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.
Highlights
Epilepsy is the most common serious neurological disorder [1] that affects approximately 70 million people of all ages throughout the world [2]
Administration of GLP1 in PTZ-treated rats caused marked reduction in seizure score (F (1,15) = 128.6, p < 0.0001) that was evident in early treatment (GLP1 + PTZ group vs. PTZ group trial 1 mean ± standard errors of mean (SEM) = 1.0 ± 0.2 vs. 2.2 ± 0.2, t = 3.15 df = 15, p = 0.006) and continued throughout treatment
At a dose of 50 mg/kg every other day for 2 weeks caused rat kindling which was associated with enhanced oxidative stress, upregulation of LC3, caspase-3, β-catenin and Hsp70 in brain tissues, and ii) treatment with liraglutide with PTZ caused significant attenuation of PTZ-induced seizures and reduction of oxidative stress and downregulation of LC3, caspase-3, β-catenin and Hsp70
Summary
Epilepsy is the most common serious neurological disorder [1] that affects approximately 70 million people of all ages throughout the world [2]. In Egypt, the prevalence of epilepsy was 6.98/1000 [3]. Brain Sci. 2019, 9, 108; doi:10.3390/brainsci9050108 www.mdpi.com/journal/brainsci. Epilepsy is characterized by persistent spontaneous seizures due to abnormal synchronous neuronal discharges within the brain [4]. Antiepileptic drugs (AEDs) are symptomatic and have more anti-seizure effects than antiepileptic effects [5]. These drugs have many side effects such as systemic and neurological toxicity, depression, loss of memory and osteoporosis [6]. Discovery of a novel line of treatment that prevents the epileptic seizure is necessary
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