NLRP3 inflammasome and endoplasmic reticulum stress in the epileptogenic zone in temporal lobe epilepsy: molecular insights into their interdependence

Abstract

Aim Nod‐like receptor protein 3 (NLRP3) inflammasome‐mediated inflammation has emerged as a contributor to epileptogenesis. Endoplasmic reticulum stress (ERS) plays an important role in epilepsy‐induced neurodegeneration. NLRP3 activation and ERS reactions share the same induction factors, suggesting that these processes may be interdependent. However, the correlation between NLRP3 and ERS in TLE has not been confirmed. Methods The expression patterns of NLRP3 inflammasome and ERS‐related markers in the temporal neocortices of TLE patients were investigated by western blotting, immunohistochemistry and immunofluorescent labelling. Correlations between the protein levels of NLRP3 and the expression of ERS‐related markers were assessed using Spearman’s rank correlation test. To observe the relationship between the NLRP3 inflammasome and ERS, inhibitors were used in a status epilepticus (SE) model. Results Our results show that NLRP3 inflammasome components and ERS‐related markers were upregulated in the temporal neocortices of TLE patients, and were mainly localized to neurons, astrocytes and microglia. We found a positive correlation between the protein levels of NLRP3 and the expression of ERS‐related markers in the temporal neocortices of 20 TLE patients. Furthermore, after blocking the NLRP3 inflammasome with MCC950, the expression of ERS‐related markers was markedly decreased in the hippocampi of SE mice. Moreover, TUDCA, a specific ERS inhibitor, also reduced the expression of NLRP3 components in the hippocampus under SE conditions. Conclusion Taken together, our data reveal the interdependence of the NLRP3 inflammasome and ERS in the epileptogenic zone of TLE patients and in the hippocampi of mice in the early post‐SE phase.

Anticonvulsive Effects of Chondroitin Sulfate on Pilocarpine and Pentylenetetrazole Induced Epileptogenesis in Mice

“…), decreased the levels of inflammatory mediators (interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and NF-kB) as compared to the PTZ and pilocarpine disease control groups, indicating that the brain injury response of activated glial cells showed increased expression of NF-kB levels, which were also decreased in epileptic brain tissue with chondroitin-sulfate-treated animals. Further, the results of the current research are supported by various studies on epilepsy demonstrating the increased levels of pro-inflammatory mediators (IL-1 beta, IL-6, TNF alpha, and NF-kB) representing neuroinflammation in epileptic-brain-mediated generation of secondary seizures, which indicates the severity of seizures [41][42][43][44]. Thus, the results indicate the neuroprotective effect of chondroitin sulfate as an anti-inflammatory agent by suppressing the NF-kB and decreasing the inflammatory mediators (IL-1β, IL-6, and TNF-alpha) that act as biomarkers of brain inflammation.…”

Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950

“…This observation was replicated in an in vivo setting with the use of NLRP3 KO mice, in which neuronal loss induced by pentylenetetrazol was inhibited in the NLRP3 knockout relative to the wild-type controls (Shen et al, 2018). MCC950 treatment has recently been shown to impair endoplasmic-reticulum stress, a feature of epilepsy that can lead to neurodegeneration in a status epilepticus model (Yue et al, 2020).…”

Pyroptosis: A promising therapeutic target for noninfectious diseases

“…Therefore, it is the star member of the inflammasomes family, targeting NLRP3 attracts the most attention. MCC950, which is a potent, selective and small‐molecule inhibitor of NLRP3, 134,135 can relieve the pathological progression of various noninfective diseases, including ischemic stroke, 136 AD, 137 epilepsy, 138 PD, 139 AS 140 and squamous cell carcinoma of the head and neck (SCCHN) 80 . Additionally, Ghrelin and Salidroside, which can also inhibit the activity of NLRP3 inflammasome, have recently been proved to ameliorate MS, PD and AS through suppressing NLRP3‐dependent pyroptosis 141–143 .…”