A Novel Neuroregenerative Approach Using ETB Receptor Agonist, IRL-1620, to Treat CNS Disorders

Abstract

Endothelin B (ETB) receptors present in abundance the central nervous system (CNS) have been shown to have significant implications in its development and neurogenesis. We have targeted ETB receptors stimulation using a highly specific agonist, IRL-1620, to treat CNS disorders. In a rat model of cerebral ischemia intravenous administration IRL-1620 significantly reduced infarct volume and improved neurological and motor functions compared to control. This improvement, in part, is due to an increase in neuroregeneration. We also investigated the role of IRL-1620 in animal models of Alzheimer’s disease (AD). IRL-1620 improved learning and memory, reduced oxidative stress and increased VEGF and NGF in Aβ treated rats. IRL-1620 also improved learning and memory in an aged APP/PS1 transgenic mouse model of AD. These promising findings prompted us to initiate human studies. Successful chemistry, manufacturing and control along with mice, rat and dog toxicological studies led to completion of a human Phase I study in healthy volunteers. We found that a dose of 0.6 µg/kg of IRL-1620 can be safely administered, three times every four hours, without any adverse effect. A Phase II clinical study with IRL-1620 has been initiated in patients with cerebral ischemia and mild to moderate AD.

Sovateltide (IRL-1620) activates neuronal differentiation and prevents mitochondrial dysfunction in adult mammalian brains following stroke

“…Recently, we confirmed sovateltide as a pro-survival and anti-apoptotic agent in ischemic brains of MCAO rats 13 . To assess its safety and efficacy in human subjects, we performed a phase I clinical trial (CTRI/2016/11/007509) in healthy human volunteers 14 and a multicentric, randomized, double-blind, parallel, saline-controlled efficacy clinical trial (NCT04046484) in patients with acute cerebral ischemic stroke 15 . Another multicentric, randomized, blinded, controlled efficacy clinical trial (NCT04047563) in 110 acute ischemic stroke patients is ongoing.…”

Endothelin A and B Receptors: Potential Targets for Microcirculatory-Mitochondrial Therapy in Experimental Sepsis

“…The ET B -Rs are heterogeneously distributed in the lungs, brain, and kidneys, with specific dual vasoactive effects, which can contribute to the fine tuning of tissue perfusion through either local endothelial vasodilation or vasoconstriction (8,13,30). Our results suggest that if microcirculatory failure occurs, the specific inactivation of vasoconstrictor ET A -Rs can amplify the vasomodulator effects of circulating ET-1 through the ET B -Rs, leading to a potentially beneficial outcome at the subcellular level.…”

“…In response to the combined treatment, however, all of the examined parameters were restored to the values of the sham-operated group ( Figure 6). Sepsis resulted in significant disintegration of the outer membrane based on the effect of exogenous Cytc, but preserved membrane integrity was observed in the animals subjected to the combined treatment (Supplementary Digital Content ET B2 -Rs have a long-lasting vasopressor effect possibly due to dominant ET A -R activity (13,(21)(22)(23), IRL-1620 shows higher affinity to the ET B1 -Rs, which are expressed by the vascular endothelium and mediate nitric oxide-dependent vasodilatation (9). The beneficial effects of ET B -R agonism have already been demonstrated in acute and chronic CNS disorders (13,21) and in the peripheral circulation as well, possibly linking these reactions to vasodilator effects (22,24).…”

Interplay Between Mitochondrial Oxidative Disorders and Proteostasis in Alzheimer’s Disease

“…One approach using BACE1 inhibitors in AD was promising few years ago, but the increase of BACE1 expression by any BACE1 inhibitors raises concern about their use for AD (Liu et al, 2019). The compound IRL-1620, an endothelin receptor type B agonist, stimulates the clearance of Aβ and cerebral blood flow, reducing OS and improving memory impairment in rat models (Briyal et al, 2014(Briyal et al, , 2015Pozhilenkova et al, 2017;Gulati et al, 2018). Another reduction approach for protein aggregates is based on immunotherapy by passive immunization (Salloway et al, 2014;Sevigny et al, 2016).…”