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

Abstract

Epilepsy comorbidities and anti-epileptic drugs (AEDs) are currently the main limitations of epilepsy treatment. Semaglutide is a glucagon like peptide-1 analogue that has entered the market as a new once-weekly drug for type II diabetes. The aim of the present study was to investigate the functions of semaglutide in epilepsy and inflammation models, in order to investigate its potential mechanism. In vitro, an inflammation model was established using lipopolysaccharide (LPS) and nigericin stimulation in BV2 cells. In vivo, chronic epilepsy model mice were generated using a pentylenetetrazole (PTZ) kindling method. BV2 cell proliferation was assessed using the Cell Counting Kit-8. The effects of semaglutide on NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and inflammatory cytokine secretion were determined using western blotting (WB) and ELISA. A lactate dehydrogenase (LDH) assay kit was used to detect the effect of semaglutide on LDH release. Electrocorticography and the modified Racine scale were used to assess seizure severity.Cognitive function was evaluated with behavioral assessment. Morphological changes in the hippocampus were observed with Nissl staining. Double immunofluorescence staining for NeuN and Iba-1, WB and immunofluorescence analysis of apoptosis-related proteins were used to evaluate neuronal apoptosis. The NLRP3 inflammasome was assessed by reverse transcription-quantitative PCR, WB and immunofluorescence staining, and inflammatory cytokine release was evaluated by WB analysis in the hippocampus of C57/BL6J model mouse. Semaglutide attenuated the LPS-and nigericin-induced inflammatory response and LDH release by blocking NLRP3 inflammasome activation in BV2 cells. Moreover, semaglutide decreased seizure severity, alleviated hippocampal neuronal apoptosis, ameliorated cognitive dysfunction, blocked NLRP3 inflammasome activation and decreased inflammatory cytokine secretion in PTZ-kindled mice. These results indicated that semaglutide reduced seizure severity, exerted neuroprotective effects and ameliorated cognitive dysfunction, possibly via inhibition of NLRP3 inflammasome activation and inflammatory cytokine secretion. Semaglutide may therefore be a novel, promising adjuvant therapeutic for epilepsy and its associated comorbidities.

A Combination of Curcuma longa and Diazepam Attenuates Seizures and Subsequent Hippocampal Neurodegeneration

“…The number of cells of six coronal sections of the hippocampus (CA1 and CA3) of each rat were counted to provide a mean count for each group ( n = 9 rats per group). The cell counts were based on the inspection of a field of 50 μm × 50 μm in each region ( Wang et al, 2021 ). The counted (treatment-blind) cells were observed using the ImageJ digital imaging software (NIH, Bethesda, MD, United States).…”

Microglial activation in the motor cortex mediated NLRP3-related neuroinflammation and neuronal damage following spinal cord injury

“…NLRP1 and AIM2 inflammasomes are found in neurons (Yuan et al, 2020 ), NLRP2 inflammasome in astrocytes (Minkiewicz et al, 2013 ), and the NLRP3 inflammasome in activated microglia (Shi et al, 2013 ); the NLRP3 inflammasome comprises NLRP3, ASC, and caspase-1. During the formation of NLRP3 inflammasomes, caspase-1 is converted from its proenzyme (inactive) form to its activated (cleaved) form, which induces the maturation and secretion of IL-1β and IL-18; the former further promotes the secretion of IL-6 and TNF-α (Alomar et al, 2016 ; Wang et al, 2021 ). Accordingly, we detected the levels of NLRP3, ASC, caspase-1, IL-1β, IL-18, IL-6, and TNF-α both in vivo and in vitro .…”

Semaglutide ameliorates lipopolysaccharide-induced acute lung injury through inhibiting HDAC5-mediated activation of NF-κB signaling pathway

“…As for ALI+SEM group, rats received SEM injection subcutaneously (25 nM/kg) 30 min ahead of LPS injection. 18 As for ALI+DEX group, rats received DEX (50 μg/kg) injection subcutaneously 30 min ahead of LPS injection. All experimental rats were sacrificed 24h as of LPS injection.…”