The neurological scores improved in both the treatment groups at 2 days after embolization. Brain edema was significantly reduced following intravenous delivery of either Z-VEID-FMK or Z-IETD-FMK: brain edema in control, Z-VEID-FMK, or Z-IETD-FMK groups was 11.5±1.02%, 7.56±1.12%, or 8.03±0.87%, respectively, at 48 h after MCA occlusion (Figure 3c).
We also measured the absolute and relative water content of the ipsilateral (ischemic) and contralateral (non-ischemic) hemispheres to further evaluate cerebral edema.
Graph depicts the Bederson scores for each of the three groups: control (Ctrl), caspase-6 inhibitor (Z-VEID), caspase-8 inhibitor (Z- IETD); (c) Bederson Scores were evaluated at baseline, 2, 8, 24, and 48 h after MCAO in the 48 h cohort; (d) Bederson Scores were evaluated at baseline, 2 h, 8 h, 24 h, 48 h, 72 h, and 7 days after MCAO, in the 7-day cohort. M., *PThe effect of CASP6 or CASP8 inhibition on brain edema was assessed by comparing the relative volumes of brain tissue between the infarcted and non-infarcted hemispheres of the brain.
Caspase-6 (CASP6) activation requires proteolytic processing (cleavage) of the zymogen into ~p10 and ~p20 fragments.
In these injury models, CASP6 appears to activate CASP8 in injured RGCs and the inhibitory peptides Z-VEID-FMK and Z-IETD-FMK confer significant neuroprotection, while promoting axon regeneration in the crushed optic nerve.
Compared with the control group, infarct volume was reduced by 62 and 52% (at 48 h post stroke) or 64 and 70% (at 7 days post stroke) in the ischemic rats that received Z-VEID- FMK or Z-IETD-FMK, respectively (PBrain edema and infarct volume at 48 h post ischemia are reduced by caspase inhibition. *PCASP6 or CASP8 inhibition reduce infarct volume and neurological deficits at 2 and 7 days post ischemia.
(a) Coronal brain slices showing the representative infarct area in a sample from control, caspase-6 inhibitor (Z-VEID)-, or caspase-8 inhibitor (Z-IETD)-treated brains. (a) Coronal brain slices showing the representative infarct area in a sample from control, caspase-6 inhibitor (Z-VEID)-, or caspase-8 inhibitor (Z-IETD)-treated brains at 7 days after stroke.