Ž . Brain Research 830 1999 285–291 Research report Acute in vivo neurotoxicity of peptides from Maedi Visna virus transactivating protein Tat Isabella Starling a , Ann Wright b , Gordon Arbuthnott b, ) , Gordon Harkiss c a DiÕision of Biomolecular Sciences, GKT Medical School, King’s College London, Guy’s Campus, St. Thomas Street, London SE1 9RT, UK b ( ) Department of Preclinical Veterinary Sciences, R D SVS, UniÕersity of Edinburgh, Summerhall, Edinburgh EH9 1QH, UK c ( ) Department of Veterinary Pathology, R D SVS, UniÕersity of Edinburgh, Summerhall, Edinburgh EH9 1QH, UK Accepted 16 March 1999 Abstract Ž . Ž . Lentiviruses such as Maedi Visna virus MVV in sheep, and human immunodeficiency virus HIV in man often cause a variety of neurological syndromes in later stages of infection. Neuropathological investigations reveal damage to myelin and astrocytosis in both white and grey matter. MVV infection induces axonal damage with some areas of necrosis while neuronal loss, and synaptic damage have been reported in HIV-1 infection. It is not clear, at present, how this neurodegeneration is mediated but, as these viruses do not directly infect neurons, an indirect neurotoxic action of the viruses is indicated. Previous experiments have shown that the intra-striatal injection in rats of a synthetic peptide derived from the basic region of the MVV transactivating protein Tat causes considerable neurotoxicity 1 week post-operatively. By in vivo stereotaxic injections of the same synthetic peptide, and subsequent immunocytochemical detection of neurons, astrocytes and microglia, we show that this neurotoxicity displays a distinctive and unusual lesion profile and is evident as rapidly as 0.5 h post-operatively. Furthermore, neuroprotection studies suggest that the early effects of the MVV tat peptide may involve Ž . Ž . glutamate neurotoxicity via the N-methyl-D-aspartate NMDA receptors since the application of dizolcipine MK801 reduces the volume of the lesion seen at 1 h after the injection of neurotoxic peptide, while L-NAME is ineffective. The mechanism of this early neurotoxicity is thus different from the longer term actions already described. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Neurotoxicity; Lentivirus; Maedi Visna virus; Human immunodeficiency virus; Tat peptides; Rat 1. Introduction Ž . Lentiviral infection of the central nervous system CNS causes damage of astrocytes, microglia and neurons. In Ž . Maedi Visna virus MVV , post-mortem examination of the brains of affected sheep also reveals areas of liquefac- tive necrosis involving both neurones and glia in foci of w x Ž . infection 12 . In human immunodeficiency virus HIV -1 infection, neuronal loss is commonly observed in several w x areas including cortical regions and the basal ganglia 7,8 . Astrocytosis and some myelin damage are also characteris- w x tic features of both infections 2,11 , although multinucle- wx ated giant cells are a hallmark of HIV infection 6 . Neither MVV nor HIV infect neurons, but HIV and MVV viral antigens have been co-localised with microglia, astrocytes w x and, occasionally oligodendrocytes 16,28,31 . Lentiviral ) Corresponding author. Fax: q44-131-650-6177; E-mail: g.arbuthnott@ed.ac.uk invasion of the CNS is believed to occur through the migration of infected macrophages across the blood brain w x barrier 23 , although HIV may also penetrate the CNS via cell-free entry. Little cell free virus is usually present in lentiviral CNS infection. The neurotoxic capabilities of lentiviruses have therefore been attributed to indirect mechanisms. Several lentiviral proteins have been proposed as neuro- toxic candidates. The HIV envelope glycoprotein gp120 has been shown to be neurotoxic both in vivo and in vitro. In vitro, the neurotoxic mechanism of gp120 has been attributed to glutamate toxicity occurring at the N-methyl- Ž . w x D-aspartate NMDA receptor 18 , aberrant calcium influx w x wx 17 or apoptotic mechanisms 1 . In vivo, gp120 causes w x neuronal damage 15 , and transgenic mice overexpressing w x gp120 develop severe neurologic abnormalities 30 . The transactivating protein Tat of HIV and MVV is necessary for efficient lentiviral replication, although it wx only functions as a weak transactivator of MVV 3. Lentiviral Tat contains amino acid sequences related to 0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. Ž . PII: S0006-8993 99 01407-9