TY - JOUR
T1 - Systemic administration of a calpain inhibitor reduces behavioral deficits and blood-brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat
AU - Germanò, A.
AU - Day, A. L.
AU - Anderson, D. K.
AU - Hayes, R. L.
AU - Costa, C.
AU - DeFord, S. M.
AU - Angileri, F. F.
AU - Arcadi, F.
AU - Pike, B. R.
AU - Bramanti, P.
AU - Bausano, B.
AU - Zhao, X.
PY - 2002
Y1 - 2002
N2 - 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 μl 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.
AB - 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 μl 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.
KW - Behavioral deficits
KW - Blood-brain barrier
KW - Calpain
KW - Rats
KW - Subarachnoid hemorrhage
UR - http://www.scopus.com/inward/record.url?scp=0036325878&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036325878&partnerID=8YFLogxK
M3 - Article
C2 - 12184858
AN - SCOPUS:0036325878
VL - 19
SP - 887
EP - 896
JO - Journal of Neurotrauma
JF - Journal of Neurotrauma
SN - 0897-7151
IS - 7
ER -