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      Neurotoxic mechanisms of transactivating protein Tat of Maedi-Visna virus

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      Neuroscience Letters

      Elsevier BV

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          Abstract

          Infection by lentiviruses such as human immunodeficiency virus (HIV) and Maedi-Visna virus (MVV) is associated with neurodegenerative disorders. We have investigated the neurotoxic mechanisms of a synthetic peptide of transactivating protein tat of MVV in striatal neuronal cultures. Tat peptide (but not control peptide) caused neuronal death, without affecting glial viability, in a time- and dose-dependent manner. Significant neuronal death was not observed until 6-8 h after tat peptide application (2.35-2350 nM), whereas half maximal and maximal cell death was observed after 12 and 24 h respectively. Tat peptide neurotoxicity could be partially inhibited by blockade of either N-methyl-D-aspartate (NMDA)- or non-NMDA receptors, suggesting that excessive neuroexcitation by glutamate or its analogues may contribute to tat-neurotoxicity. Furthermore, when both these glutamate receptor subtypes were blocked simultaneously, an increased degree of neuroprotection was observed. Finally, tat peptide toxicity was also reduced by blockade of L-type calcium channels. Calcium imaging revealed that intracellular calcium increases slowly upon tat application, predominantly due to entry of extracellular calcium. These results indicate that cellular calcium entry through voltage-gated calcium channels following activation of both NMDA and non-NMDA receptors, and subsequent accumulation of intracellular calcium may contribute to the neuronal death induced by tat protein.

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          Author and article information

          Journal
          Neuroscience Letters
          Neuroscience Letters
          Elsevier BV
          03043940
          September 1995
          September 1995
          : 197
          : 3
          : 215-218
          Article
          10.1016/0304-3940(95)11940-X
          8552302
          © 1995

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