Blood-brain barrier disruption, HSP70 expression and apoptosis due to 3-nitropropionic acid, a mitochondrial toxin.
3-Nitropropionic acid (3-NP), a mitochondrial toxin, induces apoptosis in the striatum. We wanted to determine if there was a relationship between mitochondrial dysfunction, disruption of the blood-brain barrier (BBB), and apoptosis. BBB disruption following intrastriatal injection of 3-NP was assessed by Evans blue leakage, brain water content, and by the expression of the 70 kDa heat shock protein (HSP70) and mRNA. Apoptosis was assessed by in situ terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling (TUNEL) and gel electrophoresis to detect internucleosomal DNA fragmentation. Microscopic evidence of Evans blue leakage due to 3-NP was present only 3 hr after injection. Both internucleosomal DNA fragmentation and TUNEL-labeling did not appear until 24 hr after injection. HSP70 (protein and mRNA) was also elevated by 24 hr. There was a quantitative increase in Evans blue leakage and brain water content due to 3-NP by 3 days after injection. Our results suggest that BBB disruption is an early event followed by increased HSP70 expression and apoptosis. We speculate that 3-NP damages endothelial cells, leading to vasogenic edema and apoptosis.
Sato
S
S
Department of Neurological Surgery, University of California, School of Medicine, San Francisco, USA.
Gobbel
G T
GT
Li
Y
Y
Kondo
T
T
Murakami
K
K
Sato
M
M
Hasegawa
K
K
Copin
J C
JC
Honkaniemi
J
J
Sharp
F R
FR
Chan
P H
PH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000502:physiology*; D004396:Coloring Agents; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005070:Evans Blue; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005821:Genetic Techniques; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity*; D009574:Nitro Compounds; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*
D004396:Coloring Agents; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D005070:Evans Blue; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid