Effects of GLP-1 Receptor Activation on a Pentylenetetrazole—Kindling Rat Model

Abstract

Objectives: To study the possible anti-seizure and neuroprotective effect of glucagon like peptide 1 (GLP1) analogue (liraglutide) in a pentylenetetrazole (PTZ) induced kindled rat model and its underlying mechanisms. Methods: Thirty Sprague Dawley rats were allocated into 3 equal groups; i) Normal group: normal rats received normal saline, ii) PTZ (kindling) group: received PTZ (50 mg/Kg intraperitoneally (i.p.)) every other day for 2 weeks and iii) PTZ + GLP1 group: same as the PTZ group but rats received liraglutide (75 µg/kg i.p. daily) for 2 weeks before PTZ injection. Seizure severity score, seizure latency and duration were assessed. Also, the expression of caspase-3 (apoptotic marker) and β-catenin (Wnt pathway) by western blotting, markers of oxidative stress (GSH, CAT and MDA) by biochemical assay and the expression of LC3 (marker of autophagy) and heat shock protein 70 (Hsp70) by immunostaining were assessed in hippocampal regions of brain tissues. Results: PTZ caused a significant increase in Racine score and seizure duration with a significant decrease in seizure latency. These effects were associated with a significant increase in MDA, β-catenin, caspase-3, Hsp70 and LC3 in brain tissues (p < 0.05). Meanwhile, liraglutide treatment caused significant attenuation in PTZ-induced seizures, which were associated with significant improvement in markers of oxidative stress, reduction in LC3, caspase-3 and β-catenin and marked increase in Hsp70 in hippocampal regions (p < 0.05). Conclusion: Activation of GLP1R might have anticonvulsant and neuroprotective effects against PTZ-induced epilepsy. These effects could be due to suppression of oxidative stress, apoptosis and autophagy and upregulation of Hsp70.

The Glucagon-Like Peptide-1 Analogue Liraglutide Reduces Seizures Susceptibility, Cognition Dysfunction and Neuronal Apoptosis in a Mouse Model of Dravet Syndrome

“…It has been reported in some research that GLP-1 analogues demonstrate neuroprotective effects in acute and chronic epileptic mouse models. GLP-1 analogs may exert antiepileptic effects through apoptotic pathways in epileptic mouse models (Koshal and Kumar, 2016;Hussein et al, 2019;Wen et al, 2019). Moreover, the mTOR signaling pathway has been shown to be involved in regulating neuronal function, proliferation, apoptosis, and other cellular processes associated with epileptogenesis.…”

“…The GLP-1 receptor (GLP-1R) is widely expressed in neurons of several brain subregions such as hypothalamus, hippocampus, and cortex (Cork et al, 2015;Yoshino et al, 2015), suggesting the GLP-1 signaling could modulate a variety of neuronal functions (Korol et al, 2015;Prashant et al, 2018). Indeed, it has been reported that GLP-1 analogues exert neuroprotective effects in mouse models of acute and chronic epilepsy (Koshal et al, 2018;Wang et al, 2018;Hussein et al, 2019). Previous studies have shown that different apoptosis signaling pathways including BCL-2 associated X protein (BAX)/B cell lymphoma 2 (BCL-2) proteins are involved in seizure-induced neuronal death (Guo et al, 2017;Rubio et al, 2019), and liraglutide treatment could reduce the expression of an apoptotic marker caspase-3 in the brain of a Pentylenetetrazole (PTZ)-induced kindled rat model (Hussein et al, 2019).…”

“…Indeed, it has been reported that GLP-1 analogues exert neuroprotective effects in mouse models of acute and chronic epilepsy (Koshal et al, 2018;Wang et al, 2018;Hussein et al, 2019). Previous studies have shown that different apoptosis signaling pathways including BCL-2 associated X protein (BAX)/B cell lymphoma 2 (BCL-2) proteins are involved in seizure-induced neuronal death (Guo et al, 2017;Rubio et al, 2019), and liraglutide treatment could reduce the expression of an apoptotic marker caspase-3 in the brain of a Pentylenetetrazole (PTZ)-induced kindled rat model (Hussein et al, 2019).…”

The Effects of High-Altitude Environment on Brain Function in a Seizure Model of Young-Aged Rats

“…After preconditioning, all experimental animals received an intraperitoneal injection (i.p.) of 20 mg/kg (The dosage was a moderate dosage compared with those reported by other institutions) pentylenetetrazol (PTZ, Sigma, USA) to generate the convulsion model freely dissolved in saline (solution: 20 mg PTZ dissolved in 1 ml saline) ( 11 , 12 ). Extracorporeal electroencephalogram (EEG) electrodes was placed on 16 rats of each group to monitor the seizure (which don't get the additional PTZ).…”

Effects of Hydro-ethanolic Extract of Tanacetum parthenium and its N-Butanol and Aqueous Fractions on Brain Oxidative Damage in Pentylenetetrazole-Induced Seizures in Mice

“…15 Researchers also reported that the activation of glucagon like peptide 1 receptor (GLP1R) associated with inhibition of oxidative stress and up-regulation of heat shock protein70 (Hsp70) in hippocampus of rats could exert the protective effects against PTZ-stimulated seizures. 16 In addition, increased level of pro-inflammatory mediators such as IL-1β, IL-6, IL-18 and tumor necrosis factor-α (TNF-α) was reported in rats kindled by PTZ. 17 Tanacetum parthenium (TP), named feverfew, is a member from Asteraceae family which grows in different areas of the world such as Iran.…”