Liraglutide Activates the Nrf2/HO-1 Antioxidant Pathway and Protects Brain Nerve Cells against Cerebral Ischemia in Diabetic Rats

This study aimed to determine the effect of liraglutide pretreatment and to elucidate the mechanism of nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) signaling after focal cerebral ischemia injury in diabetic rats model. Adult male Sprague-Dawley rats were randomly divided into the sham-operated (S) group, diabetes mellitus ischemia (DM + MCAO) group, liraglutide pretreatment normal blood glucose ischemia (NDM+MCAO+L) group, and liraglutide pretreatment diabetes ischemia (DM + MCAO + L) group. At 48 h after middle cerebral artery occlusion (MCAO), neurological deficits and infarct volume of brain were measured. Oxidative stress brain tissue was determined by superoxide dismutase (SOD) and myeloperoxidase (MPO) activities. The expression levels of Nrf2 and HO-1 of brain tissue were analyzed by western blotting. In the DM + MCAO + L group, neurological deficits scores and cerebral infarct volume seemed to decrease at 48 h after MCAO cerebral ischemia compared with those in DM + MCAO group (P < 0.05). In addition, the expression of Nrf2 and HO-1 increased in 48 h at liraglutide pretreatment groups after MCAO cerebral ischemia if compared with those in the DM + MCAO group (P < 0.05). Furthermore, the DM + MCAO + L group has no significant difference compared with the NDM + MCAO + L group (P > 0.05). To sum up, alleviating effects of liraglutide on diabetes complicated with cerebral ischemia injury rats would be related to Nrf2/HO-1 signaling pathway.

[1]  D. Mozaffarian,et al.  Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. , 2010, Circulation.

[2]  P. Reddy,et al.  Peripheral biomarkers of stroke: Focus on circulatory microRNAs. , 2016, Biochimica et biophysica acta.

[3]  P. Weinstein,et al.  Reversible middle cerebral artery occlusion without craniectomy in rats. , 1989, Stroke.

[4]  E. Solá,et al.  Relationship between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues , 2019, Journal of clinical medicine.

[5]  George Howard,et al.  Global stroke statistics , 2017, International journal of stroke : official journal of the International Stroke Society.

[6]  Ye Chen,et al.  Propofol Reduces Inflammatory Reaction and Ischemic Brain Damage in Cerebral Ischemia in Rats , 2014, Neurochemical Research.

[7]  I. Markaki,et al.  Hyperglycaemia in acute ischaemic stroke is associated with an increased 5-year mortality. , 2009, Age and ageing.

[8]  T. Vilsbøll,et al.  Liraglutide: a new treatment for type 2 diabetes. , 2009, Drugs of today.

[9]  Yuichiro Yamada,et al.  The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential. , 2014, Kidney international.

[10]  Chen Weian,et al.  Protective effects of mangiferin on cerebral ischemia-reperfusion injury and its mechanisms. , 2016, European journal of pharmacology.

[11]  M. Fornage,et al.  Guidelines for the Primary Prevention of Stroke: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association , 2011, Stroke.

[12]  Fang Yang,et al.  Cell-Permeable Peptide Targeting the Nrf2–Keap1 Interaction: A Potential Novel Therapy for Global Cerebral Ischemia , 2015, The Journal of Neuroscience.

[13]  Mitsunori Matsumae,et al.  Neuroprotective Effects of Liraglutide for Stroke Model of Rats , 2013, International journal of molecular sciences.

[14]  P. Ghadjar,et al.  Open Access RESEARCH , 2010 .

[15]  Oprs Alert.  Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers , 2005 .

[16]  Susanne Bremer-Hoffmann,et al.  Evaluation of the rotenone-induced activation of the Nrf2 pathway in a neuronal model derived from human induced pluripotent stem cells , 2017, Neurochemistry International.

[17]  F. Santilli,et al.  Oxidative stress-related mechanisms affecting response to aspirin in diabetes mellitus. , 2015, Free radical biology & medicine.

[18]  Cheng Xu,et al.  Coenzyme Q10 and oxidative stress, the association with peripheral sensory neuropathy and cardiovascular disease in type 2 diabetes mellitus. , 2015, Journal of diabetes and its complications.

[19]  Kerstin Iverfeldt,et al.  Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats , 2011, Clinical science.

[20]  Mark D. Huffman,et al.  Executive Summary: Heart Disease and Stroke Statistics—2015 Update A Report From the American Heart Association , 2011, Circulation.

[21]  Emmanuel Touzé,et al.  Inclusion of stroke in cardiovascular risk prediction instruments: a statement for healthcare professionals from the American Heart Association/American Stroke Association. , 2012, Stroke.

[22]  Feng Chen,et al.  Histone deacetylase 6 interference protects mice against experimental stroke-induced brain injury via activating Nrf2/HO-1 pathway , 2019, Animal cells and systems.

[23]  He Meng,et al.  Myeloid-Specific Deletion of the Mineralocorticoid Receptor Reduces Infarct Volume and Alters Inflammation During Cerebral Ischemia , 2011, Stroke.

[24]  Hui Chen,et al.  Oxymatrine ameliorates renal ischemia-reperfusion injury from oxidative stress through Nrf2/HO-1 pathway. , 2015, Acta cirurgica brasileira.

[25]  D E Griswold,et al.  Assessment of myeloperoxidase activity in whole rat kidney. , 1990, Journal of pharmacological methods.

[26]  Liguo An,et al.  Multidose Streptozotocin Induction of Diabetes in BALB/c Mice Induces a Dominant Oxidative Macrophage and a Conversion of TH1 to TH2 Phenotypes During Disease Progression , 2005, Mediators of inflammation.

[27]  P N Viswanathan,et al.  A modified spectrophotometric assay of superoxide dismutase. , 1984, Indian journal of biochemistry & biophysics.