Systemic administration of a calpain inhibitor reduces behavioral deficits and blood-brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat.
Increases in intracellular calcium and subsequent activation of calcium-activated proteases (e.g., calpains) may play a critical role in central nervous system injury. Several studies have implicated calpain activation following subarachnoid hemorrhage (SAH). This study evaluated the effect of a calpain inhibitor administration following SAH in the rat on behavioral deficits (postinjury days 1-5, employing a battery of well-characterized assessment tasks), and blood-brain barrier permeability changes (48 h post-SAH, quantifying the microvascular alterations according to the extravasation of protein-bound Evans Blue using a spectrophotofluorimetric technique). Rats were injected with 400 microl of autologous blood into the cisterna magna to induce SAH. Within 5 min after the surgical procedure, Calpain Inhibitor II or vehicle was continuously administered intravenously for 2 days. Results indicated that Calpain Inhibitor II treatment after SAH significantly improved (a) beam balance time (day 1, p < 0.05), but not beam balance score, (b) latency to traverse the beam on days 1-4 (day 1-3, p < 0.001; day 4, p < 0.01), and (c) loss in body weight on days 4-5 (p < 0.05). Evans Blue dye extravasation was significantly less in SAH Calpain Inhibitor II-treated rats compared to SAH vehicle-treated rats in seven out of the eight brain regions studied (p < 0.001, 0.01, and 0.05). These results suggest that pharmacological inhibition of a relatively selective, membrane-permeant calpain inhibitor can significantly reduce some pathophysiological SAH consequences, and indicate that the inhibition of calpain may be a beneficial therapeutic approach to reduce post-SAH global brain dysfunction.
Germanò
A
A
Neurosurgical Clinic, University of Messina, Messina, Italy.
Costa
C
C
DeFord
S M
SM
Angileri
F F
FF
Arcadi
F
F
Pike
B R
BR
Bramanti
P
P
Bausano
B
B
Zhao
X
X
Day
A L
AL
Anderson
D K
DK
Hayes
R L
RL
D000818:Animals; D001526:Behavioral Symptoms / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002154:Calpain / Q000037:antagonists & inhibitors*; D008297:Male; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000008:administration & dosage*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology / Q000523:psychology
D009842:Oligopeptides; C069861:calpain inhibitor 2; D002154:Calpain