glucagon-like-peptide-1 and Brain-Injuries

Traumatic brain injury remains a major cause of death and disability; it is estimated that annually 10 million people are affected. Preclinical studies have shown the potential therapeutic value of stem cell therapies. Neuroprotective as well as regenerative properties of stem cells have been suggested to be the mechanism of action in preclinical studies. However, up to now stem cell therapy has not been studied extensively in clinical trials. This article summarizes the current experimental evidence and points out hurdles for clinical application. Focusing on a cell therapy in the acute stage of head injury, the potential of encapsulated cell biodelivery as a novel cell-therapeutic approach will also be discussed.

Topics: Animals; Brain Injuries; Cell- and Tissue-Based Therapy; Glucagon-Like Peptide 1; Humans; Mesenchymal Stem Cell Transplantation; Transfection; Translational Research, Biomedical

The febrile seizure (FS) is a common disease in emergency pediatrics, and about 30% of patients are children aged between 6 months and 5 years. Therefore, we aim to observe the protective impact of liraglutide (LIR) on brain injury in mice with FS and to explore its relevant mechanisms. Male SD mice were selected, and the FS model was established by heat bath method. The behavioral score was performed on mice with Racine grading, and nerve cells in apoptosis in the hippocampus were determined by TUNEL. The content of glutamate was determined by ELISA. mRNA levels and protein expression of GLP-1, GLP-1R, IL-1

Topics: Animals; Brain Injuries; gamma-Aminobutyric Acid; Glucagon-Like Peptide 1; Glutamates; Humans; Interleukin-6; Liraglutide; Male; Mice; Rats; Rats, Sprague-Dawley; Seizures, Febrile; Tumor Necrosis Factor-alpha

Neuronal apoptosis is considered to be a crucial therapeutic target against early brain injury (EBI) after subarachnoid hemorrhage (SAH). Emerging evidence indicates that Exendin-4 (Ex-4), a glucagon-like peptide 1 receptor (GLP-1R) agonist, plays a neuroprotective role in cerebrovascular disease. This study was conducted in order to verify the neuroprotective role of EX-4 in EBI after SAH in rats. The endovascular perforation model of SAH was performed in Sprague-Dawley rats (n = 153). Ex-4 was intraperitoneally injected 1 h after SAH induction in the rats (SAH + Ex-4). To elucidate the underlying molecular mechanism, small interfering ribonucleic acid (siRNA) for GLP-1R and a specific inhibitor of PI3K, LY294002, were injected intracerebroventricularly into SAH + Ex-4 rats before induction of SAH (n = 6 per group). SAH grading evaluation, immunohistochemistry, Western blots, neurobehavioral assessment, and Fluoro-Jade C (FJC) staining experiments were performed. Expression of GLP-1R was significantly increased and mainly expressed in neurons at 24 h after SAH induction. Administration of Ex-4 significantly improved both short- and long-term neurobehavior in SAH + Ex-4 group compared to SAH + Vehicle group after SAH. Ex-4 treatment significantly increased the expression of GLP-1R, PI3K, p-Akt, Bcl-xl, and Bcl-2, while at the same time was found to decrease expression of Bax in the brain. Effects of Ex-4 were reversed by the intervention of GLP-1R siRNA and LY294002 in SAH + Ex-4+GLP-1R siRNA and SAH + Ex-4+LY294002 groups, respectively. In conclusion, the neuroprotective effect of Ex-4 in EBI after SAH was mediated by attenuation of neuronal apoptosis via GLP-1R/PI3K/Akt signaling pathway, therefore EX-4 should be further investigated as a potential therapeutic agent in stroke patients.

Topics: Animals; Apoptosis; Brain Injuries; Calcium-Binding Proteins; Chromones; Disease Models, Animal; Enzyme Inhibitors; Exenatide; Glucagon-Like Peptide 1; Injections, Intraventricular; Male; Microfilament Proteins; Morpholines; Nerve Tissue Proteins; Neuroprotective Agents; Oncogene Protein v-akt; Peptides; Phosphatidylinositol 3-Kinases; Rats; Rats, Sprague-Dawley; RNA, Small Interfering; Signal Transduction; Subarachnoid Hemorrhage; Venoms

Cerebral edema is a common complication following moderate and severe traumatic brain injury (TBI), and a significant risk factor for development of neuronal death and deterioration of neurological outcome. To this date, medical approaches that effectively alleviate cerebral edema and neuronal death after TBI are not available. Glucagon-like peptide-1 (GLP-1) has anti-inflammatory properties on cerebral endothelium and exerts neuroprotective effects. Here, we investigated the effects of GLP-1 on secondary injury after moderate and severe TBI. Male Sprague Dawley rats were subjected either to TBI by Controlled Cortical Impact (CCI) or sham surgery. After surgery, vehicle or a GLP-1 analogue, Liraglutide, were administered subcutaneously twice daily for two days. Treatment with Liraglutide (200 μg/kg) significantly reduced cerebral edema in pericontusional regions and improved sensorimotor function 48 hours after CCI. The integrity of the blood-brain barrier was markedly preserved in Liraglutide treated animals, as determined by cerebral extravasation of Evans blue conjugated albumin. Furthermore, Liraglutide reduced cortical tissue loss, but did not affect tissue loss and delayed neuronal death in the thalamus on day 7 post injury. Together, our data suggest that the GLP-1 pathway might be a promising target in the therapy of cerebral edema and cortical neuronal injury after moderate and severe TBI.

Topics: Animals; Blood Glucose; Blood-Brain Barrier; Brain Edema; Brain Injuries; Cell Death; Cerebral Cortex; Disease Models, Animal; Glucagon-Like Peptide 1; Liraglutide; Male; Neurons; Neuroprotective Agents; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Sensorimotor Cortex

Traumatic brain injury (TBI), a brain dysfunction for which there is no present effective treatment, is often caused by a concussive impact to the head and affects an estimated 1.7 million Americans annually. Our laboratory previously demonstrated that exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of TBI. Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). Liraglutide promoted dose-dependent proliferation in SH-SY5Y cells and in a GLP-1R over-expressing cell line at reduced concentrations. Pre-treatment with liraglutide rescued neuronal cells from oxidative stress- and glutamate excitotoxicity-induced cell death. Liraglutide produced neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro. The cAMP/PKA/pCREB pathway appears to play an important role in this neuroprotective activity of liraglutide. Furthermore, our findings in cell culture were well-translated in a weight drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI when evaluated 7 and 30 days post trauma. These data cross-validate former studies of exendin-4 and suggest that liraglutide holds therapeutic potential for the treatment of mTBI. Exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of traumatic brain injury (TBI). Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). Liraglutide promoted dose-dependent proliferation in SH-SY5Y cells and in a GLP-1R over-expressing cell line at reduced concentrations. Pretreatment with liraglutide rescued neuronal cells from oxidative stress- and glutamate excitotoxicity-induced cell death. Liraglutide produced neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro, likely involving the cAMP/PKA/pCREB pathway. Our findings in cell culture were well-translated in a weight-drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI.

Topics: Animals; Brain Concussion; Brain Injuries; Cell Death; Cell Line; Disease Models, Animal; Exenatide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Liraglutide; Mice; Neurons; Neuroprotective Agents; Peptides; Receptors, Glucagon; Venoms

This Editorial highlights a study by Li et al. (2015) in the current issue of J. Neurochem. The image depicts the hypothesized neuroprotective pathway that is proposed by the authors. Using a combination of SH-SY5Y and primary rat neuron cultures the GLP-1R agonist, Liraglutide, was shown to increase SH-SY5Y proliferation and CREB phosphorylation correlating with reduced toxicity, preservation of Bcl2 protein levels, and decreased caspase 3 activity following glutamate or H2 O2 stimulations. These in vitro observations correlated with a Liraglutide-dependent improvement in memory performance in mice subjected to a mild TBI. Bcl2, B-cell lymphoma 2; CREB, cAMP-response element binding protein; GLP-1R, glucagon-like peptide 1 receptor; TBI, traumatic brain injury; PKA, protein kinase A.

Topics: Animals; Brain Injuries; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Neuroprotective Agents; Signal Transduction

Mild traumatic brain injury (mTBI) represents a major and increasing public health concern and is both the most frequent cause of mortality and disability in young adults and a chief cause of morbidity in the elderly. Albeit mTBI patients do not show clear structural brain defects and, generally, do not require hospitalization, they frequently suffer from long-lasting cognitive, behavioral, and emotional problems. No effective pharmaceutical therapy is available, and existing treatment chiefly involves intensive care management after injury. The diffuse neural cell death evident after mTBI is considered mediated by oxidative stress and glutamate-induced excitotoxicity. Prior studies of the long-acting GLP-1 receptor agonist, exendin-4 (Ex-4), an incretin mimetic approved for type 2 diabetes mellitus treatment, demonstrated its neurotrophic/protective activity in cellular and animal models of stroke, Alzheimer's and Parkinson's diseases, and, consequent to commonalities in mechanisms underpinning these disorders, Ex-4 was assessed in a mouse mTBI model. In neuronal cultures in this study, Ex-4 ameliorated H2O2-induced oxidative stress and glutamate toxicity. To evaluate in vivo translation, we administered steady-state Ex-4 (3.5 pM/kg/min) or saline to control and mTBI mice over 7 days starting 48 h prior to or 1 h post-sham or mTBI (30 g weight drop under anesthesia). Ex-4 proved well-tolerated and fully ameliorated mTBI-induced deficits in novel object recognition 7 and 30 days post-trauma. Less mTBI-induced impairment was evident in Y-maze, elevated plus maze, and passive avoidance paradigms, but when impairment was apparent Ex-4 induced amelioration. Together, these results suggest that Ex-4 may act as a neurotrophic/neuroprotective drug to minimize mTBI impairment.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Brain; Brain Injuries; Cell Line; Disease Models, Animal; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Male; Memory; Mice; Neuroprotective Agents; Oxidative Stress; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Recognition, Psychology; Trauma Severity Indices; Venoms

Traumatic brain injury (TBI) is a global problem reaching near epidemic numbers that manifests clinically with cognitive problems that decades later may result in dementias like Alzheimer's disease (AD). Presently, little can be done to prevent ensuing neurological dysfunctions by pharmacological means. Recently, it has become apparent that several CNS diseases share common terminal features of neuronal cell death. The effects of exendin-4 (Ex-4), a neuroprotective agent delivered via a subcutaneous micro-osmotic pump, were examined in the setting of mild TBI (mTBI). Utilizing a model of mTBI, where cognitive disturbances occur over time, animals were subjected to four treatments: sham; Ex-4; mTBI and Ex-4/mTBI. mTBI mice displayed deficits in novel object recognition, while Ex-4/mTBI mice performed similar to sham. Hippocampal gene expression, assessed by gene array methods, showed significant differences with little overlap in co-regulated genes between groups. Importantly, changes in gene expression induced by mTBI, including genes associated with AD were largely prevented by Ex-4. These data suggest a strong beneficial action of Ex-4 in managing secondary events induced by a traumatic brain injury.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Brain Injuries; Cognition; Computational Biology; DNA, Complementary; Exenatide; Gene Expression; Glucagon-Like Peptide 1; Hippocampus; Male; Memory Disorders; Mice; Mice, Inbred ICR; Neuroprotective Agents; Peptides; Real-Time Polymerase Chain Reaction; Recognition, Psychology; RNA; Signal Transduction; Venoms

"Naked" human mesenchymal stem cells (MSC) are neuro-protective in experimental brain injury (TBI). In a controlled cortical impact (CCI) rat model, we investigated whether encapsulated MSC (eMSC) act similarly, and whether efficacy is augmented using cells transfected to produce the neuro-protective substance glucagon-like peptide-1 (GLP-1).. Thirty two Sprague-Dawley rats were randomized to five groups: controls (no CCI), CCI-only, CCI+eMSC, CCI+GLP-1 eMSC, and CCI+empty capsules. On day 14, cisternal cerebro-spinal fluid (CSF) was sampled for measurement of GLP-1 concentration. Brains were immuno-histochemically assessed using specific antibody staining for NeuN, MAP-2 and GFAP. In another nine healthy rats, in vitro.. GLP-1 production rates were measured from cells explanted after 2, 7 and 14 days. GLP-1 production rate in transfected cells, before implantation, was 7.03 fmol/capsule/h. Cells were still secreting GLP-1 at a rate of 3.68+/-0.49, 2.85+/-0.45 and 3.53+/-0.55 after 2, 7 and 14 days, respectively. In both of the stem cell treated CCI groups, hippocampal cell loss was reduced, along with an attenuation of cortical neuronal and glial abnormalities, as measured by MAP-2 and GFAP expression. The effects were more pronounced in animals treated with GLP-1 secreting eMSC. This group displayed an increased CSF level of GLP-1 (17.3+/-3.4pM).. Hippocampal neuronal cell loss, and cortical glial and neuronal cyto-skeletal abnormalities, after CCI are reduced following transplantation of encapsulated eMSC. These effects were augmented by GLP-1 transfected eMSC.

Topics: Animals; Brain Injuries; Capsules; Cerebral Cortex; Cerebral Ventricles; Glucagon-Like Peptide 1; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Random Allocation; Rats; Rats, Sprague-Dawley; Transfection

Glucagon-like peptide-1 (GLP-1)(7-36) amide, a member of the glucagon and related peptides family, and its receptor have an anatomically specific expression in the brain. Furthermore, the GLP-1 receptor is expressed in both neurons and glia. Because after a penetrating injury a large population of astrocytes become activated and augment their expression of numerous substances, we have used in situ hybridization to determine whether the expression of the GLP-1 receptor increases in response to a penetrating injury. We have found that GLP-1 receptor expression increases dramatically along the border of the injury. Furthermore, this expression can be colocalized to glial fibrillary acidic protein (GFAP) and non-GFAP mRNA containing cells, suggesting that at least part of this increase is due to an increase in GLP-1 receptor expression in glial cells.

Topics: Animals; Brain Injuries; Gene Expression; Glial Fibrillary Acidic Protein; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; In Situ Hybridization; Male; Neuroglia; Peptide Fragments; Rats; Rats, Wistar; Receptors, Glucagon; RNA, Messenger; Wounds, Stab