A pharmacological vasoconstrictor cocktail targeting endothelin signalling generates a stable, reproducible focal cerebral infarct with associated functional deficits in mice

Abstract

Necessary for enhanced understanding of brain injury, and for developing new therapies, is the generation of reliable animal models. While many models are available, each comes with benefits and limitations. Intracerebral injection of the vasoconstrictive peptide endothelin-1 creates one of the most widely adopted models of focal ischemic stroke in rats, yet its potency is underwhelming in mice. This is likely underpinned by the greater proportions of vasodilatory compared to vasoconstrictive receptor subtypes in the mouse brain. Yet mouse models of ischemic stroke provide the benefit of exploiting the wide range of transgenic strains that can aid in further understanding pathophysiology mechanisms of acute and secondary damage, as well as endogenous recovery. To improve the efficiency of focal endothelin-1 infarcts in mice, we investigated the impact of co-administering pharmacological compounds that target endothelin receptor subtypes and downstream signalling, aimed at selectively enhancing vasoconstriction whilst reducing vasodilation. We report exacerbated neuronal loss and tissue atrophy resulting in motor and cognitive dysfunction when endothelin-1 was co-administered with the nitric oxide synthase inhibitor L-NAME and the selective ET_B1 antagonist RES-701-1. These infarcts were stable, reproducible and achievable across brain regions. These findings demonstrate a new and effective mouse model to study focal ischemic stroke.