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Lixisenatide ameliorates cerebral ischemia-reperfusion injury via GLP-1 receptor dependent/independent pathways.
Eur J Pharmacol. 2018 Aug 15; 833:145-154.EJ

Abstract

Ischemic stroke is a major cause of neurological damage and brain dysfunction with consequent strong cerebral oxidative imbalance, inflammatory and apoptotic responses. Lixisenatide is a new potent glucagon-like peptide -1 (GLP-1) analogue that has been used clinically in the treatment of type II diabetes. Recent studies suggested the beneficial central effects of GLP-1-based therapies on different neurodegenerative diseases. This study aimed to investigate the ameliorative effect of lixisenatide in global cerebral ischemia-reperfusion (I/R) rat model and elaborate the underline mechanisms that could mediate the proposed activity. Adult male Wistar rats were subjected to sham operation or global cerebral I/R injury. Rats were administered the following drugs in two scheduled doses at 1 h and 24 h after reperfusion: lixisenatide (1 and 10 nmole/kg), lixisenatide plus GLP-1 receptor (GLP-1R) antagonist (exendin(9-39)), and pentoxiphylline. Comparable to pentoxiphylline; both doses of lixisenatide produced a significant reduction in infarct volume and amelioration of neurobehavioural functions along with suppression of oxidative stress parameters (catalase, reduced glutathione, malondialdehyde and NO), inflammatory marker (tumor necrosis factor-alpha) and apoptotic marker (caspase-3) in ischemic rat brains. However, these effects weren'tinhibited by GLP-1R antagonist, exendin(9-39), indicating that they are independent on GLP-1R mediation. Also, lixisenatide upregulated protein expression of cerebral endothelial nitric oxide synthase and the angiogenic marker, vascular endothelial growth factor. It's worth noting that this effect was blocked by exendin(9-39). Overall, these data indicated that lixisenatide may offer a promising approach for alleviating cerebral I/R injury via different mechanisms that could be mediated, in part, through GLP-1R.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt.Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt. Electronic address: gehan_heeba@mu.edu.eg.Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt.Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29864411

Citation

Abdel-Latif, Rania G., et al. "Lixisenatide Ameliorates Cerebral Ischemia-reperfusion Injury Via GLP-1 Receptor Dependent/independent Pathways." European Journal of Pharmacology, vol. 833, 2018, pp. 145-154.
Abdel-Latif RG, Heeba GH, Taye A, et al. Lixisenatide ameliorates cerebral ischemia-reperfusion injury via GLP-1 receptor dependent/independent pathways. Eur J Pharmacol. 2018;833:145-154.
Abdel-Latif, R. G., Heeba, G. H., Taye, A., & Khalifa, M. M. A. (2018). Lixisenatide ameliorates cerebral ischemia-reperfusion injury via GLP-1 receptor dependent/independent pathways. European Journal of Pharmacology, 833, 145-154. https://doi.org/10.1016/j.ejphar.2018.05.045
Abdel-Latif RG, et al. Lixisenatide Ameliorates Cerebral Ischemia-reperfusion Injury Via GLP-1 Receptor Dependent/independent Pathways. Eur J Pharmacol. 2018 Aug 15;833:145-154. PubMed PMID: 29864411.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lixisenatide ameliorates cerebral ischemia-reperfusion injury via GLP-1 receptor dependent/independent pathways. AU - Abdel-Latif,Rania G, AU - Heeba,Gehan H, AU - Taye,Ashraf, AU - Khalifa,Mohamed M A, Y1 - 2018/06/01/ PY - 2018/01/05/received PY - 2018/05/25/revised PY - 2018/05/29/accepted PY - 2018/6/5/pubmed PY - 2018/10/30/medline PY - 2018/6/5/entrez KW - Cerebral ischemia/reperfusion KW - Exendin(9−39) KW - GLP-1 KW - Lixisenatide KW - Stroke SP - 145 EP - 154 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 833 N2 - Ischemic stroke is a major cause of neurological damage and brain dysfunction with consequent strong cerebral oxidative imbalance, inflammatory and apoptotic responses. Lixisenatide is a new potent glucagon-like peptide -1 (GLP-1) analogue that has been used clinically in the treatment of type II diabetes. Recent studies suggested the beneficial central effects of GLP-1-based therapies on different neurodegenerative diseases. This study aimed to investigate the ameliorative effect of lixisenatide in global cerebral ischemia-reperfusion (I/R) rat model and elaborate the underline mechanisms that could mediate the proposed activity. Adult male Wistar rats were subjected to sham operation or global cerebral I/R injury. Rats were administered the following drugs in two scheduled doses at 1 h and 24 h after reperfusion: lixisenatide (1 and 10 nmole/kg), lixisenatide plus GLP-1 receptor (GLP-1R) antagonist (exendin(9-39)), and pentoxiphylline. Comparable to pentoxiphylline; both doses of lixisenatide produced a significant reduction in infarct volume and amelioration of neurobehavioural functions along with suppression of oxidative stress parameters (catalase, reduced glutathione, malondialdehyde and NO), inflammatory marker (tumor necrosis factor-alpha) and apoptotic marker (caspase-3) in ischemic rat brains. However, these effects weren'tinhibited by GLP-1R antagonist, exendin(9-39), indicating that they are independent on GLP-1R mediation. Also, lixisenatide upregulated protein expression of cerebral endothelial nitric oxide synthase and the angiogenic marker, vascular endothelial growth factor. It's worth noting that this effect was blocked by exendin(9-39). Overall, these data indicated that lixisenatide may offer a promising approach for alleviating cerebral I/R injury via different mechanisms that could be mediated, in part, through GLP-1R. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/29864411/Lixisenatide_ameliorates_cerebral_ischemia_reperfusion_injury_via_GLP_1_receptor_dependent/independent_pathways_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(18)30315-7 DB - PRIME DP - Unbound Medicine ER -