Specific peptide based Caspase-6 inhibition leads to recovery from motor deficits in a mouse model of focal ischemic injury

Stroke is a life-threatening neurological disease with debilitating effects and limited therapeutic options. Cell death by apoptosis appears in cerebral ischemia, and it occurs through various pathways. Inflammation is also believed to be involved in the pathogenesis of ischemic stroke and contributes to the degree of brain injury. Over the past years, increasing evidence has implied a significant connection between caspase-6 activity and the progression and severity of stroke through those pathways. Therefore, inhibiting caspase-6 activity was suggested as a promising therapeutic strategy in order to provide protection from inflammation and cell death induced motor and behavioral deficits.

To this end, a novel caspase-6 inhibitor peptide, ED-11, based on the caspase-6 cleavage site and fused with a cell-penetrating sequence was used to treat stroke induced mice.

In this study, we used the vasoconstrictor endothelin-1 to induce focal ischemic injury in mice by direct injection into the striatum. Daily subcutaneous administration of the peptide for five days following stroke protected mice from motor deficits and behavioral abnormalities. Mice treated with the peptide showed significant decreased motor asymmetry compared to the control group. Moreover, administration of the peptide showed a reduction in mRNA levels of pro-inflammatory cytokines suggesting a pathway dependent mode of action.

Our findings reveal the potential of substrate-based caspase inhibition as a therapeutic strategy, and present a promising agent for the treatment of stroke.