| pubmed-article:21483469 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C0019682 | lld:lifeskim |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C0019699 | lld:lifeskim |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C0019704 | lld:lifeskim |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C0086418 | lld:lifeskim |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C0026549 | lld:lifeskim |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C0027882 | lld:lifeskim |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C1328247 | lld:lifeskim |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C0018284 | lld:lifeskim |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C0599946 | lld:lifeskim |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C0205263 | lld:lifeskim |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C0868928 | lld:lifeskim |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C1883709 | lld:lifeskim |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C0961954 | lld:lifeskim |
| pubmed-article:21483469 | lifeskim:mentions | umls-concept:C1100939 | lld:lifeskim |
| pubmed-article:21483469 | pubmed:issue | 3 | lld:pubmed |
| pubmed-article:21483469 | pubmed:dateCreated | 2011-4-12 | lld:pubmed |
| pubmed-article:21483469 | pubmed:abstractText | The neuropathological abnormalities of human immunodeficiency virus (HIV)-1 patients abusing illicit drugs suggest extensive interactions between the two agents, thereby leading to increased rate of progression to neurodegeneration. The role of HIV-1 transactivating protein, Tat has been elucidated in mediating neuronal damage via apoptosis, a hallmark of HIV-associated dementia (HAD), however the underlying mechanisms involved in enhanced neurodegeneration by illicit drugs remain elusive. In this study, we demonstrated that morphine enhances HIV-Tat induced toxicity in human neurons and neuroblastoma cells. Enhanced toxicity by Tat and morphine was accompanied by increased numbers of TUNEL positive apoptotic neurons, elevated caspase-3 levels and decreased ratio of anti- and pro-apoptotic proteins, Bcl2/Bax. Tat and morphine together elicited high levels of reactive oxygen species that were NADPH dependent. Significant alterations in mitochondrial membrane homeostasis were also observed with co-exposure of these agents. Extensive studies of mitogen activated protein kinase (MAPK) signaling pathways revealed the involvement of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase-1/2 (ERK1/2) pathways in enhanced toxicity of Tat and morphine. In addition to this, we found that pre-treatment of cells with platelet derived growth factor (PDGF-BB) protected neurons from HIV-Tat and morphine induced damage. PDGF-BB alleviated ROS production, maintained mitochondrial membrane potential, decreased caspase-3 activation and hence protected the cells from undergoing apoptosis. PDGF-BB mediated protection against Tat and morphine involved the phosphatidylinositol-3 kinase (PI3K) pathway, as specific inhibitor of PI3K abrogated the protection conferred by PDGF-BB. This study demonstrates the mechanism of enhanced toxicity in human neurons subjected to co-exposure of HIV protein Tat and morphine, thus implying its importance in HIV positive drug abusers, where damage to the brain is reported to be more severe than non-drug abusers. We have also showed for the first time that PDGF-BB can protect against simultaneous exposure of Tat and morphine, strengthening its role as a neuroprotective agent that could be considered for therapeutic intervention. | lld:pubmed |
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| pubmed-article:21483469 | pubmed:language | eng | lld:pubmed |
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| pubmed-article:21483469 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:21483469 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
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| pubmed-article:21483469 | pubmed:status | MEDLINE | lld:pubmed |
