PMID- 36897515 OWN - NLM STAT- MEDLINE DCOM- 20230517 LR - 20230519 IS - 1573-7365 (Electronic) IS - 0885-7490 (Linking) VI - 38 IP - 5 DP - 2023 Jun TI - Necrostatin-1S mitigates type-2 diabetes-associated cognitive decrement and lipotoxicity-induced neuro-microglia changes through p-RIPK-RIPK3-p-MLKL axis. PG - 1581-1612 LID - 10.1007/s11011-023-01185-8 [doi] AB - Type-2 diabetes mellitus (T2DM) is associated with neuroinflammation and cognitive decrement. Necroptosis programmed necrosis is emerging as the major contributing factor to central changes. It is best characterized by the upregulation of p-RIPK(Receptor Interacting Kinase), p-RIPK3, and the phosphorylated-MLKL (mixed-lineage kinase domain-like protein). The present study aims to evaluate the neuroprotective effect of Necrostatin (Nec-1S), a p-RIPK inhibitor, on cognitive changes in the experimental T2DM model in C57BL/6 mice and lipotoxicity-induced neuro-microglia changes in neuro2A and BV2 cells. Further, the study also explores whether Nec-1S would restore mitochondrial and autophago-lysosomal function.T2DM was developed in mice by feeding them a high-fat diet (HFD) for 16 weeks and injecting a single dose of streptozotocin (100 mg/kg, i.p) on the 12(th) week. Nec-1S was administered for 3 weeks at (10 mg/kg, i.p) once every 3 days. Lipotoxicity was induced in neuro2A, and BV2 cells using 200 microM palmitate/bovine serum albumin conjugate. Nec-1S (50 microM), and GSK-872(10 microM) were further used to explore their relative effect. The neurobehavioral performance was assessed using mazes and task-assisted performance tests. To decipher the hypothesis plasma parameters, western blot, immunofluorescence, microscopy, and quantitative reverse transcription-PCR studies were carried out. The Nec-1S treatment restored cognitive performance and reduced the p-RIPK-p-RIPK3-p-MLKL mediated neuro-microglia changes in the brain and in cells as well, under lipotoxic stress. Nec-1S reduced tau, and amyloid oligomer load. Moreover, Nec-1S restored mitochondrial function and autophago-lysosome clearance. The findings highlight the central impact of metabolic syndrome and how Nes-1S, by acting as a multifaceted agent, improved central functioning. CI - (c) 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Preeti, Kumari AU - Preeti K AUID- ORCID: 0000-0002-2000-7491 AD - Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research (NIPER)-Hyderabad, Telangana, 500037, India. FAU - Fernandes, Valencia AU - Fernandes V AUID- ORCID: 0000-0002-6212-5947 AD - Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research (NIPER)-Hyderabad, Telangana, 500037, India. FAU - Sood, Anika AU - Sood A AUID- ORCID: 0000-0001-5868-428X AD - Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research (NIPER)-Hyderabad, Telangana, 500037, India. FAU - Khan, Islauddin AU - Khan I AUID- ORCID: 0000-0002-1352-7691 AD - Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research (NIPER)-Hyderabad, Telangana, 500037, India. FAU - Khatri, Dharmendra Kumar AU - Khatri DK AUID- ORCID: 0000-0001-7066-7706 AD - Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research (NIPER)-Hyderabad, Telangana, 500037, India. dkkhatri10@gmail.com. AD - Molecular and Cellular Neuroscience Lab, Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana, 500037, India. dkkhatri10@gmail.com. FAU - Singh, Shashi Bala AU - Singh SB AUID- ORCID: 0000-0002-1793-2619 AD - Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research (NIPER)-Hyderabad, Telangana, 500037, India. sbsingh.dipas@gmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230310 PL - United States TA - Metab Brain Dis JT - Metabolic brain disease JID - 8610370 RN - 0 (necrostatin-1) RN - 0 (Transcription Factors) RN - EC 2.7.11.1 (Ripk3 protein, mouse) RN - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases) RN - EC 2.7.- (MLKL protein, mouse) RN - EC 2.7.- (Protein Kinases) SB - IM EIN - Metab Brain Dis. 2023 Aug;38(6):2193-2196. PMID: 37204662 MH - Mice MH - Animals MH - Microglia/metabolism MH - Mice, Inbred C57BL MH - *Diabetes Mellitus, Experimental/drug therapy MH - Transcription Factors/metabolism MH - *Diabetes Mellitus, Type 2/drug therapy MH - Cognition MH - Receptor-Interacting Protein Serine-Threonine Kinases/metabolism MH - Protein Kinases/metabolism OTO - NOTNLM OT - Hippocampus OT - Hyperglycemia OT - Hyperlipidemia OT - Interleukin OT - Microglia OT - Mitochondria OT - Necrosome OT - Oligomer OT - Synapse EDAT- 2023/03/11 06:00 MHDA- 2023/05/17 06:42 CRDT- 2023/03/10 11:22 PHST- 2022/10/03 00:00 [received] PHST- 2023/02/13 00:00 [accepted] PHST- 2023/05/17 06:42 [medline] PHST- 2023/03/11 06:00 [pubmed] PHST- 2023/03/10 11:22 [entrez] AID - 10.1007/s11011-023-01185-8 [pii] AID - 10.1007/s11011-023-01185-8 [doi] PST - ppublish SO - Metab Brain Dis. 2023 Jun;38(5):1581-1612. doi: 10.1007/s11011-023-01185-8. Epub 2023 Mar 10.