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

Abstract

Moreover, liraglutide protected against Scn1a KO-induced apoptosis, which was manifested in the phosphorylation of mTOR (KO+NS: 1.99 ± 0.31 vs. KO+Lira: 0.97 ± 0.18, P = 0.0004), as well as the downregulation of cleaved caspase-3 (KO+NS: 0.49 ± 0.04 vs. KO+Lira: 0.30 ± 0.01, P = 0.0003) and restoration of the imbalance between BAX (KO+NS: 0.90 ± 0.02 vs. KO +Lira: 0.75 ± 0.04, P = 0.0005) and BCL-2 (KO+NS: 0.46 ± 0.02 vs. KO+Lira: 0.61 ± 0.02, P = 0.0006). Collectively, these results show that liraglutide reduces seizure susceptibility and cognitive dysfunction in the mouse model of Dravet syndrome, and exerts anti-apoptotic and neuroprotective effects in Scn1a KO mice and cells.

An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

“…Neuronal damage to GABAergic arborization includes cortical necrosis and disorderly cellular architecture and produces a phenotype related to the underlying Scn1a genetic defect, but seizure-related excitotoxic damage also causes neurodegeneration. Neurodegeneration is evident in Scn1a−/− mice as necrosis in cortical regions at 14 days following onset of epileptic activity [31]. Cortical damage was accompanied by apoptosis, mTOR activation indicating metabolic stress, and poor performance on four cognitive function tests evaluating learning and spatial memory [31].…”

“…Neurodegeneration is evident in Scn1a−/− mice as necrosis in cortical regions at 14 days following onset of epileptic activity [31]. Cortical damage was accompanied by apoptosis, mTOR activation indicating metabolic stress, and poor performance on four cognitive function tests evaluating learning and spatial memory [31].…”

“…In addition to the activity of fenfluramine and its major metabolite norfenfluramine at serotonergic receptors, recent preclinical studies in mouse and zebrafish models have identified previously undocumented positive modulatory activity of fenfluramine at sigma-1 receptors (Sigma1Rs) [22,23] (Supplemental Table S2; [4][5][6][22][23][24][25][26][27][28]). This interaction with Sigma1Rs suggests a new mechanism of action for fenfluramine's antiseizure activity (Table 1 [23,25,26,[28][29][30][31][32][33][34][35][36][37][38] and Table 2 [23,[39][40][41][42][43][44][45][46][47][48]). Sigma1Rs have long been associated with seizure-related conditions-from amphetamine-induced seizures to epileptic encephalopathies [49][50][51]-but one of the newer, intriguing possibilities of Sigma1R functionality may involve mediation of non-seizure comorbidities associated with DEE pathophysiology.…”

Semaglutide attenuates seizure severity and ameliorates cognitive dysfunction by blocking the NLR family pyrin domain containing 3 inflammasome in pentylenetetrazole‑kindled mice

“…GLP-1 receptors are widely expressed in various structures, such as the brainstem, cerebral cortex and hippocampus (23,24). Moreover, an increasing number of studies have suggested that GLP-1 signaling may serve as a potential drug target for the management of various neurological disorders, including epilepsy and its associated comorbidities (20,25). Semaglutide entered the market in 2017 as a novel once-weekly GLP-1 analogue for the treatment of type II diabetes (26).…”

“…Briefly, after the mice were anaesthetized with 60 mg/kg sodium pentobarbital, a stereotactic device was used to implant electrodes into the cerebral cortex on both sides of the bregma. The specific method for implanting the intracranial electrodes was the same as that used in our previous study (25). On the 45th day, seizure severity was assessed, and ECoG was recorded using an information integrated biological signal acquisition and processing system (BL-420 N; Techman).…”