Dimethyl itaconate reprograms neurotoxic to neuroprotective primary astrocytes through the regulation of NLRP3 inflammasome and NRF2/HO-1 pathways.

The activation of neurotoxic reactive astrocytes contributes to the pathogenesis of many neurodegenerative diseases. Itaconate, a product of cellular metabolism, is released from activated macrophage/microglia and has been shown to regulate inflammatory responses in several mammalian cells. This study was designed to investigate the impact of cell-permeable dimethyl itaconate (DI) on reactive astrocyte-dependent neurotoxicity. Primary murine astrocyte cells were isolated and stimulated with lipopolysaccharide (LPS) to generate reactive astrocytes. Treating these activated cells with DI was able to diminish the neurotoxic phenotype of reactive astrocytes, as we found reduced LPS-induced Nod-like receptor protein 3 (NLRP3) inflammasome activation and interleukin-1ß (IL-1ß) secretion. DI reduced the level of inflammasome components, attenuated inflammasome assembly and subsequently reduced caspase-1 cleavage and IL-1ß levels. Additionally, DI attenuated nuclear factor-kappa B (NF-κB) phosphorylation in LPS-activated astrocytes and also protected astrocytes from LPS-induced cytotoxicity, including a lowering of Bax and caspase3. DI-treated reactive astrocytes showed an elevated GSH/GSSG ratio and improved antioxidant defense factors including catalase and superoxide dismutase, while lipid peroxidation was reduced. We found that DI activated the nuclear factor 2 (NRF2) and heme oxygenase-1 (HO-1) pathway in astrocytes and thereby potentially control redox-regulation and the inflammatory state of astrocytes. Collectively, these results indicate the neuroprotective role of DI by reprogramming astrocytes from neurotoxic A1 to neuroprotective A2 states and thereby reveal a novel potential strategy for the treatment of neurodegenerative diseases.

Evaluation of oxidant/antioxidant status in serum of sheep experimentally envenomated with Hemiscorpius lepturus scorpion venom.

Scorpion envenomation is a main general health problem in developing countries, especially in tropical and subtropical regions. Hemiscorpius lepturus as a member of the Hemiscorpiidae family is cause of the most scorpion sting lethality in Iran. In the present study, the oxidative stress and antioxidant defense in serum of envenomated sheep with the venom of Hemiscorpius lepturus were investigated. Nine sheep were randomly divided into three groups (three in each). Groups A, B and C received 0.10, 0.05 and 0.01 mg kg-1 of H. lepturus venom subcutaneously, respectively. Blood sampling were performed 30 min before envenomation (control) and 30 min, 1, 2, 3 and 6 hr after envenomation and serum levels of total antioxidant capacity (TAC), malonedialdehyde (MDA) and protein carbonyl (PCO) were determined. The TAC was significantly increased at the doses of 0.10 mg kg-1 (at 3 hr) and 0.05 mg kg-1 (at 6 hr) compared to pre-injection time. However, no significant differences were observed in serum levels of MDA and PCO in different groups. It can be concluded that the dose of 0.01 mg kg-1 of venom had no effect on stress factors of serum, but according to increased level of TAC at the doses of 0.05 and 0.10 and no significant changes in serum levels of MDA and PCO, the oxidative damage has been prevented by the antioxidant defense system response.