Treatment of Hypoxic-Ischemic Brain Injury in Newborn Rats with TPCK 3 h after Hypoxia Decreases Caspase-9 Activation and Improves Neuropathologic Outcome

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Abstract
N-Tosyl-L-phenylalanyl-chloromethyl ketone (TPCK) reduces apoptosis in vitro. Pretreatment with TPCK reduces brain injury. Would treatment after injury reduce damage? Seven-day-old rats had the right carotid artery ligated and were subjected to 2.5 h of 8% oxygen and were treated intraperitoneally 3 h after hypoxia with 10 mg/kg of TPCK or vehicle. Brain damage was measured 22 days after injury. bcl-2, bax, and cytochrome c where measured by Western blot 24 h after injury. Caspase-9 and caspase-3 activity were measured enzymatically 24 h after injury. Treatment with TPCK reduced the loss of the right hemisphere caused by injury from 27.6 ± 2.8% SEM (vehicle, n = 56) to 19.8 ± 2.8% (TPCK, n = 61, p < 0.05). Hypoxic ischemia increased cytosolic cytochrome c from 0.25 ± 0.04 to 0.4 ± 0.04 optical density (OD; p < 0.05), but TPCK had no effect (0.31 ± 0.03 OD). TPCK reduced caspase-9 activity from 72 ± 30 to 43 ± 5 fluorescence units/h/mg (p < 0.05 vs. vehicle), and caspase-3 activity from 66 ± 10 to 39 ± 3.7 fluorescence units/h/mg (p < 0.05 vs. vehicle). Treatment with TPCK 3 h after hypoxic ischemia reduced brain infarct size. TPCK may act by reducing caspase-9 activation by cytochrome c.

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