A Selective Cathepsin B/L Inhibitor Improves Recovery after Experimental Intracerebral Hemorrhage

Spontaneous intracerebral hemorrhage (ICH) represents 10–15% of all strokes, and it exerts a much worse prognosis than injury caused by ischemic stroke.9 The size of the hematoma formed in the brain parenchyma from the rupture of a cerebral vessel is a significant predictor of poor outcome.40 Inflammation and toxicity triggered by extravascular blood products increase the cerebral damage observed in the early phases after hematoma formation and also lead to worsening edema around the clot.41 Effective surgical and drug approaches for clinical practice have been elusive.9,10,14 Cathepsins B and L are intracellular/lysosomal and secreted cysteine proteases that have been implicated in the process of neuronal cell death after experimental global and focal cerebral ischemia and after experimental spinal cord injury.1,6,,11,16,17,34,38 The levels of these cathepsins are significantly increased and relocate from the lysosomes to the cytoplasm following global cerebral ischemia.. Cathepsin B is one of the causative factors of microglia-induced neuronal apoptosis.32,34 In our previous study, CP-1, a non-toxic cysteine protease inhibitor which is selective for cathepsins B and L, but not the calpains or caspases, was shown to be effective at reducing infarct volume and improving functional scores when administered intravenously to rats after 2 hours of middle cerebral artery occlusion (MCAO) and reperfusion.35 The role of cathepsins in ICH has not been studied. However, results from models of cerebral ischemia suggest that inhibition of cathepsin B and L may be efficacious in preventing neuronal cell death. In this study, we investigated the ability of CP-1 to promote functional and histological recovery after ICH.