Tat, a human immunodeficiency virus-1-derived protein, augments excitotoxic hippocampal injury in neonatal rats.
To test the hypothesis that the human immunodeficiency virus-1-derived Tat protein may cause neuronal damage in the CNS, we evaluated the neurotoxicity of recombinant human immunodeficiency virus-1-derived Tat in vivo in seven-day-old rats. The intrinsic neurotoxicity of Tat (250 ng-1 microg) and the effects of direct intra-hippocampal co-infusion of Tat with N-methyl-D-aspartate were assessed. Extent of injury in the lesioned hippocampus was evaluated five days later, based on histopathology and morphometric measurements of hippocampal volume. To confirm that any observed neurotoxic effects were attributable to Tat bioactivity, all experiments included controls that received equal amounts of heat-treated (boiled) Tat. Intra-hippocampal injection of Tat, alone, elicited minimal focal tissue damage immediately adjacent to the injection track, and no hippocampal atrophy. Co-injection of Tat (500 ng) with N-methyl-D-aspartate (5 nmol, threshold excitotoxic dose) doubled the severity of hippocampal injury, quantified by comparison of bilateral hippocampal volumes, in comparison with animals that received heat-treated Tat or saline co-injections; in animals that received injections of N-methyl-D-aspartate (5 nmol) in combination with saline, heat-treated Tat, or Tat [mean(+/-S.E.M.) % volume loss values in the lesioned hippocampus were: 11(+/-3), 11(+/-3), and 26(+/-3), respectively (P<0.002, ANOVA)]. Co-injection of 100 ng Tat with 5 nmol N-methyl-D-aspartate exacerbated the severity of excitotoxic injury to a similar extent, whereas co-injection of 20 ng Tat had no effect on N-methyl-D-aspartate-mediated injury. Treatment with the N-methyl-D-aspartate antagonist 3-((RS)-2-carboxypiperazin4-yl)-propyl-1-phosphonic acid (20 mg/kg) markedly attenuated hippocampal injury resulting from co-injection of 100 ng Tat with N-methyl-D-aspartate [mean(+/-S.E.M.) % volume loss in lesioned hippocampus: 0.1(+/-2) in 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid-treated vs 19(+/-3) in controls, P<0.001, ANOVA]. Co-injection of Tat had no effect on N-methyl-D-aspartate-mediated striatal damage or on alpha-amino-3-hydroxy-5-methylisoxazole-4-pro hippocampal damage. These data support the hypothesis that locally released Tat could exert neurotoxic effects, mediated by N-methyl-D-aspartate receptor activation, in vivo in the immature brain.
Wang
P
P
Department of Pediatrics, University of Michigan, Ann Arbor 48109-0646, USA.
Barks
J D
JD
Silverstein
F S
FS
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D015696:Gene Products, tat / Q000633:toxicity*; D015658:HIV Infections / Q000503:physiopathology*; D015497:HIV-1 / Q000737:chemistry*; D006624:Hippocampus / Q000166:cytology*; D020287:In Situ Nick-End Labeling; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D015696:Gene Products, tat; D009498:Neurotoxins; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D054322:tat Gene Products, Human Immunodeficiency Virus; D016202:N-Methylaspartate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid