PMID- 37828361 OWN - NLM STAT- MEDLINE DCOM- 20240520 LR - 20240520 IS - 1573-6903 (Electronic) IS - 0364-3190 (Linking) VI - 49 IP - 6 DP - 2024 Jun TI - NL-1 Promotes PINK1-Parkin-Mediated Mitophagy Through MitoNEET Inhibition in Subarachnoid Hemorrhage. PG - 1506-1516 LID - 10.1007/s11064-023-04024-5 [doi] AB - NL-1 is a mitoNEET ligand known for its antileukemic effects and has recently shown neuroprotective effects in an ischemic stroke model. However, its underlying process in subarachnoid hemorrhage (SAH) is still unclear. Thus, we aimed to investigate the possible mechanism of NL-1 after SAH in rats. 112 male adult Sprague-Dawley rats were used for experiments. SAH model was performed with endovascular perforation. Rats were dosed intraperitoneally (i.p.) with NL-1 (3 mg/kg, 10 mg/kg, 30 mg/kg) or a vehicle (10% DMSO aqueous solution) at 1 h after SAH. A novel mitophagy inhibitor liensinine (60 mg/kg) was injected i.p. 24 h before SAH. SAH grades, short-term and long-term neurological scores were measured for neurobehavior. TdTmediated dUTP nick end labeling (TUNEL) staining, dihydroethidium (DHE) staining and western blot measurements were used to detect the outcomes and mechanisms of NL-1 administration. NL-1 treatment significantly improved short-term neurological behavior in Modified Garcia and beam balance sores in comparison with SAH + vehicle group. NL-1 administration also increased mitoNEET which induced phosphatase and tensin-induced kinase 1 (PINK1), Parkin and LC3II related mitophagy compared with SAH + vehicle group. In addition, the expressions of apoptotic protein Cleaved Caspase-3 and oxidative stress related protein Romo1 in NL-1 treatment group were reversed from SAH + vehicle group. Meanwhile, NL-1 treatment notably reduced TUNEL-positive cells, DHE-positive cells compared with SAH + vehicle group. NL-1 treatment notably improved long-term neurological behavior in rotarod and water maze tests compared to SAH + vehicle group. However, the administration of liensinine may inhibit the treatment effect of NL-1, leading to reduced expression of mitophagy markers Pink1, Parkin, LC3I/II, and increased expressions of Romo1 and Cleaved Caspase-3. NL-1 induced PINK1/PARKIN related mitophagy via mitoNEET, which reduced oxidative stress and apoptosis in early brain injury after SAH in rats. NL-1 may serve as a prospective drug for the treatment of SAH. CI - (c) 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Zhang, Tongyu AU - Zhang T AD - Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China. FAU - Zhang, Minghai AU - Zhang M AD - Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China. cqhaizi@126.com. AD - Department of Neurosurgery, Chongqing Tongnan District People's Hospital, Chongqing, China. cqhaizi@126.com. LA - eng GR - 82001324/National Natural Science Foundation of China/ PT - Journal Article DEP - 20231012 PL - United States TA - Neurochem Res JT - Neurochemical research JID - 7613461 RN - 0 (parkin protein) RN - 0 (PTEN-induced putative kinase) SB - IM EIN - Neurochem Res. 2023 Dec 29;:. PMID: 38155320 MH - Animals MH - *Ubiquitin-Protein Ligases/metabolism MH - *Rats, Sprague-Dawley MH - Male MH - *Mitophagy/drug effects MH - *Subarachnoid Hemorrhage/drug therapy/metabolism MH - *Protein Kinases/metabolism MH - Rats MH - Neuroprotective Agents/pharmacology/therapeutic use OTO - NOTNLM OT - Apoptosis OT - MitoNEET OT - Mitophagy OT - NL-1 OT - Oxidative stress OT - Subarachnoid hemorrhage EDAT- 2023/10/13 00:43 MHDA- 2024/05/20 12:41 CRDT- 2023/10/12 23:36 PHST- 2023/03/22 00:00 [received] PHST- 2023/08/30 00:00 [accepted] PHST- 2023/06/08 00:00 [revised] PHST- 2024/05/20 12:41 [medline] PHST- 2023/10/13 00:43 [pubmed] PHST- 2023/10/12 23:36 [entrez] AID - 10.1007/s11064-023-04024-5 [pii] AID - 10.1007/s11064-023-04024-5 [doi] PST - ppublish SO - Neurochem Res. 2024 Jun;49(6):1506-1516. doi: 10.1007/s11064-023-04024-5. Epub 2023 Oct 12.