Neuroprotective Effects Of Liraglutide Research Articles

Neuroprotective effect of liraglutide and memantine in a rat model of Alzheimer’s disease

Objective: To assess the effect of memantine combined with liraglutide on aluminum chloride (AlCl3) and D-galactose (D-GAL)- induced neurotoxicity in rats. Methods: Male Wistar rats were divided into 5 groups of 5 animals each: the positive control, the negative control, the memantine-treated group, the liraglutide-treated group, and the combination group treated with memantine and liraglutide. AlCl3 and D-GAL were used to induce neurotoxicity. Behavioral tests, brain beta-amyloid protein, and oxidative stress biomarkers were evaluated. Results: The Morris water maze test indicated an enhanced memory in the combination group. Moreover, the combination treatment of liraglutide and memantine resulted in a remarkable reduction in the beta-amyloid protein level in the brain tissue. Neuronal inflammation and oxidative stress biomarkers were significantly reduced, and the levels of antioxidant parameters were enhanced. Conclusions: The combination of liraglutide and memantine exerts neuroprotective effects and enhances memory and cognitive functions in rats with Alzheimer’s disease.

Neuroprotective effect of liraglutide in an experimental mouse model of multiple sclerosis: role of AMPK/SIRT1 signaling and NLRP3 inflammasome

The heterogeneous nature of multiple sclerosis (MS) and the unavailability of treatments addressing its intricate network and reversing the disease state is yet an area that needs to be elucidated. Liraglutide, a glucagon-like peptide-1 analogue, recently exhibited intriguing potential neuroprotective effects. The currents study investigated its potential effect against mouse model of MS and the possible underlying mechanisms. Demyelination was induced in C57Bl/6 mice by cuprizone (400 mg/kg/day p.o.) for 5 weeks. Animals received either liraglutide (25 nmol/kg/day i.p.) or dorsomorphin, an AMPK inhibitor, (2.5 mg/Kg i.p.) 30 min before the liraglutide dose, for 4 weeks (starting from the second week). Liraglutide improved the behavioral profile in cuprizone-treated mice. Furthermore, it induced the re-myelination process through stimulating oligodendrocyte progenitor cells differentiation via Olig2 transcription activation, reflected by increased myelin basic protein and myelinated nerve fiber percentage. Liraglutide elevated the protein content of p-AMPK and SIRT1, in addition to the autophagy proteins Beclin-1 and LC3B. Liraglutide halted cellular damage as manifested by reduced HMGB1 protein and consequently TLR-4 downregulation, coupled with a decrease in NF-κB. Liraglutide also suppressed NLRP3 transcription. Dorsomorphin pre-administration indicated a possible interplay between AMPK/SIRT1 and NLRP3 inflammasome activation as it partially reversed liraglutide’s effects. Immunohistochemical examination of Iba+ microglia emphasized these findings. In conclusion, liraglutide exerts neuroprotection against cuprizone-induced demyelination via anti-inflammatory, autophagic flux activation, NLRP3 inflammasome suppression, and anti-apoptotic mechanisms, possibly mediated, at least in part, via AMPK/SIRT1, autophagy, TLR-4/ NF-κB/NLRP3 signaling.Graphical abstractThe potential mechanistic insight of Lira in alleviating Cup-induced neurotoxicity via: (1) AMPK/SIRT1 pathways activation resulting in the stimulation of brain autophagy flux (confirmed by lowering Beclin-1 and LC3-B protein expression). (2) Inhibition of NLRP3 inflammasome activation, as evidenced by reduced HMGB1, TLR-4, NF-κB and NLRP3 protein expression, alongside diminishing the activation of its downstream cascade as reflected by reduced levels of caspase-1 and IL-1β protein expression. (3) A possible modulating interplay between the previously mentioned two pathways.

Neuroprotective effects of liraglutide against inflammation through the AMPK/NF-κB pathway in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease with increasing incidence in aged populations, second only to Alzheimer's disease. Increasing evidence has shown that inflammation plays an important role in the occurrence and development of Parkinson's disease. Growing evidence has shown that AMP-activated protein kinase (AMPK) and NF-κB are closely related to inflammation. Glucagon-like peptide 1 (GLP-1) is a hormone that is primarily secreted by intestinal endocrine L cells, and it has a variety of physiology through binding to GLP-1 receptor. GLP-1can be used for treatment of type 2 diabetes. In addition, GLP-1 also has anti-neuroinflammation activity. However, the exact mechanism behind how GLP-1 regulates neuroinflammation remains unclear. This study was designed to examine the effect of liraglutide on 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-induced injury in mice and its potential mechanism of action. Results showed that liraglutide dose-dependently ameliorated mouse behavior including swimming time and locomotor activity, increased the number of tyrosine hydroxylase (TH)-positive neurons and protein level, and reduced Iba1 and GFAP expression in the substantia nigra (SN). Liraglutide treatment also increased p-AMPK expression and reduced NF-κB protein level. Applying the AMPK inhibitor Dorsomorphin (Compound C) reversed the effect of liraglutide-reducing p-AMPK and increasing NF-κB expression. Finally, GFAP protein level increased, along with a decrease in TH expression. In conclusion, these results suggest that liraglutide can suppress neuroinflammation. Moreover, this effect is mediated through the AMPK/NF-κB signaling pathway.

Neuroprotection in Rats Following Ischaemia-Reperfusion Injury by GLP-1 Analogues\u2014Liraglutide and Semaglutide

PurposeA substantial number of ischaemic stroke patients who receive reperfusion therapy in the acute phase do not ever fully recover. This reveals the urgent need to develop new adjunctive neuroprotective treatment strategies alongside reperfusion therapy. Previous experimental studies demonstrated the potential of glucagon-like peptide-1 (GLP-1) to reduce acute ischaemic damage in the brain. Here, we examined the neuroprotective effects of two GLP-1 analogues, liraglutide and semaglutide.MethodsA non-diabetic rat model of acute ischaemic stroke involved 90, 120 or 180 min of middle cerebral artery occlusion (MCAO). Liraglutide or semaglutide was administered either i.v. at the onset of reperfusion or s.c. 5 min before the onset of reperfusion. Infarct size and functional status were evaluated after 24 h or 72 h of reperfusion.ResultsLiraglutide, administered as a bolus at the onset of reperfusion, reduced infarct size by up to 90% and improved neuroscore at 24 h in a dose-dependent manner, following 90-min, but not 120-min or 180-min ischaemia. Semaglutide and liraglutide administered s.c. reduced infarct size by 63% and 48%, respectively, and improved neuroscore at 72 h following 90-min MCAO. Neuroprotection by semaglutide was abolished by GLP1-R antagonist exendin(9-39).ConclusionInfarct-limiting and functional neuroprotective effects of liraglutide are dose-dependent. Neuroprotection by semaglutide is at least as strong as by liraglutide and is mediated by GLP-1Rs.

Liraglutide protects against diabetes mellitus complicated with focal cerebral ischemic injury by activating mitochondrial ATP-sensitive potassium channels.

Cerebral infarction is a common disease that threatens the health of humankind worldwide. Diabetes is one of the important causes of cerebral ischemic (CI) injury. CI complicated with diabetes has a worse prognosis and lacks effective treatment. Our preliminary study demonstrated that liraglutide mitigates CI injuries in diabetic rats. However, the essential mechanism underlying this effect remained to be fully investigated. Recent research has shown that damaged mitochondrial ATP-sensitive potassium channels (mitoKATP) play a critical role in diabetes-aggravated CI injury. Therefore, we hypothesized that liraglutide may confer therapeutic effects against CI with diabetes by activating mitoKATP channels. In this study, liraglutide, but not insulin, significantly improved ischemia-induced neurological deficits and decreased infarct volumes following CI in diabetic rats, down-regulated the expression of myeloperoxidase and up-regulated the expression of superoxide dismutase and two subunits of the mitoKATP channel (SUR1 and Kir6.2). However, these effects were weakened by the mitoKATP antagonist 5-hydroxydecanoic acid. Our study demonstrated that the neuroprotective effects of liraglutide on CI injury with diabetes, which occurs by reducing oxidative stress and the inflammatory response, are associated with the activation of the mitoKATP channel.

Long-term liraglutide ameliorates nigrostriatal impairment via regulating AMPK/PGC-1a signaling in diabetic mice

Growing evidence indicates links between type 2 diabetes and Parkinson’s disease. The glucagon-like peptide 1 analogue, liraglutide, a commonly used anti-diabetic drug, has protective effects on neurons. The goal of this study was to determine whether long-term liraglutide treatment could reduce the risk of adult type 2 diabetic mice developing Parkinson’s disease. Male diabetic db/db mice (12 weeks old) were injected daily with liraglutide (n = 8), or saline (n = 8), and non-diabetic m/m littermates (n = 6) were included as controls. Motor function was assessed every 4 weeks and all mice were sacrificed after 8 weeks of drug intervention for further analysis. The results revealed that long-term treatment of liraglutide protected the db/db mice against the motor function decay and the dopaminergic neuron loss. Liraglutide also restored the impaired AMP kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator 1a (PGC-1a) signaling in the striatum of db/db mice. Further experiments in SH-SY5Y cells supported that AMPK is involved in the neuroprotective effect of liraglutide. In summary, long-term liraglutide ameliorated motor dysfunction and dopaminergic neuron impairment in type 2 diabetic mice, probably via enhancing AMPK/PGC-1a signaling.

Liraglutide ameliorated peripheral neuropathy in diabetic rats: Involvement of oxidative stress, inflammation and extracellular matrix remodeling.

Diabetic peripheral neuropathy is one of the most common microvascular complications that occurs with both type 1 and type 2 diabetes mellitus. It has a significant negative impact on patients' quality of life; as it starts with loss of limbs' sensation and may lead to lower limb amputation. This study aimed at investigating the effect of liraglutide on peripheral neuropathy in diabetic rats. Experimental diabetes was induced by single intraperitoneal injections of nicotinamide (50mg/kg) and streptozotocin (52.5mg/kg). Rats were allocated into five groups. Two groups were given saline or liraglutide (0.8mg/kg, s.c.). Three diabetic groups were either untreated or treated with liraglutide (0.8mg/kg, s.c.) or pregabalin (10mg/kg, i.p.). After 2weeks of treatment, behavioral, biochemical, histopathological, and immunohistochemical investigations were performed. Treatment with liraglutide-restored animals' body weight, normalized blood glucose, decreased glycated hemoglobin, and increased insulin levels. In parallel, it normalized motor coordination and the latency withdrawal time of both tail flick and hind paw cold allodynia tests and reversed histopathological alterations. Treatment with liraglutide also normalized malondialdehyde, matrix metalloproteinase-2 and -9 contents in sciatic nerve. Likewise, it decreased sciatic nerve nitric oxide and interleukin-6 contents, DNA fragmentation and expression of cyclooxygenase-2. Meanwhile, it increased superoxide dismutase and interleukin-10 contents in sciatic nerve. These findings indicate the neuroprotective effect of liraglutide against diabetic peripheral neuropathy probably via modulating oxidative stress, inflammation, and extracellular matrix remodeling.

Effects of liraglutide in hypothalamic arcuate nucleus of obese mice.

The neuroprotective effects of liraglutide (200 μg/kg, twice daily, subcutaneous administration) in the hypothalamic arcuate nucleus (ARC) of diet-induced obese mice were investigated. C57BL/6 mice were separated into groups: standard chow treated with vehicle or liraglutide and the respective liraglutide pair-fed group; high-fat diet treated with vehicle or liraglutide and the respective pair-fed group. Body mass (BM) evolution, carbohydrate metabolism, leptin resistance, proteins involved in energetic balance, apoptosis, and microglia in the ARC were studied. Obese animals showed glucose intolerance, resistance to insulin and to anorexigenic effect of leptin, and microgliosis accompanied by elevated Bax/Bcl2 ratio in the ARC. Liraglutide improved the carbohydrate metabolism, BM loss, and the activation of pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) in the ARC. The liraglutide enhanced leptin sensitivity and diminished the microgliosis with decrease in Bax/Bcl2 ratio. Liraglutide activates central anorexigenic pathways, thereby diminishing the energy intake of obese mice and improving the metabolic parameters related to obesity. Liraglutide is a relevant neuroprotective agent, which can decrease the microgliosis and stimulate the anti-apoptotic pathway, a significant effect in the treatment of obesity and its comorbidities. Some benefits of liraglutide are independent of the BM loss, which usually accompanies the drug administration.

Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide.

Long-acting glucagon-like peptide-1 (GLP-1) analogues marketed for type 2 diabetes (T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors (GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions (e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation (thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2D, stroke and Alzheimer disease (AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia inhibition, behavior and cognition, and in AD biomarkers. Herein, we discuss the GLP-1 action through the gut-brain axis, the hormone's regulation of some autonomic functions and liraglutide's neuroprotective potential.

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.