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Rabies virus infection of primary neuronal cultures and adult mice: failure to demonstrate evidence of excitotoxicity.

ABSTRACT: Cultures derived from the cerebral cortices and hippocampi of 17-day-old mouse fetuses infected with the CVS strain of rabies virus showed loss of trypan blue exclusion, morphological apoptotic features, and activated caspase 3 expression, indicating apoptosis. The NMDA (N-methyl-D-aspartate acid) antagonists ketamine (125 microM) and MK-801 (60 microM) were found to have no significant neuroprotective effect on CVS-infected neurons, while the caspase inhibitor Ac-Asp-Glu-Val aspartic acid aldehyde (25 microM) exerted a marked neuroprotective effect. Glutamate-stimulated increases in levels of intracellular calcium were reduced in CVS-infected hippocampal neurons. Ketamine (120 mg/kg of body weight/day intraperitoneally) given to CVS-infected adult mice produced no beneficial effects. We have found no supportive evidence that excitotoxicity plays an important role in rabies virus infection.

SUBMITTER: Weli SC

PROVIDER: S-EPMC1617316 | biostudies-literature | 2006 Oct

REPOSITORIES: biostudies-literature

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Rabies virus infection of primary neuronal cultures and adult mice: failure to demonstrate evidence of excitotoxicity.

Weli Simon C SC Scott Courtney A CA Ward Christopher A CA Jackson Alan C AC

Journal of virology 20061001 20

Cultures derived from the cerebral cortices and hippocampi of 17-day-old mouse fetuses infected with the CVS strain of rabies virus showed loss of trypan blue exclusion, morphological apoptotic features, and activated caspase 3 expression, indicating apoptosis. The NMDA (N-methyl-D-aspartate acid) antagonists ketamine (125 microM) and MK-801 (60 microM) were found to have no significant neuroprotective effect on CVS-infected neurons, while the caspase inhibitor Ac-Asp-Glu-Val aspartic acid aldeh ...[more]

PMID: 17005706

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Project description:Poly-arginine peptide-18 (R18) has recently emerged as a highly effective neuroprotective agent in experimental stroke models, and is particularly efficacious in protecting cortical neurons against glutamic acid excitotoxicity. While we have previously demonstrated that R18 can reduce excitotoxicity-induced neuronal calcium influx, other molecular events associated with R18 neuroprotection are yet to investigated. Therefore, in this study we were particularly interested in protein expression changes in R18 treated neurons subjected to excitotoxicity. Proteomic analysis was used to compare protein expression patterns in primary cortical neuronal cultures subjected to: (i) R18-treatment alone (R18); (ii) glutamic acid excitotoxic injury (Glut); (iii) R18-treatment and glutamic acid injury (R18?+?Glut); (iv) no treatment (Cont). Whole cell lysates were harvested 24?h post-injury and subjected to quantitative proteomic analysis (iTRAQ), coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and subsequent bioinformatic analysis of differentially expressed proteins (DEPs). Relative to control cultures, R18, Glut, and R18?+?Glut treatment resulted in the detection of 5, 95 and 14 DEPs respectively. Compared to Glut alone, R18?+?Glut revealed 98 DEPs, including 73 proteins whose expression was also altered by treatment with Glut and/or R18 alone, as well as 25 other uniquely regulated proteins. R18 treatment reversed the up- or down-regulation of all 73 Glut-associated DEPs, which included proteins involved in mitochondrial integrity, ATP generation, mRNA processing and protein translation. Analysis of protein-protein interactions of the 73 DEPs showed they were primarily associated with mitochondrial respiration, proteasome activity and protein synthesis, transmembrane trafficking, axonal growth and neuronal differentiation, and carbohydrate metabolism. Identified protein pathways associated with proteostasis and energy metabolism, and with pathways involved in neurodegeneration. Collectively, the findings indicate that R18 neuroprotection following excitotoxicity is associated with preservation of neuronal protein profiles, and differential protein expression that assists in maintaining mitochondrial function and energy production, protein homeostasis, and membrane trafficking.

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Rabies virus infection of primary neuronal cultures and adult mice: failure to demonstrate evidence of excitotoxicity.

Publications

Rabies virus infection of primary neuronal cultures and adult mice: failure to demonstrate evidence of excitotoxicity.

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