       Document 0625
 DOCN  M9640625
 TI    Neurotoxic mechanisms of transactivating protein Tat of Maedi-Visna
       virus.
 DT    9604
 AU    Strijbos PJ; Zamani MR; Rothwell NJ; Arbuthnott G; Harkiss G; Department
       of Molecular Pharmacology, Wellcome Research; Laboratories, Beckenham,
       Kent, UK.
 SO    Neurosci Lett. 1995 Sep 15;197(3):215-8. Unique Identifier : AIDSLINE
       MED/96117198
 AB    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.
 DE    Animal  Calcium/METABOLISM  Cell Death  Cells, Cultured  Corpus
       Striatum/CYTOLOGY  Dose-Response Relationship, Drug  Gene Products,
       tat/*PHARMACOLOGY  Immunohistochemistry  Nerve Degeneration
       Neurons/DRUG EFFECTS/METABOLISM  Neurotoxins/*PHARMACOLOGY  Rats  Rats,
       Sprague-Dawley  Support, Non-U.S. Gov't  Time Factors  *Visna-Maedi
       Virus  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

