 on motor function was then examined by a standard locomotion rating scale (BBB) starting at 1 day after injury and continuing up to 14 days. NCX 1015 improved significantly locomotor activity by 4 days after injury, whereas PRE had an effect equivalent to that of vehicle, thus providing a correlation between the antiapoptotic effect of NCX1015 and its ability to improve recovery of function. The data suggest that NCX 1015 might be a novel experimental therapeutic compound for recovery of function in SCI patients.

Brain-derived neurotrophic factor is neuroprotective against human immunodeficiency virus-1 envelope proteins.

Human immunodeficiency virus type 1 (HIV-1)-positive patients in the late phase of infection develop AIDS dementia complex, an array of neurological complications that include extrapyramidal symptoms, cognitive impairments, and psychiatric disturbances. Brains of these patients exhibit brain injury. The HIV-1 envelope glycoprotein 120 (gp120) has been suggested to be a causal agent of neuronal loss; however, several strains of gp120 exist during the infection and the relative neurotoxic potential of each strain is presently unknown. Using cultured cerebellar granule neurons, we determined whether two strains of gp120, gp120IIIB and gp120BaL, which bind to CXCR4 and CCR5 chemokine receptors, respectively, induce cell death. Apoptotic cell death and activated caspase-3 were evident within a few hours in neurons exposed to low nanomolar concentrations of either gp120IIIB or gp120BaL. However, the neurotoxic effect of gp120IIIB was more rapid and occurred at lower concentrations than that of gp120BaL, suggesting that cerebellar granule cells may be more sensitive to apoptotic signals activated by the CXCR4 receptor. The neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to block neuronal apoptosis. Therefore, we examined whether BDNF protects against both strains of gp120. Preexposure of cerebellar granule cells to BDNF prior to both gp120s decreased apoptosis and consequently enhanced their survival. These findings underlie the rationale for exploring the ability of BDNF to reduce HIV-1-mediated neuronal cell death in vivo.