Inhibition of neuronal necroptosis mediated by RIP1/RIP3/MLKL provides neuroprotective effects on kaolin‐induced hydrocephalus in mice

Abstract

Objectives Necroptosis is widespread in neurodegenerative diseases. Here, we examined necroptosis in the hippocampus and cortex after hydrocephalus and found that a necroptosis pathway inhibitor alleviates necroptosis and provides neuroprotective effects. Materials and methods Hydrocephalus was induced in C57BL/6 mice by kaolin. Haematoxylin and eosin (HE), Nissl, PI and Fluoro‐Jade B (FJB) staining were used for general observations. Phosphorylated receptor‐interacting protein kinase 3 (p‐RIP3) and phosphorylated mixed lineage kinase domain‐like (p‐MLKL) were measured by Western blotting and immunohistochemistry. Scanning electron microscopy (SEM) was used to observe ependymal cilia. Magnetic resonance imaging (MRI) and the Morris water maze (MWM) test were used to assess neurobehavioral changes. Immunofluorescence was used to detect microglial and astrocyte activation. Inflammatory cytokines were measured by Western blotting and RT‐PCR. Results Obvious pathological changes appeared in the hippocampus and cortex after hydrocephalus, and expression of the necroptosis markers p‐RIP3, p‐MLKL and inflammatory cytokines increased. Necrostatin‐1 (Nec‐1) and GSK872 reduced necrotic cell death, attenuated p‐RIP3 and p‐MLKL levels, slightly improved neurobehaviours and inhibited microglial and astrocyte activation and inflammation. Conclusions RIP1/RIP3/MLKL mediates necroptosis in the cortex and hippocampus in a hydrocephalus mouse model, and Nec‐1 and GSK872 have some neuroprotective effects.

Triclosan-induced neuroinflammation develops caspase-independent and TNF-α signaling pathway associated necroptosis in Neuro-2a cells

“…This was another reason of choosing the said time period for all subsequent experiments. Also, the dosage of TCS used in this study was within the range that has been reported to be present in biological fluids and confirming same or similar exposure conditions ( Liu et al, 2021 ).…”

RIP3 knockdown inhibits necroptosis of human intestinal epithelial cells via TLR4/MyD88/NF-κB signaling and ameliorates murine colitis

“…In this study, we applied two RIP3 inhibitors—Nec-1 and GSK872. They can both inhibit necroptosis and inflammation [ 43 – 45 ]. In our study, sulfasalazine (SASP), a first line therapeutic medicine of IBD, was used as a positive control at the dose of 50 mg/kg to evaluate the efficacy of Necrostatin-1.…”

Necroptosis in CNS diseases: Focus on astrocytes

“…There were studies conducted on the potential therapeutic effect of Nec-1 in many diseases affecting all organ systems. Briefly, the neuroprotective effect of necrostatin in ischemic injuries (Liu et al, 2019a;Mitroshina et al, 2022), hydrocephalus (Liu et al, 2021a), mitochondrial dysfunction (Apaijai et al, 2021), intracranial hypertension (Qian et al, 2022) was revealed. Necrostatin reduces postoperative cognitive dysfunction (Yin et al, 2022), neonatal neurotoxicity (Xu et al, 2021b), and cardiotoxicity (Erdogmus Ozgen et al, 2022).…”

“…A search on pubmed reveals 46 articles published in the last 5 years describing the results of RIPK3 inhibition using GSK'872. It was shown to have a neuroprotective effect in hydrocephalus (Liu et al, 2021a) and to affect reducing collagen expression in fibroblasts in vitro when modeling fat graft fibrosis (Chen et al, 2021b). GSK'872 decreases neurobehavioral brain defects and edema in intracranial hemorrhage (Chen et al, 2018), protects from emphysema, suppresses the lung inflammation (Chen et al, 2021a), prevents from heat stressinduced intestinal cell death (Li et al, 2020), alleviates liver damage caused by non-alcoholic fatty disease (Zhang et al, 2021a), and reduces astrocyte death caused by Zika virus (Wen et al, 2021).…”