The effects of IRL-1620 in post-ischemic brain injury: A systematic review of experimental studies

Introduction: Endothelin (ET) is a vasoconstrictive substance, which consists of 21 amino acid residues with two disulfide bonds. Studies showed that endothelin is involved in the regulation of the sympathetic nervous system, and acts as a regulator in the differentiation, proliferation, and migration of neurons during pre- and post-natal development. IRL-1620 (Sovateltide) an endothelin-B receptor agonist, has previously been shown to increase cerebral blood flow, to have anti-apoptotic activity and to produce neurovascular remodeling when administered intravenously following acute cerebral ischemic stroke in rats. The aim of this study is to systematically investigate whether stimulation of ET B receptors by its agonist IRL-1620 (INN, sovateltide), may be used as a first-in-class neuronal progenitor cell therapeutic for the treatment of ischemia–induced brain injury. Methodology A systematic review was performed following the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Eligible studies published in MEDLINE (PubMed) and Scopus databases, up to the study data collection time point (December 2022) were selected to be included in the review. The database https://ClinicalTrials.gov, and Pharmazz Inc. were searched for unpublished or ongoing trials. Only studies in English language were selected. No restriction on the year of publication were set, while restrictions on the publication type were posed, i.e. Only experimental animal studies were requested. Results Seven studies were included in the review, all in animal rat models. Mortality was assessed in 3 studies, and in all, in the IRL-1620 treated group it was significantly lower at 24h post-intervention in comparison to that of the vehicle groups. Difference was even higher on day 7 (11.1%vs56.3%) or day 10 (0%vs16-25%). IRL-1620 was associated with lower neurological deficit at 24h and on day 7 (p < 0.001). However, when IRL-1620 was administered, spontaneous activity was significantly (p < 0.01) increased. Differentiation potential of neuronal progenitor cells (NPCs), mitochondrial fate, vascular endothelian growth factor (VEGF) and infract volume improved with IRL-1620 administration. Conclusion In general, administration of the ET B agonist, enhanced neurogenesis and neuroprotection, lowered mortality rate and improved all motor performance tests. Future studies should investigate the effects of IRL-1620 in other common causes of cerebral ischemia including cardiac arrest.