Acute in vivo neurotoxicity of peptides from Maedi Visna virus transactivating protein Tat.
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 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.
Starling
I
I
Division of Biomolecular Sciences, GKT Medical School, King's College London, Guy's Campus, St. Thomas Street, London SE1 9RT, UK.
Wright
A
A
Arbuthnott
G
G
Harkiss
G
G
D000595:Amino Acid Sequence; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D008297:Male; D008969:Molecular Sequence Data; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity*; D009569:Nitric Oxide / Q000096:biosynthesis; D010455:Peptides / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013997:Time Factors; D015534:Trans-Activators / Q000633:toxicity*; D014764:Viral Proteins / Q000633:toxicity*; D014790:Visna-maedi virus
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D015534:Trans-Activators; D014764:Viral Proteins; D009569:Nitric Oxide