PMID- 10197777
OWN - NLM
STAT- MEDLINE
DCOM- 19990601
LR  - 20190712
IS  - 0306-4522 (Print)
IS  - 0306-4522 (Linking)
VI  - 88
IP  - 2
DP  - 1999 Jan
TI  - Tat, a human immunodeficiency virus-1-derived protein, augments excitotoxic
      hippocampal injury in neonatal rats.
PG  - 585-97
AB  - 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.
FAU - Wang, P
AU  - Wang P
AD  - Department of Pediatrics, University of Michigan, Ann Arbor 48109-0646, USA.
FAU - Barks, J D
AU  - Barks JD
FAU - Silverstein, F S
AU  - Silverstein FS
LA  - eng
GR  - NS 31054/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (Excitatory Amino Acid Agonists)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (Gene Products, tat)
RN  - 0 (Neurotoxins)
RN  - 0 (Piperazines)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (tat Gene Products, Human Immunodeficiency Virus)
RN  - 6384-92-5 (N-Methylaspartate)
RN  - 98Y1I8ZD4M (3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid)
SB  - IM
SB  - X
MH  - Animals
MH  - Animals, Newborn
MH  - Apoptosis/drug effects
MH  - Excitatory Amino Acid Agonists/pharmacology
MH  - Excitatory Amino Acid Antagonists/pharmacology
MH  - Female
MH  - Gene Products, tat/*toxicity
MH  - HIV Infections/*physiopathology
MH  - HIV-1/*chemistry
MH  - Hippocampus/*cytology
MH  - In Situ Nick-End Labeling
MH  - Male
MH  - N-Methylaspartate/pharmacology
MH  - Neurons/chemistry/*drug effects
MH  - Neurotoxins/pharmacology
MH  - Piperazines/pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, N-Methyl-D-Aspartate/physiology
MH  - tat Gene Products, Human Immunodeficiency Virus
EDAT- 1999/04/10 00:00
MHDA- 1999/04/10 00:01
CRDT- 1999/04/10 00:00
PHST- 1999/04/10 00:00 [pubmed]
PHST- 1999/04/10 00:01 [medline]
PHST- 1999/04/10 00:00 [entrez]
AID - S0306452298002425 [pii]
AID - 10.1016/s0306-4522(98)00242-5 [doi]
PST - ppublish
SO  - Neuroscience. 1999 Jan;88(2):585-97. doi: 10.1016/s0306-4522(98)00242-5.