glucagon-like-peptide-1 and Seizures

Topics: Amyloid; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Biomarkers; Brain-Derived Neurotrophic Factor; Cognition Disorders; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3 beta; Hippocampus; Insulin-Like Growth Factor I; Kindling, Neurologic; Male; Matrix Metalloproteinase 9; Neural Inhibition; Neurons; Neurotransmitter Agents; Pentylenetetrazole; Rats, Wistar; Receptor for Advanced Glycation End Products; Seizures; Signal Transduction; Sitagliptin Phosphate; Spatial Memory; tau Proteins

This study aimed to investigate the role of glucagon-like peptide-1 (GLP-1)/GLP-1 receptor(R) signaling in the regulation of seizure susceptibility and to explore the potential mechanism in rats.. Hyperthermia-induced seizures in SD rats were generated using hot bath methods, and seizure severity was measured according to Racine scores and electroencephalogram (EEG). Protein levels of GLP-1 and GLP-1R in the brain tissues of rats were evaluated through ELISA, western blot analysis, and immunohistochemistry to explore the possible roles of each in FS. Neuronal excitability, spontaneous inhibitory postsynaptic currents (sIPSCs) and transient receptor potential cation channel subfamily V member 1(TRPV1) currents were tested using the patch-clamp method in cultured hippocampal neurons.. Significant decreases in the levels of GLP-1 and GLP-1R were observed in the hippocampi of rats compared to those in the control group. Furthermore, treatment with the GLP-1R pharmacological inhibitor exendin9-39 increased hyperthermia- induced seizure severity in rats and promoted neuronal firing activity in cultured neurons. Importantly, exendin9-39 and GLP-1R knockdown decreased the amplitude and frequency of sIPSCs in cultured neurons. In addition, GLP-1R knockdown elevated downstream TRPV1 expression and promoted capsaicin-induced TRPV1 function, which may regulate inhibitory neurotransmission to affect seizure susceptibility.. The present study suggests that inhibition of GLP-1R signaling promotes seizure activity, which plays a key role in the pathogenesis of FS.

Topics: Action Potentials; Animals; Cells, Cultured; Central Nervous System Agents; Disease Susceptibility; Female; Fever; Gene Knockdown Techniques; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hippocampus; Inhibitory Postsynaptic Potentials; Male; Neurons; Peptide Fragments; Rats, Sprague-Dawley; Seizures; Signal Transduction; TRPV Cation Channels

Local biological drug delivery in the brain is an innovative field of medicine that developed rapidly in recent years. Our report illustrates a unique case of de novo development of a cerebral arteriovenous malformation (AVM) after implantation of genetically modified allogeneic mesenchymal stem cells in the brain.. A 50-year-old man was included in a prospective clinical study (study ID number CM GLP-1/01, 2007-004516-31) investigating a novel neuroprotective approach in stroke patients to prevent perihematomal neuronal damage. In this study, alginate microcapsules containing genetically modified allogeneic mesenchymal stem cells producing the neuroprotective glucagon-like peptide-1 (GLP-1) were implanted. Three years later, the patient presented with aphasia and a focal seizure due to a new left frontal intracerebral hemorrhage. Angiography revealed a de novo left frontal AVM.. The development of an AVM within a period of 3 years after implantation of the glucagon-like peptide-1-secreting mesenchymal stem cells suggests a possible relationship. This case exemplifies that further investigations are necessary to assess the safety of genetically modified cell lines for local biological drug delivery in the brain.

Topics: Aphasia; Brain; Capsules; Cerebral Hemorrhage; Genetic Therapy; Glucagon-Like Peptide 1; Humans; Intracranial Arteriovenous Malformations; Male; Mesenchymal Stem Cell Transplantation; Middle Aged; Neurons; Seizures; Stroke; Treatment Outcome

Glucagon-like peptide-1 (7-36)-amide (GLP-1) is a gut peptide, which exerts significant effects on glucose homeostasis. GLP-1 and GLP-1 receptors are also widely distributed in the central nervous system. In the present study, we aimed to investigate the effects of intracerebroventricularly (i.c.v.)-injected GLP-1 on pilocarpine-induced seizures, anxiety and locomotor and exploratory activity in rat. Rats were pretreated with GLP-1 (1-1000 ng/5 microl; i.c.v.) or saline (5 microl; i.c.v.) 30 min before seizure induction by pilocarpine (2.4 mg/5 microl; i.c.v.) and with GLP-1 (1, 10, 100 ng/5 microl; i.c.v.) or saline (5 microl; i.c.v.) 30 min before the open field test or the elevated plus maze test. GLP-1 did not produce any protective effect against pilocarpine-induced seizures and did not also produce statistically significant differences in the number of squares visited (measure of locomotor activity) or number of rearings (measure of exploratory behaviour), compared to the saline-treated rats in the open field test. On the other hand, GLP-1 (1 ng and 10 ng; i.c.v.) induced an anxiogenic effect, indicated by a decrease in the time spent in open arms, an increase in the time spent in closed arms, and a decrease in the anxiety scores in the elevated plus maze test. Pretreatment with an arginine vasopressin (AVP) V(1) receptor antagonist (125 ng/5 microl; i.c.v.) and L-NAME (100 microg/5 microl and 200 microg/5 microl) significantly abolished the anxiogenic effect of GLP-1 (1 ng/5 microl; i.c.v.). These results suggest that, centrally-injected GLP-1 produces anxiogenic effects via NO pathway and AVP V(1) receptors, but does not have any effects on pilocarpine-induced seizures or locomotor and exploratory activity in the open field test.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Antidiuretic Hormone Receptor Antagonists; Anxiety; Exploratory Behavior; Glucagon-Like Peptide 1; Injections, Intraventricular; Male; Motor Activity; Muscarinic Agonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type I; Pilocarpine; Rats; Rats, Sprague-Dawley; Seizures; Vasopressins

Glucagon-like peptide-1 (GLP-1) is a gut peptide that, together with its receptor, GLP-1R, is expressed in the brain. Here we show that intracerebroventricular (i.c.v.) GLP-1 and [Ser(2)]exendin(1-9) (HSEGTFTSD; homologous to a conserved domain in the glucagon/GLP-1 family) enhance associative and spatial learning through GLP-1R. [Ser(2)]exendin(1-9), but not GLP-1, is also active when administered peripherally. GLP-1R-deficient mice have a phenotype characterized by a learning deficit that is restored after hippocampal Glp1r gene transfer. In addition, rats overexpressing GLP-1R in the hippocampus show improved learning and memory. GLP-1R-deficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with an intermediate phenotype in heterozygotes and phenotypic correction after Glp1r gene transfer in hippocampal somatic cells. Systemic administration of [Ser(2)]exendin(1-9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for both cognitive-enhancing and neuroprotective agents.

Topics: Administration, Intranasal; Amino Acid Sequence; Animals; Apoptosis; Behavior, Animal; Cognition; Gene Expression; Gene Transfer Techniques; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hippocampus; Kainic Acid; Learning; Male; Mice; Mice, Knockout; Molecular Sequence Data; Neurons; Neuroprotective Agents; Peptide Fragments; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Seizures; Sequence Homology, Amino Acid; Signal Transduction