• Autophagy
• Lipid metabolism
• Metabolic syndrome
• Mitophagy
• Neurodegenerative diseases

• Humans
• Neurodegenerative Diseases/metabolism
• Neurodegenerative Diseases/drug therapy
• Metabolic Syndrome/metabolism
• Metabolic Syndrome/drug therapy
• Mitochondria/metabolism
• Mitochondria/drug effects
• Animals
• Energy Metabolism/drug effects
• Neurons/metabolism
• Glucose/metabolism
• Lipid Metabolism/drug effects
• Insulin/metabolism

• CRISPR/cas9
• GLP‐1R
• GPCR
• arrestins
• receptor internalization

• 846827 HORIZON EUROPE Marie Sklodowska-Curie Actions
• JP22ama121038 Japan Agency for Medical Research and Development
• JP22zf0127007 Japan Agency for Medical Research and Development
• NNF17OC0027004 Novo Nordisk Fonden
• JPMJFR215T Japan Science and Technology Agency
• JPMJMS2023 Japan Science and Technology Agency
• JP21H04791 Japan Society for the Promotion of Science
• JP21H05037 Japan Society for the Promotion of Science
• JP21H05113 Japan Society for the Promotion of Science
• 4183-00131A Danmarks Frie Forskningsfond
• 8020-02308 Danmarks Frie Forskningsfond

• benefits of glp-1 agonists
• diabetes
• glp-1 agonist
• glucagon-like peptide
• liraglutide
• management of type 2 diabetes
• obstructive sleep apnea
• tirzepatide

• Dementia
• cognitive
• diabetes-related-dementia
• gliptins
• incretin.
• insulin

• Humans
• Incretins/therapeutic use
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/metabolism
• Dementia/drug therapy
• Insulin/metabolism
• Insulin/therapeutic use
• Signal Transduction/drug effects
• Animals
• Hypoglycemic Agents/therapeutic use

• Blood-brain barrier
• Cognitive
• DPP4
• Gastric inhibitory peptide
• Glucagon-like peptide-1
• Incretins
• Insulin
• Tau phosphorylation
• Type 2 diabetes mellitus.

• Alzheimer Disease/drug therapy
• Alzheimer Disease/metabolism
• Humans
• Dipeptidyl-Peptidase IV Inhibitors/pharmacology
• Dipeptidyl-Peptidase IV Inhibitors/chemistry
• Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis
• Glucagon-Like Peptide 1/metabolism
• Dipeptidyl Peptidase 4/metabolism
• Animals
• Gastric Inhibitory Polypeptide/pharmacology
• Gastric Inhibitory Polypeptide/metabolism

• Akkermansia muciniphila
• Alzheimer’s disease
• depression
• microbiota-gut-brain axis
• neuropsychiatric disorders

• Akkermansia/physiology
• Humans
• Animals
• Neurodegenerative Diseases/microbiology
• Neurodegenerative Diseases/pathology
• Mental Disorders/microbiology
• Brain-Gut Axis
• Gastrointestinal Microbiome
• Inflammation/pathology
• Nervous System Diseases/microbiology
• Nervous System Diseases/pathology

• GLP-1R agonists
• Human pancreatic beta cells
• Wolfram syndrome
• iPSC-derived beta cells
• iPSC-derived neurons

• Humans
• Animals
• Mice
• Wolfram Syndrome/drug therapy
• Wolfram Syndrome/genetics
• Exenatide/therapeutic use
• Induced Pluripotent Stem Cells
• Optic Atrophy/pathology
• Insulin-Secreting Cells/pathology
• Mice, Knockout

• UH3 TR002065 NCATS NIH HHS
• U01 DK127786 NIDDK NIH HHS
• R01 DK132090 NIDDK NIH HHS
• UL1 TR000448 NCATS NIH HHS
• P60 DK020579 NIDDK NIH HHS
• P30 DK020579 NIDDK NIH HHS
• UL1 TR002345 NCATS NIH HHS
• UH2 TR002065 NCATS NIH HHS
• Pandarome project FWO and F.R.S.-FNRS under the Excellence of Science (EOS) programme
• Welbio-FNRS
• National Institutes of Health (NIH)/NIDDK
• Philanthropic supports from the Silberman Fund, the Ellie White Foundation for the Rare Genetic Disorders, the Snow Foundation, the Unravel Wolfram Syndrome Fund, the Stowe Fund, the Feiock Fund, the Cachia Fund, the Gildenhorn Fund, the Eye Hope Foundation, Ontario Wolfram League, Associazione Gentian - Sindrome di Wolfram Italia, Alianza de Familias Afectadas por el Sindrome Wolfram Spain, Wolfram syndrome UK, and Association Syndrome de Wolfram France.
• the Walloon Region SPW-EER Win2Wal project BetaSource
• National Institutes of Health Human Islet Research Network Consortium on Beta Cell Death & Survival from Pancreatic β-Cell Gene Networks to Therapy [HIRN-CBDS])
• Eye Hope Foundation
• Fonds Erasme for Medical Research
• Alianza de familias afectadas por el síndrome de Wolfram (AFASW)
• Brussels Region Innoviris (Bridge) project DiaType
• Dutch Diabetes Research Foundation (Innovate2CureType1)
• Fonds National de la Recherche Scientifique (FNRS)
• Francophone Foundation for Diabetes Research (FFRD, that is sponsored by the French Diabetes Federation, Abbott, Eli Lilly,Merck Sharp & Dohme and Novo Nordisk)
• NIH/ National Center for Advancing Translational Sciences (NCATS)

• Depression
• Diabetes mellitus
• GLP-1
• GLP-1 receptor agonist
• Incretin
• Neuroprotective

• Humans
• Drug Repositioning
• Diabetes Mellitus
• Obesity
• Cardiovascular Diseases/drug therapy
• Dyslipidemias

Defects in brain energy metabolism and proteopathic stress are implicated in age-related degenerative neuronopathies, exemplified by Alzheimer’s disease (AD) and Parkinson’s disease (PD). As the currently available drug regimens largely aim to mitigate cognitive decline and/or motor symptoms, there is a dire need for mechanism-based therapies that can be used to improve neuronal function and potentially slow down the underlying disease processes. In this context, a new class of pharmacological agents that achieve improved glycaemic control via the glucagon-like peptide 1 (GLP-1) receptor has attracted significant attention as putative neuroprotective agents. The experimental evidence supporting their potential therapeutic value, mainly derived from cellular and animal models of AD and PD, has been discussed in several research reports and review opinions recently. In this review article, we discuss the pathological relevance of derangements in the neurovascular unit and the significance of neuron–glia metabolic coupling in AD and PD. With this context, we also discuss some unresolved questions with regard to the potential benefits of GLP-1 agonists on the neurovascular unit (NVU), and provide examples of novel experimental paradigms that could be useful in improving our understanding regarding the neuroprotective mode of action associated with these agents.

• Diabetes
• GIP
• Glucagon-like peptide 1
• Insulin resistance
• Parkinson’s disease
• autophagy
• inflammation

Cocaine use disorder (CUD) is a major public health challenge with a high relapse rate and lack of effective pharmacotherapies; therefore, there is a substantial need to identify novel medications to treat this epidemic. Since the advent of glucagon-like peptide-1 (GLP-1) receptors (GLP-1Rs) agonists (GLP-1RAs), their potential has been extensively explored and expanded. In this review, we first summarized the biological effects of GLP-1, GLP-1Rs, and GLP-1RAs. Subsequently, the recent literature examining the behavioral effects and the possible pharmacological mechanisms of GLP-1RAs on CUD was reviewed. Increasing preclinical evidence suggests that GLP-1RAs are promising in regulating dopamine release, dopamine transporter (DAT) surface expression and function, mesolimbic reward system and GABAergic neurons, and maladaptive behaviors in animal models of self-administration and conditioned place preference. In addition, the emerging role of GLP-1RAs in inhibiting inflammatory cytokines was reported. These findings indicate that GLP-1RAs perform essential functions in the modulation of cocaine-seeking and cocaine-taking behaviors likely through multifaceted mechanisms. Although the current preclinical evidence provides convincing evidence to support GLP-1RA as a promising pharmacotherapy for CUD, other questions concerning clinical availability, impact and specific mechanisms remain to be addressed in further studies.

• GABA
• arachidonic acid
• cocaine
• dopamine
• glucagon-like peptide-1 receptor agonist
• glutamate
• neuroinflammation

Rare diseases are life-threatening or chronically debilitating low-prevalent disorders caused by pathogenic mutations or particular environmental insults. Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Since new drug discovery is a very costly and time-consuming process, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high cost of investments compared to the low market return of the product. Drug repurposing–based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases. In this article, we discuss the scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington’s disease, Friedreich’s ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis. The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation will also be discussed.

• European Medicines Agency (EMA)
• Food and Drug Administration (FDA, US)
• Friedreich’s ataxia
• Huntington’s disease
• amyotrophic lateral sclerosis
• drug repurposing
• orphanet
• wolfram syndrome

• Alzheimer’s disease
• GLP-1R agonists
• amyloid beta
• cognitive function
• tau phosphorylation

• Humans
• Alzheimer Disease/drug therapy
• Glucagon-Like Peptide-1 Receptor
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/drug therapy
• Drug-Related Side Effects and Adverse Reactions
• Insulin Resistance

The present study investigates the antiParkinsonian activity of dipeptidyl peptidase-4 (DPP-IV) inhibitor, linagliptin. The experimental Parkinson's disease (PD) was induced by administration of rotenone at a dose of 1.5 mg/kg at alternate day subcutaneously for 21 days. Standard drug (levodopa-200 mg/kg and carbidopa-50 mg/kg) and treatment drug (linagliptin-5 mg/kg, 10 mg/kg, and 20mg/kg) were administered orally daily 1 h before rotenone administration. In a rat rotenone model, linagliptin improved muscle coordination, motor performance, and corrected akinesia. Pretreatment with linagliptin showed significant higher levels of superoxide dismutase, catalase, and glutathione in brain homogenate of animals. Linagliptin significantly elevated the levels of striatal DA and active glucagon-like peptide 1 in brain homogenate of animals. Furthermore, linagliptin amended alterations induced by rotenone in the thiobarbituric acid reactive substances and inflammatory marker such as tumor necrosis factor-α level. The results of the present study indicate the neuroprotective potential of linagliptin for the management of PD might be due to remarkable improvement in motor functions, antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective mechanisms.

• Dipeptidyl peptidase-4 inhibitors
• Parkinson's disease
• glucagon-like peptide 1
• linagliptin
• rotenone

• Faecal metabolomics
• Gut microbiome
• L. plantarum-pMG36e-GLP-1
• T2DM

• Alzheimer’s disease
• DPP-4 inhibitor
• SGLT2 inhibitor
• insulin resistance
• insulin signaling
• type 2 diabetes mellitus

Exendin-4 (Ex4), a long-lasting glucagon-like peptide-1 analog, was reported to exert favourable actions on inhibiting cocaine-associated rewarding and reinforcing effects of drug in animal models of addiction. However, the therapeutic potential of different dose of GLP-1 receptor agonist Ex4 in different behavioral paradigms and the underlying pharmacological mechanisms of action are incompletely understood. Herein, we firstly investigated the effects of Ex4 on cocaine-induced condition place preference (CPP) as well as extinction and reinstatement in male C57BL/6J mice. Additionally, we sought to elucidate the underlying pharmacological mechanism of these actions of Ex4. The paradigm of cocaine-induced CPP was established using 20 mg/kg cocaine or saline alternately during conditioning, while the reinstatement paradigm was modeled using 10 mg/kg cocaine on the reinstatement day. Different dose of Ex4 was administrated intraperitoneally either during conditioning or during extinction state or only on the test day. To elucidate the molecular mechanism underlying the potential effects of Ex4 on maladaptive behaviors of cocaine, the TLR4-related inflammation within the hippocampus was observed by immunofluorescence staining, and the expression levels of toll-like receptor 4 (TLR4), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β were detected by Western blotting. As a consequence, systemic administration of different dose of Ex4 was sufficient to inhibit the acquisition and expression of cocaine-induced CPP, facilitate the extinction of cocaine-associated reward and attenuate reinstatement of cocaine-induced behavior. Furthermore, Ex4 treatment diminished expression levels of TLR4, TNF-α, and IL-1β, which were up-regulated by cocaine exposure. Altogether, our results indicated that Ex4 effectively ameliorated cocaine-induced behaviors likely through neurobiological mechanisms partly attributable to the inhibition of TLR4, TNF-α and IL-1β in mice. Consequently, our findings improved our understanding of the efficacy of Ex4 for the amelioration of cocaine-induced behavior and suggested that Ex4 may be applied as a drug candidate for cocaine addiction.

• cocaine
• condition place preference
• exendin-4
• extinction
• neuroinflammation
• reinstatement
• toll-like receptor 4

• Diabetic neuropathy
• ERK
• cAMP
• dipeptidyl peptidase-4 inhibitors
• glucagon-like peptide-1 receptor agonists
• hyperglycemia
• schwann cells

• Short-chain fatty acids
• microbiota-gut-brain axis
• probiotics
• psychiatric disorders
• psychobiotics

• Albiglutide
• Body weight
• Cardiovascular disease
• Dulaglutide
• Exenatide
• Glucagon-like peptide-1 receptor agonists
• Liraglutide
• Lixisenatide
• Semaglutide
• Type 2 diabetes

• Animals
• Blood Glucose
• Body Weight
• Cardiovascular System/drug effects
• Diabetes Mellitus, Type 2/drug therapy
• Exenatide/pharmacology
• Glucagon-Like Peptide 1/analogs & derivatives
• Glucagon-Like Peptide-1 Receptor/agonists
• Glucagon-Like Peptide-1 Receptor/metabolism
• Glucagon-Like Peptides/analogs & derivatives
• Glucagon-Like Peptides/pharmacology
• Humans
• Hypoglycemia
• Immunoglobulin Fc Fragments
• Insulin/pharmacology
• Liraglutide/pharmacology
• Neurodegenerative Diseases
• Peptides/pharmacology
• Psoriasis
• Recombinant Fusion Proteins

• cerebral ischaemia
• hypoxic ischaemic brain injury
• post-cardiac arrest syndrome
• postanoxic coma
• resuscitation

• Anti-neuroinflammatory
• Antioxidant
• Chalcones
• Neuroprotection
• Neurotrophic
• Redox balance

• Animals
• Anti-Inflammatory Agents/pharmacology
• Antioxidants/pharmacology
• Central Nervous System/drug effects
• Central Nervous System/metabolism
• Central Nervous System/pathology
• Central Nervous System/physiopathology
• Central Nervous System Diseases/drug therapy
• Central Nervous System Diseases/metabolism
• Central Nervous System Diseases/pathology
• Central Nervous System Diseases/physiopathology
• Chalcones/therapeutic use
• Humans
• Inflammation Mediators/metabolism
• Neurogenesis/drug effects
• Neurons/drug effects
• Neurons/metabolism
• Neurons/pathology
• Neuroprotective Agents/therapeutic use
• Oxidation-Reduction
• Oxidative Stress/drug effects
• Signal Transduction

Background: Hyperglycemia-induced oxidative stress plays a key role in diabetic complications, including diabetic retinopathy. The main goal of this study was to assess whether the topical administration (eye drops) of glucagon-like peptide-1 (GLP-1) has any effect on oxidative stress in the retina. Methods: db/db mice were treated with eye drops of GLP-1 or vehicle for three weeks, with db/+ mice being used as control. Studies included the assessment by western blot of the antioxidant defense markers CuZnSOD, MnSOD, glutathione peroxidase and reductase; immunofluorescence measurements of DNA/RNA damage, nitro tyrosine and Ki67 and Babam2 proteins. Results: GLP-1 eye drops protected from oxidative stress by increasing the protein levels of glutathione reductase, glutathione peroxidase and CuZnSOD and MnSOD in diabetic retinas. This was associated with a significant reduction of DNA/RNA damage and the activation of proteins involved in DNA repair in the retina (Babam2) and Ki67 (a biomarker of cell proliferation). Conclusions: GLP-1 modulates the antioxidant defense system in the diabetic retina and has a neuroprotective action favoring DNA repair and neuron cells proliferation.

• GLP-1
• diabetic retinopathy
• free radicals
• oxidative stress
• superoxide dismutase

• Alzheimer's disease
• GLP1
• Insulin
• Neurodegenerative diseases
• Parkinson's disease

• Acute ischemic stroke
• Diabetes mellitus
• Dipeptidyl Peptidase-IV Inhibitors
• Glucagon-like 1 receptor agonists
• Hyperglycemia

• Cerebral ischemia
• DPP-4 inhibitor
• Hyperglycemia
• Linagliptin
• Neuroprotection

• anti-inflammation
• diabetic neuropathy
• glucagon-like peptide-1 agonist
• interleukin-6
• liraglutide

• Parkinson’s disease
• immunization
• neuroinflammation
• neuroprotection
• neuroregeneration

• Alzheimer disease
• Cognition
• Galactose
• Metabolism
• Positron-emission tomography
• Transgenic mice

The aim of the present study was to determine whether treatment with liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, would alter mammalian target of rapamycin complex 1 (mTORC1) signaling and/or α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor activity under dexamethasone-induced toxic conditions. Western blot analyses were performed to assess changes in mTORC1-mediated proteins, brain-derived neurotrophic factor (BDNF), and various synaptic proteins (PSD-95, synapsin I, and GluA1) in rat hippocampal cultures under toxic conditions induced by dexamethasone, which causes hippocampal cell death. Hippocampal dendritic outgrowth and spine formation were measured using immunostaining procedures. Dexamethasone significantly decreased the phosphorylation levels of mTORC1 as well as its downstream proteins. However, treatment with liraglutide prevented these reductions and significantly increased BDNF expression. The increase in BDNF expression was completely blocked by rapamycin and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). Liraglutide also recovered dexamethasone-induced decreases in the total length of hippocampal dendrites and reductions in spine density in a concentration-dependent manner. However, the positive effects of liraglutide on neural plasticity were abolished by the blockade of mTORC1 signaling and AMPA receptors. Furthermore, liraglutide significantly increased the expression levels of PSD-95, synapsin I, and GluA1, whereas rapamycin and NBQX blocked these effects. The present study demonstrated that liraglutide activated mTORC1 signaling and AMPA receptor activity as well as increased dendritic outgrowth, spine density, and synaptic proteins under toxic conditions in rat primary hippocampal neurons. These findings suggest that GLP-1 receptor (GLP-1R) activation by liraglutide may affect neuroplasticity through mTORC1 and AMPA receptors.

• glucagon-like peptide 1 receptor
• liraglutide
• mammalian target of rapamycin complex 1 signaling
• neuroplasticity
• toxic condition
• α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor

• Alzheimer’s disease (AD)
• COX-2
• GLP-1
• MG1363-pMG36e-GLP-1
• TLR-4

• Cognition
• antipsychotic
• glucagon-like peptide-1
• liraglutide
• obesity

Multiple population based analyses have demonstrated a high incidence of cardiovascular disease (CVD) and cardiovascular (CV) mortality in subjects with T2DM that reduces life expectancy by as much as 15 years. Importantly, the CV system is particularly sensitive to the metabolic and immune derangements present in obese pre-diabetic and diabetic individuals; consequently, CV dysfunction is often the initial CV derangement to occur and promotes the progression to end organ/tissue damage in T2DM. Specifically, diabetic CVD can manifest as microvascular complications, such as nephropathy, retinopathy, and neuropathy, as well as, macrovascular impairments, including ischemic heart disease, peripheral vascular disease, and cerebrovascular disease. Despite some progress in prevention and treatment of CVD, mainly via blood pressure and dyslipidemia control strategies, the impact of metabolic disease on CV outcomes is still a major challenge and persists in proportion to the epidemics of obesity and diabetes. There is abundant pre-clinical and clinical evidence implicating the DPP-4-incretin axis in CVD. In this regard, linagliptin is a unique DPP-4 inhibitor with both CV and renal safety profiles. Moreover, it exerts beneficial CV effects beyond glycemic control and beyond class effects. Linagliptin is protective for both macrovascular and microvascular complications of diabetes in preclinical models, as well as clinical models. Given the role of endothelial-immune cell interactions as one of the key events in the initiation and progression of CVD, linagliptin modulates these cell–cell interactions by affecting two important pathways involving stimulation of NO signaling and potent inhibition of a key immunoregulatory molecule.

• Diastolic dysfunction
• Incretin
• Insulin resistance
• Obesity
• Vascular dysfunction

• Animals
• Diabetes Mellitus, Type 2/drug therapy
• Exenatide
• Gastric Inhibitory Polypeptide/pharmacology
• Humans
• Hypoglycemic Agents/therapeutic use
• Incretins/therapeutic use
• Neurodegenerative Diseases/drug therapy
• Peptides/therapeutic use
• Venoms/therapeutic use

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain where it regulates activity of neuronal networks. The receptor for glucagon-like peptide-1 (GLP-1) is expressed in the hippocampus, which is the center for memory and learning. In this study we examined effects of liraglutide, a GLP-1 analog, on GABA signaling in CA3 hippocampal pyramidal neurons.

We used patch-clamp electrophysiology to record synaptic and tonic GABA-activated currents in CA3 pyramidal neurons in rat hippocampal brain slices.

We examined the effects of liraglutide on the neurons at concentrations ranging from one nM to one μM. Significant changes of the spontaneous inhibitory postsynaptic currents (sIPSCs) were only recorded with 100 nM liraglutide and then in just ≈50% of the neurons tested at this concentration. In neurons affected by liraglutide both the sIPSC frequency and the most probable amplitudes increased. When the action potential firing was inhibited by tetrodotoxin (TTX) the frequency and amplitude of IPSCs in TTX and in TTX plus 100 nM liraglutide were similar.

The results demonstrate that liraglutide regulation of GABA signaling of CA3 pyramidal neurons is predominantly presynaptic and more limited than has been observed for GLP-1 and exendin-4 in hippocampal neurons.

• Electrophysiology
• GABA
• GLP-1 receptor
• Hippocampus
• Inhibitory postsynaptic and tonic currents
• Patch-clamp

• Alzheimer’s disease (AD)
• Amyloid beta (Aβ)
• diabetes-induced dementia
• glucagon like peptide 1 (GLP-1)
• insulin resistance
• type 3 diabetes

• Diabetes mellitus
• Diabetic enteropathy
• Motility
• Prokinetics
• Small intestine

Glucagon like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors, which block inactivation of GLP-1, are currently in clinical use for type 2 diabetes mellitus. Recently, GLP-1 has also been reported to have neuroprotective effects in cases of cerebral ischemia. We therefore investigated the neuroprotective effects of GLP-1 receptor (GLP-1R) agonist, exendin-4 (ex-4), after cerebral ischemia-reperfusion injury. Transient middle cerebral artery occlusion (tMCAO) was induced in rats by intracerebroventricular (i.c.v.) administration of ex-4 or ex9-39. Oxygen-glucose deprivation was also induced in primary neurons, bEnd.3 cells, and BV-2. Ischemia-reperfusion injury reduced expression of GLP-1R. Additionally, higher oxidative stress in SOD2 KO mice decreased expression of GLP-1R. Downregulation of GLP-1R by ischemic injury was 70% restored by GLP-1R agonist, ex-4, which resulted in significant reduction of infarct volume. Levels of intracellular cyclic AMP, a second messenger of GLP-1R, were also increased by 2.7-fold as a result of high GLP-1R expression. Moreover, our results showed that ex-4 attenuated pro-inflammatory cyclooxygenase-2 (COX-2) and prostaglandin E₂ after MCAO. C-Jun NH₂ terminal kinase (JNK) signaling, which stimulates activation of COX-2, was 36% inhibited by i.c.v. injection of ex-4 at 24 h. Islet-brain 1 (IB1), a scaffold regulator of JNK, was 1.7-fold increased by ex-4. GLP-1R activation by ex-4 resulted in reduction of COX-2 through increasing IB1 expression, resulting in anti-inflammatory neuroprotection during stroke. Our study suggests that the anti-inflammatory action of GLP-1 could be used as a new strategy for the treatment of neuroinflammation after stroke accompanied by hyperglycemia.

• Cerebral ischemia
• Exendine-4
• Glucagon like peptide-1 receptor
• Islet-brain 1
• Neuroinflammation
• c-Jun NH2 terminal kinase

• Alzheimer’s disease
• Bariatric surgery
• Dementia
• Diabetes
• Gastric bypass
• Glucagon-like peptide 1
• Insulin
• Metabolic surgery
• Obesity
• Weight loss

• appetite
• central nervous system
• glucagon-like peptide-1
• neurodegenerative diseases
• type 2 diabetes

• Animals
• Central Nervous System/metabolism
• Diabetes Mellitus/metabolism
• Diabetes Mellitus, Type 2/metabolism
• Glucagon-Like Peptide 1/metabolism
• Humans
• Neurodegenerative Diseases/metabolism
• Peripheral Nervous System/metabolism

• Advanced oxidative protein products
• Apoptosis
• Glucagon-like peptide-1
• Podocytes
• Receptor for advanced glycation endproducts

• Diabetes
• Dysfunction
• Gastrointestinal tract
• Mechanosensory
• Remodeling