Work

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

Year: 2025

Type: article

Abstract: Necessary for enhancing understanding of brain injury and 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 infarct in mice, we investigated the impact of co-administering pharmacological compounds that target endothelin receptors subtypes and downstream signalling, aimed at selectively enhancing vasoconstriction whilst reducing vasodilation. We report exacerbated neuronal loss, 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. • Preclinical research requires more reliable models of focal ischemic stroke. • A pharmacological cocktail targeting endothelin signalling induces focal infarcts. • Focal infarcts are stable and reproducible across brain regions. • The focal ischemia model shows neuroinflammation. • Focal infarcts cause motor and cognitive dysfunction.

Source: Experimental Neurology

DOI: 10.1016/j.expneurol.2025.115215

Authors: Kevin CL Law, Andrew T. Quattrocchi, Brianna E. Xuereb, Niamh Moriarty, Lachlan H. Thompson, Clare L. Parish

Institutions: The University of Sydney, The University of Melbourne, Florey Institute of Neuroscience and Mental Health

Language: English

Topic: Acute Ischemic Stroke Management

Subfield: Epidemiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,110