Protective Effects Of Liraglutide Research Articles

Abstract TP103: Liraglutide Reduces Amyloid-β Deposits and Secondary Damage in the Thalamus After Focal Cortical Infarction in Rats

Introduction: Focal cerebral cortical infarction causes β-amyloid (Aβ) deposition and secondary neuronal degeneration in the ipsilateral thalamus. The present study aimed to investigate the protective effects of liraglutide, a long-acting glucagon-like peptide-1 (GLP-1) analogue, on Aβ deposits and secondary neuron damage in thalamus after cerebral infarction. Methods: Sixteen male Sprague-Dawley rats were subjected to distal middle cerebral artery occlusion (MCAO) and then randomly divided into liraglutide and vehicle groups and 8 sham-operated rats as control. At 1 hour after MCAO, rats were subcutaneously injected with liraglutide (100 μg/kg/d) and isopyknic vehicle, respectively, then continuously injected once a day for 7 days. Sensory function and secondary thalamic damage were assessed with adhesive-removal test, Nissl staining and immunostaining. Terminal-deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) staining and Western blot were employed to detect the neuronal apoptosis at 7 days after MCAO. Results: At 7 days after MCAO, liraglutide decreased the mean time of adhesive-removal at left forepaw compared with the vehicle group (P < 0.05). Treatment with liraglutide reduced Aβ deposition compared with that in the vehicle group (P < 0.05). The number of intact neurons in the ipsilateral thalamus was decreased compared with the control group at 7 days post-MCAO, liraglutide significantly improved the number of intact neurons compared with the vehicle group (P < 0.05). Liraglutide decreased the glial fibrillary acidic protein (GFAP)-positive area and the number of ionized calcium bindingadaptor molecule-1 (Iba-1)-positive cells in the ipsilateral thalamus compared with the vehicle group (P < 0.05). Liraglutide significantly decreased the number of TUNEL-positive neurons in the ipsilateral thalamus compared with the vehicle group (P < 0.05). Consistent with the TUNEL staining results, liraglutide increased the ratio of Bcl-2/Bax (P < 0.05) and decreased the expression level of cleaved Caspase-3 relative to the vehicle group (P < 0.05). Conclusions: Liraglutide reduces Aβ deposits in the ipsilateral thalamus, improves the secondary thalamic damage and neurological deficit after cerebral infarction.

Neurochemical modulation involved in the beneficial effect of liraglutide, GLP-1 agonist on PTZ kindling epilepsy-induced comorbidities in mice

Epilepsy is a neurological disorder which occurs due to excessive firing of excitatory neurons in specific region of brain and associated with cognitive impairment and depression. GLP-1 has been reported to maintain hyperexcitability of neurons. Therefore, this study was designed to investigate the neuroprotective effect of liraglutide, GLP-1 analogue in PTZ kindling epilepsy-induced comorbidities and neurochemical alteration in mice. Male albino mice were administered PTZ (35mg/kg) on every alternate day up to 29th days and challenge test was performed on 33rd day. From 1st day liraglutide (75 and 150µg/kg) and diazepam (3mg/kg) were administered up to 33rd day, 30min prior to PTZ treatment. On 30th day animals were trained on elevated plus maze and passive shock avoidance paradigm and retention was recorded on 31st and 33rd day. On 32nd day tail suspension test was performed. Animals were sacrificed on 34th day for biochemical (LPO, GSH, and nitrite) and neurotransmitters (GABA, glutamate, DA, NE, 5-HT and their metabolites) estimation. Chronic treatment with PTZ developed generalized tonic-clonic seizures, reduced cognitive skills, increased oxidative stress and alteration in the level of neurotransmitters. Pre-treatment with liraglutide (75 and 150μg/kg) significantly prevented the seizure severity, restored behavioural activity, oxidative defence enzymes, and altered level of neurochemicals in mice brain. The protective effect of liraglutide is attributed to restoration of altered level of GABA, glutamate, DA, NE, and 5-HT by the up-regulation of GLP-1Rs in mice brain.

Protective Effects of Liraglutide and Linagliptin in C. elegans as a New Model for Glucose-Induced Neurodegeneration.

Liraglutide and linagliptin are novel drugs for the treatment of diabetes. Antioxidative and neuroprotective effects have been described for both compounds. However, it is not yet known, whether these mechanisms are also protective against diabetic retinal neurodegeneration. We assessed the antioxidative and neuroprotective capabilities of liraglutide and linagliptin as well as the signaling pathways involved, by using C. elegans as a model for glucose-induced neurodegeneration. C. elegans were cultivated under conditions, which mimic clinical hyperglycemia, and treated with 160 μmol/l liraglutide or 13 μmol/l linagliptin. Oxidative stress was reduced by 29 or 78% and methylglyoxal-derived advanced glycation endproducts (AGEs) by 33 or 22%, respectively. This resulted in an improved neuronal function by 42 or 60% and an extended mean lifespan by 9 or 11%, respectively. Antioxidative and AGE reducing effects of liraglutide and linagliptin were not dependent on v-akt murine thymoma viral oncogene homologue 1/forkhead box O1 (AKT1/FOXO). Neuroprotection by liraglutide was AKT1/FOXO dependent, yet AKT1/FOXO independent upon linagliptin treatment. Both liraglutide and linagliptin exert neuroprotective effects in an experimental model for glucose-induced neurodegeneration, however, the signaling pathways differ in the present study. Further pharmacological intervention with these pathways may help to delay the clinical onset of diabetic retinopathy by preserving neuronal integrity.

The Neuroprotective Effect of Liraglutide is Mediated by Glucagon-Like Peptide 1 Receptor-Mediated Activation of cAMP/PKA/CREB Pathway

Background/Aims: Glucagon-like peptide-1 (GLP-1)-based drugs are being used to achieve better glucose control in patients with type 2 diabetes, and GLP-1 mimetics such as liraglutide have shown therapeutic potential in preventing diabetes-related microvascular and macrovascular complications as well as comorbidities such as neurodegenerative disorders. In the present study, we investigated the effects of liraglutide on primary rat cortical astrocytes treated with advanced glycation end-products (AGEs). Methods: Gene and protein expression was analyzed by quantitative real time PCR, western blots, and enzyme-linked immunosorbent assay. The caspase-3 activity was assessed using a caspase-3 colorimetric assay kit. The ROS production was measured with CM-H2DCFDA staining. The cell viability of rat astrocytes was determined using MTT assay. Results: Liraglutide ameliorated AGEs-induced oxidative stress, inflammatory cytokine secretion, caspase activation, and cell death in astrocytes, and reversed the AGEs mediated reduction in intracellular cyclic AMP (cAMP) levels, protein kinase A (PKA) activity, and the phosphorylation of the cAMP response element-binding (CREB) protein. The protective effects of liraglutide against AGEs-mediated toxicity were abolished by GLP-1 receptor (GLP-1R) knockdown or pretreatment of cells with the adenylyl cyclase inhibitor SQ22536 or the PKA inhibitor Rp-cAMP. Conclusions: Liraglutide exerts its neuroprotective effects via the GLP-1R-mediated activation of the cAMP/PKA/CREB pathway. The results of the present study support the therapeutic potential of liraglutide for the treatment of neurodegenerative disorders.

Protective effect of liraglutide against ER stress in the liver of high-fat diet-induced insulin-resistant rats.

The purpose of this study was to investigate whether the glucagon-like peptide-1 (GLP-1) analog liraglutide can alleviate endoplasmic reticulum (ER) stress and insulin resistance (IR) in the liver of high-fat diet-induced insulin-resistant rats. Eighty-five male Sprague-Dawley rats were fed with normal chow or a high-fat diet for 12 weeks. The IR was evaluated using the hyperinsulinemic-euglycemic clamp technique. The rats in the HF group were further divided into four groups and were treated with or without liraglutide by subcutaneous injection. Body weight (BW), fasting blood glucose (FBG), fasting insulin (FINS), and insulin sensitivity were measured. The expression of ER stress marker GRP78 and its signaling mediators, such as IRE1α, PERK, and ATF6, in the liver were examined. The ultrastructure of the ER in the liver was examined by transmission electron microscopy. The expression levels of chemerin in the liver and the serum were also measured. After 4 weeks of liraglutide treatment, the BW, FBG, and FINS levels were significantly reduced, and the insulin sensitivity was increased compared with the HF only rats. Liraglutide reduced the expression of GRP78 and chemerin in liver tissue at both the mRNA and protein levels. Interestingly, the chemerin mRNA was closely correlated with the level of GRP78 mRNA, while the level of chemerin in serum was also associated with the FINS level. As a representative GLP-1 analog, liraglutide can suppress ER stress and reduce chemerin expression in the liver of rats exposed to a high-fat diet.

Protective effects of liraglutide on cardiovascular system

[Summary] Recently liraglutide,which is based on incretin,has attracted considerable attention gradually.Except for decreasing blood glucose favorably,liraglutide has the protective effects on cardiovascular system in patients with diabetes mellitus.It protects vascular endothelial cells and myocardial cells,defends atherosclerosis and improves cardiac function through various mechanisms.In addition,liraglutide also reduces blood pressure,regulates blood lipid,controls body weight,and reduces chronic inflammation.To sum up,liraglutide protects the cardiovascular system directly and reduces cardiovascular risk factors.It may improve the prognosis and the life quality of the patients with type 2 diabetes mellitus. Key words: Liraglutide ; Cardiovascular system ; Protection ;