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09-05-2024 | Stroke | Review Article

The Effects of IRL-1620 in Post-ischemic Brain Injury: A Systematic Review and Meta-analysis of Experimental Studies

Authors: Dimitris Moustakas, Iliana Mani, Abraham Pouliakis, Nikoletta Iacovidou, Theodoros Xanthos

Published in: Neurocritical Care

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Abstract

Background

Sovateltide (IRL-1620), an endothelin B receptor agonist, has previously demonstrated neuroprotective and neuroregenerative effects in animal models of acute ischemic stroke. Recently, clinical trials indicated that it could also be effective in humans with stroke. Here, we systematically investigate whether IRL-1620 may be used for the treatment of ischemia-induced brain injury.

Methods

A systematic review was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. MEDLINE (PubMed) and Scopus databases were searched for eligible studies up to December 2022. The databases ClinicalTrials.gov and Pharmazz Inc. were screened for unpublished or ongoing trials. Only studies in English were evaluated for eligibility. Meta-analysis of the included studies was also conducted.

Results

Finally, seven studies were included in the review, all in animal rat models because of scarcity of clinical trials. Six studies, all in middle cerebral artery occlusion (MCAO) models, were selected for meta-analysis. In the two studies assessing mortality, no deaths were reported in the IRL-1620 group 24 h after MCAO, whereas the vehicle group had almost a five times higher mortality risk (risk ratio 5.3, 95% confidence interval 0.7–40.1, I2 = 0%). In all five studies evaluating outcome on day 7 after MCAO, IRL-1620 was associated with statistically significantly lower neurological deficit and improved motor performance compared with the vehicle. Infract volume, differentiation potential of neuronal progenitor cells, and mitochondrial fate also improved with IRL-1620 administration.

Conclusions

According to the above, in animal MCAO models, IRL-1620 enhanced neurogenesis and neuroprotection and improved outcome. Future studies are needed to expand our understanding of its effects in human study participants with acute ischemic stroke as well as in other common causes of cerebral ischemia including cardiac arrest.
Appendix
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Literature
1.
go back to reference Hossmann KA. The hypoxic brain. Insights from ischemia research. Adv Exp Med Biol. 1999;474:155–69.CrossRefPubMed Hossmann KA. The hypoxic brain. Insights from ischemia research. Adv Exp Med Biol. 1999;474:155–69.CrossRefPubMed
2.
go back to reference Varvarousis D, Varvarousi G, Iacovidou N, D’Aloja E, Gulati A, Xanthos T. The pathophysiologies of asphyxial vs dysrhythmic cardiac arrest: implications for resuscitation and post-event management. Am J Emerg Med. 2015;33(9):1297–304.CrossRefPubMed Varvarousis D, Varvarousi G, Iacovidou N, D’Aloja E, Gulati A, Xanthos T. The pathophysiologies of asphyxial vs dysrhythmic cardiac arrest: implications for resuscitation and post-event management. Am J Emerg Med. 2015;33(9):1297–304.CrossRefPubMed
3.
go back to reference Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a “two-hit” model | Critical Care | Full Text [Internet]. [cited 2022 Oct 31]. Available from: https://ccforum.biomedcentral.com/articles/https://doi.org/10.1186/s13054-017-1670-9 Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a “two-hit” model | Critical Care | Full Text [Internet]. [cited 2022 Oct 31]. Available from: https://​ccforum.​biomedcentral.​com/​articles/​https://​doi.​org/​10.​1186/​s13054-017-1670-9
7.
go back to reference Sandroni C, Cronberg T, Sekhon M. Brain injury after cardiac arrest: pathophysiology, treatment, and prognosis. Intensive Care Med. 2021;47(12):1393–414.CrossRefPubMedPubMedCentral Sandroni C, Cronberg T, Sekhon M. Brain injury after cardiac arrest: pathophysiology, treatment, and prognosis. Intensive Care Med. 2021;47(12):1393–414.CrossRefPubMedPubMedCentral
8.
go back to reference Greco P, Nencini G, Piva I, Scioscia M, Volta CA, Spadaro S, et al. Pathophysiology of hypoxic–ischemic encephalopathy: a review of the past and a view on the future. Acta Neurol Belg. 2020;120(2):277–88.CrossRefPubMed Greco P, Nencini G, Piva I, Scioscia M, Volta CA, Spadaro S, et al. Pathophysiology of hypoxic–ischemic encephalopathy: a review of the past and a view on the future. Acta Neurol Belg. 2020;120(2):277–88.CrossRefPubMed
9.
go back to reference Madden LK, Hill M, May TL, Human T, Guanci MM, Jacobi J, et al. The implementation of targeted temperature management: an evidence-based guideline from the neurocritical care society. Neurocrit Care. 2017;27(3):468–87.CrossRefPubMed Madden LK, Hill M, May TL, Human T, Guanci MM, Jacobi J, et al. The implementation of targeted temperature management: an evidence-based guideline from the neurocritical care society. Neurocrit Care. 2017;27(3):468–87.CrossRefPubMed
11.
go back to reference Gulati A, Hornick MG, Briyal S, Lavhale MS. A novel neuroregenerative approach using ET(B) receptor agonist, IRL-1620, to treat CNS disorders. Physiol Res. 2018;67(Suppl 1):S95-113.CrossRefPubMed Gulati A, Hornick MG, Briyal S, Lavhale MS. A novel neuroregenerative approach using ET(B) receptor agonist, IRL-1620, to treat CNS disorders. Physiol Res. 2018;67(Suppl 1):S95-113.CrossRefPubMed
12.
go back to reference Rincon F. Targeted temperature management in brain injured patients. Neurosurg Clin N Am. 2018;29(2):231–53.CrossRefPubMed Rincon F. Targeted temperature management in brain injured patients. Neurosurg Clin N Am. 2018;29(2):231–53.CrossRefPubMed
13.
go back to reference Carloni S, Facchinetti F, Pelizzi N, Buonocore G, Balduini W. Melatonin acts in synergy with hypothermia to reduce oxygen-glucose deprivation-induced cell death in rat hippocampus organotypic slice cultures. Neonatology. 2018;114(4):364–71.CrossRefPubMed Carloni S, Facchinetti F, Pelizzi N, Buonocore G, Balduini W. Melatonin acts in synergy with hypothermia to reduce oxygen-glucose deprivation-induced cell death in rat hippocampus organotypic slice cultures. Neonatology. 2018;114(4):364–71.CrossRefPubMed
14.
go back to reference Ramos MD, Briyal S, Prazad P, Gulati A. Neuroprotective effect of sovateltide (IRL 1620, PMZ 1620) in a neonatal rat model of hypoxic-ischemic encephalopathy. Neuroscience. 2022;1(480):194–202.CrossRef Ramos MD, Briyal S, Prazad P, Gulati A. Neuroprotective effect of sovateltide (IRL 1620, PMZ 1620) in a neonatal rat model of hypoxic-ischemic encephalopathy. Neuroscience. 2022;1(480):194–202.CrossRef
15.
go back to reference Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–5.CrossRefPubMed Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–5.CrossRefPubMed
16.
go back to reference Puppala B, Awan I, Briyal S, Mbachu O, Leonard M, Gulati A. Ontogeny of endothelin receptors in the brain, heart, and kidneys of neonatal rats. Brain Develop. 2015;37(2):206–15.CrossRef Puppala B, Awan I, Briyal S, Mbachu O, Leonard M, Gulati A. Ontogeny of endothelin receptors in the brain, heart, and kidneys of neonatal rats. Brain Develop. 2015;37(2):206–15.CrossRef
18.
go back to reference Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990;348(6303):730–2.CrossRefPubMed Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990;348(6303):730–2.CrossRefPubMed
20.
go back to reference Castañeda MM, Cubilla MA, López-Vicchi MM, Suburo AM. Endothelinergic cells in the subependymal region of mice. Brain Res. 2010;19(1321):20–30.CrossRef Castañeda MM, Cubilla MA, López-Vicchi MM, Suburo AM. Endothelinergic cells in the subependymal region of mice. Brain Res. 2010;19(1321):20–30.CrossRef
21.
go back to reference Bhalla S, Leonard M, Briyal S, Gulati A. Distinct alteration in brain endothelin A and B receptor characteristics following focal cerebral ischemia in rats. Drug Res (Stuttg). 2015;66(04):189–95.CrossRefPubMed Bhalla S, Leonard M, Briyal S, Gulati A. Distinct alteration in brain endothelin A and B receptor characteristics following focal cerebral ischemia in rats. Drug Res (Stuttg). 2015;66(04):189–95.CrossRefPubMed
23.
go back to reference Gulati A, Agrawal N, Vibha D, Misra UK, Paul B, Jain D, et al. Safety and efficacy of sovateltide (IRL-1620) in a multicenter randomized controlled clinical trial in patients with acute cerebral ischemic stroke. CNS Drugs. 2021;35(1):85–104.CrossRefPubMedPubMedCentral Gulati A, Agrawal N, Vibha D, Misra UK, Paul B, Jain D, et al. Safety and efficacy of sovateltide (IRL-1620) in a multicenter randomized controlled clinical trial in patients with acute cerebral ischemic stroke. CNS Drugs. 2021;35(1):85–104.CrossRefPubMedPubMedCentral
24.
go back to reference Pharmazz, Inc. A prospective, multicentric, randomized, double-blind, parallel, phase III clinical study to assess efficacy of PMZ-1620 along with standard treatment in patients of acute ischemic stroke [Internet]. clinicaltrials.gov; 2022 Feb [cited 2023 Jan 1]. Report No.: NCT04047563. Available from: https://clinicaltrials.gov/study/NCT04047563 Pharmazz, Inc. A prospective, multicentric, randomized, double-blind, parallel, phase III clinical study to assess efficacy of PMZ-1620 along with standard treatment in patients of acute ischemic stroke [Internet]. clinicaltrials.gov; 2022 Feb [cited 2023 Jan 1]. Report No.: NCT04047563. Available from: https://​clinicaltrials.​gov/​study/​NCT04047563
25.
go back to reference Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;29:n71.CrossRef Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;29:n71.CrossRef
26.
go back to reference Friedrich J, Lindauer U, Höllig A. Procedural and methodological quality in preclinical stroke research-a cohort analysis of the rat MCAO model comparing periods before and after the publication of STAIR/ARRIVE. Front Neurol. 2022;30(13):834003.CrossRef Friedrich J, Lindauer U, Höllig A. Procedural and methodological quality in preclinical stroke research-a cohort analysis of the rat MCAO model comparing periods before and after the publication of STAIR/ARRIVE. Front Neurol. 2022;30(13):834003.CrossRef
27.
go back to reference Evans NJ. Assessing the practical differences between model selection methods in inferences about choice response time tasks. Psychon Bull Rev. 2019;26(4):1070–98.CrossRefPubMedPubMedCentral Evans NJ. Assessing the practical differences between model selection methods in inferences about choice response time tasks. Psychon Bull Rev. 2019;26(4):1070–98.CrossRefPubMedPubMedCentral
28.
go back to reference Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40(6):2244–50.CrossRefPubMedPubMedCentral Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40(6):2244–50.CrossRefPubMedPubMedCentral
29.
go back to reference Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14(1):43.CrossRefPubMedPubMedCentral Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14(1):43.CrossRefPubMedPubMedCentral
30.
31.
go back to reference Schwarzer G. meta: An R package for meta-analysis. R news. 2007;7:40. Schwarzer G. meta: An R package for meta-analysis. R news. 2007;7:40.
32.
go back to reference Cifuentes EG, Hornick MG, Havalad S, Donovan RL, Gulati A. Neuroprotective effect of IRL-1620, an endothelin B receptor agonist, on a pediatric rat model of middle cerebral artery occlusion. Front Pediatr. 2018;23(6):310.CrossRef Cifuentes EG, Hornick MG, Havalad S, Donovan RL, Gulati A. Neuroprotective effect of IRL-1620, an endothelin B receptor agonist, on a pediatric rat model of middle cerebral artery occlusion. Front Pediatr. 2018;23(6):310.CrossRef
33.
go back to reference Ranjan AK, Briyal S, Khandekar D, Gulati A. Sovateltide (IRL-1620) affects neuronal progenitors and prevents cerebral tissue damage after ischemic stroke. Can J Physiol Pharmacol. 2020;98(9):659–66.CrossRefPubMed Ranjan AK, Briyal S, Khandekar D, Gulati A. Sovateltide (IRL-1620) affects neuronal progenitors and prevents cerebral tissue damage after ischemic stroke. Can J Physiol Pharmacol. 2020;98(9):659–66.CrossRefPubMed
34.
go back to reference Briyal S, Ranjan AK, Hornick MG, Puppala AK, Luu T, Gulati A. Anti-apoptotic activity of ETB receptor agonist, IRL-1620, protects neural cells in rats with cerebral ischemia. Sci Rep. 2019;9(1):10439.CrossRefPubMedPubMedCentral Briyal S, Ranjan AK, Hornick MG, Puppala AK, Luu T, Gulati A. Anti-apoptotic activity of ETB receptor agonist, IRL-1620, protects neural cells in rats with cerebral ischemia. Sci Rep. 2019;9(1):10439.CrossRefPubMedPubMedCentral
35.
go back to reference Ranjan AK, Briyal S, Gulati A. Sovateltide (IRL-1620) activates neuronal differentiation and prevents mitochondrial dysfunction in adult mammalian brains following stroke. Sci Rep. 2020;10(1):12737.CrossRefPubMedPubMedCentral Ranjan AK, Briyal S, Gulati A. Sovateltide (IRL-1620) activates neuronal differentiation and prevents mitochondrial dysfunction in adult mammalian brains following stroke. Sci Rep. 2020;10(1):12737.CrossRefPubMedPubMedCentral
36.
go back to reference Leonard MG, Gulati A. Endothelin B receptor agonist, IRL-1620, enhances angiogenesis and neurogenesis following cerebral ischemia in rats. Brain Res. 2013;1528:28–41.CrossRefPubMed Leonard MG, Gulati A. Endothelin B receptor agonist, IRL-1620, enhances angiogenesis and neurogenesis following cerebral ischemia in rats. Brain Res. 2013;1528:28–41.CrossRefPubMed
37.
go back to reference Leonard MG, Briyal S, Gulati A. Endothelin B receptor agonist, IRL-1620, reduces neurological damage following permanent middle cerebral artery occlusion in rats. Brain Res. 2011;28(1420):48–58.CrossRef Leonard MG, Briyal S, Gulati A. Endothelin B receptor agonist, IRL-1620, reduces neurological damage following permanent middle cerebral artery occlusion in rats. Brain Res. 2011;28(1420):48–58.CrossRef
39.
go back to reference Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV. Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Mol Neurodegener. 2011;6(1):11.CrossRefPubMedPubMedCentral Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV. Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Mol Neurodegener. 2011;6(1):11.CrossRefPubMedPubMedCentral
40.
go back to reference Rogers SD, Demaster E, Catton M, Ghilardi JR, Levin LA, Maggio JE, et al. Expression of endothelin-B receptors by glia in vivo is increased after CNS injury in rats, rabbits, and humans. Exp Neurol. 1997;145(1):180–95.CrossRefPubMed Rogers SD, Demaster E, Catton M, Ghilardi JR, Levin LA, Maggio JE, et al. Expression of endothelin-B receptors by glia in vivo is increased after CNS injury in rats, rabbits, and humans. Exp Neurol. 1997;145(1):180–95.CrossRefPubMed
43.
go back to reference Davidson JO, Wassink G, van den Heuij LG, Bennet L, Gunn AJ. Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy—Where to from Here? Front Neurol. 2015;14(6):198. Davidson JO, Wassink G, van den Heuij LG, Bennet L, Gunn AJ. Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy—Where to from Here? Front Neurol. 2015;14(6):198.
46.
go back to reference Van Norman GA. Limitations of animal studies for predicting toxicity in clinical trials: part 2: potential alternatives to the use of animals in preclinical trials. JACC Basic Transl Sci. 2020;5(4):387–97.CrossRefPubMedPubMedCentral Van Norman GA. Limitations of animal studies for predicting toxicity in clinical trials: part 2: potential alternatives to the use of animals in preclinical trials. JACC Basic Transl Sci. 2020;5(4):387–97.CrossRefPubMedPubMedCentral
47.
go back to reference Deleidi M, Cooper O, Hargus G, Levy A, Isacson O. Oct4-induced reprogramming is required for adult brain neural stem cell differentiation into midbrain dopaminergic neurons. PLoS ONE. 2011;6(5):e19926.CrossRefPubMedPubMedCentral Deleidi M, Cooper O, Hargus G, Levy A, Isacson O. Oct4-induced reprogramming is required for adult brain neural stem cell differentiation into midbrain dopaminergic neurons. PLoS ONE. 2011;6(5):e19926.CrossRefPubMedPubMedCentral
Metadata
Title
The Effects of IRL-1620 in Post-ischemic Brain Injury: A Systematic Review and Meta-analysis of Experimental Studies
Authors
Dimitris Moustakas
Iliana Mani
Abraham Pouliakis
Nikoletta Iacovidou
Theodoros Xanthos
Publication date
09-05-2024
Publisher
Springer US
Keyword
Stroke
Published in
Neurocritical Care
Print ISSN: 1541-6933
Electronic ISSN: 1556-0961
DOI
https://doi.org/10.1007/s12028-024-01994-4