Mouse Anti-Rat Gsk3b Hybridoma [U2.8]

Overactivation of N-methyl-D-aspartate (NMDA) receptors has been associated with neurodegenerative disorders such as Alzheimer's disease (AD), cerebral vascular disorders and amyotrophic lateral sclerosis (ALS). We have previously designed and synthesized a series of memantine nitrate and some of them have shown vessel dilatory effects and neuroprotective effects; however, the detailed mechanisms have not been elucidated. In this study, we further demonstrated that memantine nitrate-06 (MN-06), one of the novel compounds derived from memantine, possessed significant neuroprotective effects against glutamate-induced excitotoxicity in rat primary cerebellar granule neurons (CGNs). Pretreatment of MN-06 reversed the activation of GSK3b and the suppression of phosphorylated Akt induced by glutamate. In addition, the neuroprotective effects of MN-06 could be abolished by LY294002, the specific phosphatidylinositol 3-kinase (PI3-K) inhibitor. Ca2+ imaging shown that pretreatment of MN-06 prevented Ca2+ influx induced by glutamate. Moreover, MN-06 might inhibit the NMDA-mediated current by antagonizing NDMA receptors, which was further confirmed by molecular docking simulation. Taken together, MN-06 protected against glutamate-induced excitotoxicity by blocking calcium influx and attenuating PI3-K/Akt/GSK-3b pathway, indicating that MN-06 might be a potential drug for treating neurodegenerative disorders.

A variety of chemicals are capable of provoking mitochondrial dysfunction and thereby contribute to metabolic disorder related effects in wildlife and human. For better identifying new mitochondrial toxicants and assessing mitochondria-related risk, an in-depth understanding of toxic mechanisms and biomarkers should be attained. In the current study, a representative mitotoxicant, azoxystrobin, was assessed for lethal and sublethal outcomes in Chironomus dilutus after 96-h exposure and the toxic mechanism was explored. Global transcriptomic profiles by RNA-sequencing revealed that ampk, acc1, atp2a, gsk3b, pi3k, fak, atr, chk1, and map3k5 were the key genes which involved in the toxic action of azoxystrobin and could serve as potential molecular biomarkers. A major network of common toxicity pathways was then developed for mitotoxicants towards aquatic insects. In particular, calcium ion-PI3K/AKT and cAMP-AMPK-lethality pathways were demonstrated, in addition to the well-known mitochondrial electron transfer-oxidative damage-apoptosis pathway. These analyses could help developing adverse outcome pathways that integrate toxicological information at various levels and support more effective risk assessment and management of mitotoxicants. (C) 2020 Elsevier Ltd. All rights reserved.