Systemic administration of a calpain inhibitor reduces behavioral deficits and blood-brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat

A. Germanò, A. L. Day, D. K. Anderson, R. L. Hayes, C. Costa, S. M. DeFord, F. F. Angileri, F. Arcadi, B. R. Pike, P. Bramanti, B. Bausano, X. Zhao

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)887-896
Number of pages10
JournalJournal of Neurotrauma
Volume19
Issue number7
Publication statusPublished - 2002

Keywords

  • Behavioral deficits
  • Blood-brain barrier
  • Calpain
  • Rats
  • Subarachnoid hemorrhage

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

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