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The Sigma-1 Receptor Antagonist, S1RA, Reduces Stroke Damage, Ameliorates Post-Stroke Neurological Deficits and Suppresses the Overexpression of MMP-9.
Mol Neurobiol. 2018 Jun; 55(6):4940-4951.MN

Abstract

The glutamate N-methyl-D-aspartate receptor (NMDAR) plays an essential role in the excitotoxic neural damage that follows ischaemic stroke. Because the sigma-1 receptor (σ1R) can regulate NMDAR transmission, exogenous and putative endogenous regulators of σ1R have been investigated using animal models of ischaemic stroke. As both agonists and antagonists provide some neural protection, the selective involvement of σ1Rs in these effects has been questioned. The availability of S1RA (E-52862/MR309), a highly selective σ1R antagonist, prompted us to explore its therapeutic potential in an animal model of focal cerebral ischaemia. Mice were subjected to right middle cerebral artery occlusion (MCAO), and post-ischaemic infarct volume and neurological deficits were determined across a range of intervals after the stroke-inducing surgery. Intracerebroventricular or intravenous treatment with S1RA significantly reduced the cerebral infarct size and neurological deficits caused by permanent MCAO (pMCAO). Compared with the control/sham-operated mice, the neuroprotective effects of S1RA were observed when delivered up to 5 h prior to surgery and 3 h after ischaemic onset. Interestingly, neither mice with the genetic deletion of σ1R nor wild-type mice that were pre-treated with the σ1R agonist PRE084 showed beneficial effects after S1RA administration with regard to stroke infarction. S1RA-treated mice showed faster behavioural recovery from stroke; this finding complements the significant decreases in matrix metalloproteinase-9 (MMP-9) expression and reactive astrogliosis surrounding the infarcted cortex. Our data indicate that S1RA, via σ1R, holds promising potential for clinical application as a therapeutic agent for ischaemic stroke.

Authors+Show Affiliations

Neuropharmacology. Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Doctor Arce, 37, 28002, Madrid, Spain. psb@cajal.csic.es. Drug Discovery and Preclinical Development, Esteve, Scientific Park of Barcelona, Baldiri i Reixac 4-8, 08028, Barcelona, Spain. psb@cajal.csic.es.Neuropharmacology. Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Doctor Arce, 37, 28002, Madrid, Spain.Drug Discovery and Preclinical Development, Esteve, Scientific Park of Barcelona, Baldiri i Reixac 4-8, 08028, Barcelona, Spain.Neuropharmacology. Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Doctor Arce, 37, 28002, Madrid, Spain.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28779350

Citation

Sánchez-Blázquez, Pilar, et al. "The Sigma-1 Receptor Antagonist, S1RA, Reduces Stroke Damage, Ameliorates Post-Stroke Neurological Deficits and Suppresses the Overexpression of MMP-9." Molecular Neurobiology, vol. 55, no. 6, 2018, pp. 4940-4951.
Sánchez-Blázquez P, Pozo-Rodrigálvarez A, Merlos M, et al. The Sigma-1 Receptor Antagonist, S1RA, Reduces Stroke Damage, Ameliorates Post-Stroke Neurological Deficits and Suppresses the Overexpression of MMP-9. Mol Neurobiol. 2018;55(6):4940-4951.
Sánchez-Blázquez, P., Pozo-Rodrigálvarez, A., Merlos, M., & Garzón, J. (2018). The Sigma-1 Receptor Antagonist, S1RA, Reduces Stroke Damage, Ameliorates Post-Stroke Neurological Deficits and Suppresses the Overexpression of MMP-9. Molecular Neurobiology, 55(6), 4940-4951. https://doi.org/10.1007/s12035-017-0697-x
Sánchez-Blázquez P, et al. The Sigma-1 Receptor Antagonist, S1RA, Reduces Stroke Damage, Ameliorates Post-Stroke Neurological Deficits and Suppresses the Overexpression of MMP-9. Mol Neurobiol. 2018;55(6):4940-4951. PubMed PMID: 28779350.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Sigma-1 Receptor Antagonist, S1RA, Reduces Stroke Damage, Ameliorates Post-Stroke Neurological Deficits and Suppresses the Overexpression of MMP-9. AU - Sánchez-Blázquez,Pilar, AU - Pozo-Rodrigálvarez,Andrea, AU - Merlos,Manuel, AU - Garzón,Javier, Y1 - 2017/08/05/ PY - 2017/01/16/received PY - 2017/07/26/accepted PY - 2017/8/6/pubmed PY - 2019/2/12/medline PY - 2017/8/6/entrez KW - Astrogliosis KW - MMP-9 KW - Neuroprotective effects KW - S1RA KW - Sigma 1 receptor KW - Stroke SP - 4940 EP - 4951 JF - Molecular neurobiology JO - Mol Neurobiol VL - 55 IS - 6 N2 - The glutamate N-methyl-D-aspartate receptor (NMDAR) plays an essential role in the excitotoxic neural damage that follows ischaemic stroke. Because the sigma-1 receptor (σ1R) can regulate NMDAR transmission, exogenous and putative endogenous regulators of σ1R have been investigated using animal models of ischaemic stroke. As both agonists and antagonists provide some neural protection, the selective involvement of σ1Rs in these effects has been questioned. The availability of S1RA (E-52862/MR309), a highly selective σ1R antagonist, prompted us to explore its therapeutic potential in an animal model of focal cerebral ischaemia. Mice were subjected to right middle cerebral artery occlusion (MCAO), and post-ischaemic infarct volume and neurological deficits were determined across a range of intervals after the stroke-inducing surgery. Intracerebroventricular or intravenous treatment with S1RA significantly reduced the cerebral infarct size and neurological deficits caused by permanent MCAO (pMCAO). Compared with the control/sham-operated mice, the neuroprotective effects of S1RA were observed when delivered up to 5 h prior to surgery and 3 h after ischaemic onset. Interestingly, neither mice with the genetic deletion of σ1R nor wild-type mice that were pre-treated with the σ1R agonist PRE084 showed beneficial effects after S1RA administration with regard to stroke infarction. S1RA-treated mice showed faster behavioural recovery from stroke; this finding complements the significant decreases in matrix metalloproteinase-9 (MMP-9) expression and reactive astrogliosis surrounding the infarcted cortex. Our data indicate that S1RA, via σ1R, holds promising potential for clinical application as a therapeutic agent for ischaemic stroke. SN - 1559-1182 UR - https://www.unboundmedicine.com/medline/citation/28779350/The_Sigma_1_Receptor_Antagonist_S1RA_Reduces_Stroke_Damage_Ameliorates_Post_Stroke_Neurological_Deficits_and_Suppresses_the_Overexpression_of_MMP_9_ L2 - https://dx.doi.org/10.1007/s12035-017-0697-x DB - PRIME DP - Unbound Medicine ER -