Endocrine modulation of the neurotoxicity of gp120: Implications for AIDS-related dementia complex

Brooke, Sheila M.; Chan, Roger S.; Howard, Sarah A.; Sapolsky, Robert M.

doi:10.1073/pnas.94.17.9457

Cited by 78 publications

(53 citation statements)

References 52 publications

(45 reference statements)

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“…Tissue culture methods were described previously (Brooke et al 1997) Briefly, hippocampus from 18-day-old fetal rats were removed, dissociated with papain, filtered through an 80-lm cell strainer, and resuspended in a modified minimum essential medium (MEM; UCSF Tissue Culture Facility, San Francisco, CA, USA) containing 25 mM glucose and 10% horse serum (Hyclone, Logan, UT, USA). Cells were plated at a density of 30 000/cm 2 on poly-Dlysine-treated 96-well plates for the toxicity and superoxide studies, on 24-well plates for the lipid peroxidation studies, and on 48-well plates for the anoxia and anoxia/aglycemia studies.…”

Section: Hippocampal Cell Culturesmentioning

confidence: 99%

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Neuroprotective effects of bcl‐2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage

Howard

Bottino

Brooke

et al. 2002

Journal of Neurochemistry

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Overexpression of bcl-2 protects neurons from numerous necrotic insults, both in vitro and in vivo. While the bulk of such protection is thought to arise from Bcl-2 blocking cytochrome c release from mitochondria, thereby blocking apoptosis, the protein can target other steps in apoptosis, and can protect against necrotic cell death as well. There is evidence that these additional actions may be antioxidant in nature, in that Bcl-2 has been reported to protect against generators of reactive oxygen species (ROS), to increase antioxidant defenses and to decrease levels of ROS and of oxidative damage. Despite this, there are also reports arguing against either the occurrence, or the importance of these antioxidant actions. We have examined these issues in neuron-enriched primary hippocampal cultures, with overexpression of bcl-2 driven by a herpes simplex virus amplicon: (i) Bcl-2 protected strongly against glutamate, whose toxicity is at least partially ROS-dependent. Such protection involved reduction in mitochondrially derived superoxide. Despite that, Bcl-2 had no effect on levels of lipid peroxidation, which is thought to be the primary locus of glutamate-induced oxidative damage; (ii) Bcl-2 was also mildly protective against the pro-oxidant adriamycin. However, it did so without reducing levels of superoxide, hydrogen peroxide or lipid peroxidation; (iii) Bcl-2 protected against permanent anoxia, an insult likely to involve little to no ROS generation. These findings suggest that Bcl-2 can have antioxidant actions that may nonetheless not be central to its protective effects, can protect against an ROS generator without targeting steps specific to oxidative biochemistry, and can protect in the absence of ROS generation. Thus, the antioxidant actions of Bcl-2 are neither necessary nor sufficient to explain its protective actions against these insults in hippocampal neurons.

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Section: Hippocampal Cell Culturesmentioning

confidence: 99%

“…After 24 h, cells were fixed with cold methanol and analyzed according to a published method (Brooke et al 1997). Briefly, cells were blocked with 5% milk in phosphate-buffered saline (PBS), followed by immunocytochemistry with a neuron specific primary antibody against MAP-2 (Sigma) at a dilution of 1 : 1000 in 5% milk in PBS.…”

Section: Solutionsmentioning

confidence: 99%

Neuroprotective effects of bcl‐2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage

Howard

Bottino

Brooke

et al. 2002

Journal of Neurochemistry

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“…These include aspirin and indomethacin, which block cyclooxygenases; paradoxically, glucocorticoids, although inhibitory for cyclooxygenase 2 activity, may increase the pathological effect of HIV-1 neurotoxins by prolonging the survival of HIV-1-infected macrophages [57][58][59]. No clinically available therapies exist that would specifically target pathologically increased arachidonic acid generation via phospholipase A 2 in the CNS.…”

Section: Therapeutic Strategies For Hiv-1 Infection In the Developingmentioning

confidence: 99%

HIV-1-induced neuronal injury in the developing brain

Epstein

Gelbard

1999

Journal of Leukocyte Biology

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HIV-1 infection of the nervous system causes neuronal injury and death, resulting in cognitive, motor, and behavioral dysfunction in both adults and children. In infants a characteristic feature of HIV-1 infection is impaired brain growth resulting in secondary microcephaly with onset between 2 and 4 months of age. This post-natal period of brain development is particularly vulnerable to excitotoxic neuronal injury due to the active synaptogenesis and pruning that takes place at this age associated with over-expression of excitatory amino acid (EAA) receptors. HIV-1 infection of brain microglia and perivascular macrophages results in chronic inflammation manifest pathologically as diffuse microglial activation and reactive astrogliosis. Several inflammatory products of activated microglia, including tumor necrosis factor ␣ (TNF-␣) and platelet-activating factor (PAF) have been shown to act as neuronal toxins. This toxic effect can be antagonized by blocking NMDA (or AMPA) glutamate receptors, suggesting that (weak) excitotoxicity leads to oxidative stress, neuronal injury, and apoptosis. HIV-1 infection and chronic inflammation may also contribute disruption of the blood-brain barrier and could result in further entry into the CNS of toxic viral or cellular products or additional HIV-1-infected cells. We hypothesize that prolonged microglial activation during HIV-1 infection underlies the neuronal injury and impaired brain growth in affected infants. Further investigation of the interaction between HIV-1-infected/activated microglia and developing neurons seems warranted. The current understanding of HIV neuropathogenesis implies that therapeutic strategies should target the sustained immune activation in microglia, attempt to repair the integrity of the blood-brain barrier, and provide ''neuroprotection'' from excitotoxic neuronal injury. J. Leukoc. Biol. 65: 453-457; 1999.

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“…The HIV envelope glycoprotein, gp120, has been associated with the neurotoxicity seen in this dementia through an as-yet-undetermined mechanism that is thought to include activation of NMDA receptors, an increase in cytosolic calcium levels, and an immune response (Lipton, 1994;Barks et al, 1995;Dubois-Dalcq et al, 1995). We have previously shown that corticosterone (CORT) exacerbates gpl2O neurotoxicity and gpl2O-induced increases in cytosolic calcium in hippocampal mixed cultures (Brooke et al, 1997). CORT, the primary rodent glucocorticoid (GC), is secreted in response to stress and at physiological concentrations impairs the capacity of hippocampal and cortical neurons to survive a variety of neurological insults including seizure, ischemia, hypoglycemia, exposure to antimetabolite toxins, and excitatory amino acids (EAAs) (for review, see Sapolsky, 1996;Reagan and McEwen, 1997).…”

mentioning

confidence: 99%

Energy Dependency of Glucocorticoid Exacerbation of gp120 Neurotoxicity

Brooke

Howard

Sapolsky

1998

Journal of Neurochemistry

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Abstract:The HIV envelope glycoprotein, gpl 20, a well documented neurotoxin, may be involved in AIDS-related dementia complex. gpl2O works through an NMDA receptor-and calcium-dependent mechanism to damage neurons. We have previously demonstrated that both natural and synthetic glucocorticoids (GCs) exacerbate gpl 20-induced neurotoxicity and calcium mobilization in hippocampal mixed cultures. GCs, steroid hormones secreted during stress, are now shown to work in conjunction with gpl 20 to decrease ATP levels and to work synergistically with gpl2O to decrease the mitochondrial potential in hippocampal cultures. Furthermore, energy supplementation blocked the ability of GCs to worsen gpl2O's effects on neuronal survival and calcium mobilization. A GC-induced reduction in glucose transport in hippocampal neurons, as previously documented, may contribute to this energetic dependency. These results may have clinical significance, considering the common treatment of severe cases of Pneumocystis carinii pneumonia, typical of HIV infection, with large doses of synthetic GCs. Key Words: Glucocorticoids-Stress-AIDS-related dementia-Neurotoxicity-Calcium-Hippocampus-gpl 20.

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Endocrine modulation of the neurotoxicity of gp120: Implications for AIDS-related dementia complex

Cited by 78 publications

References 52 publications

Neuroprotective effects of bcl‐2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage

Neuroprotective effects of bcl‐2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage

HIV-1-induced neuronal injury in the developing brain

Energy Dependency of Glucocorticoid Exacerbation of gp120 Neurotoxicity

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