PMID- 30718467 OWN - NLM STAT- MEDLINE DCOM- 20200406 LR - 20240409 IS - 2041-4889 (Electronic) VI - 10 IP - 2 DP - 2019 Feb 4 TI - Chemerin reverses neurological impairments and ameliorates neuronal apoptosis through ChemR23/CAMKK2/AMPK pathway in neonatal hypoxic-ischemic encephalopathy. PG - 97 LID - 10.1038/s41419-019-1374-y [doi] LID - 97 AB - Hypoxic-ischemic encephalopathy (HIE) is a devastating neurological event that contributes to the prolonged neurodevelopmental consequences in infants. Therapeutic strategies focused on attenuating neuronal apoptosis in the penumbra appears to be promising. Given the increasingly recognized neuroprotective roles of adipokines in HIE, we investigated the potential anti-apoptotic roles of a novel member of adipokines, Chemerin, in an experimental model of HIE. In the present study, 10-day-old rat pups underwent right common carotid artery ligation followed by 2.5 h hypoxia. At 1 h post hypoxia, pups were intranasally administered with human recombinant chemerin (rh-chemerin). Here, we showed that rh-chemerin prevented the neuronal apoptosis and degeneration as evidenced by the decreased expression of the pro-apoptotic markers, cleaved caspase 3 and Bax, as well as the numbers of Fluoro-Jade C and TUNEL-positive neurons. Furthermore, rh-Chemerin reversed neurological and morphological impairments induced by hypoxia-ischemia in neonatal rats at 24 h and 4 weeks after HIE. In addition, chemerin-mediated neuronal survival correlated with the elevation of chemerin receptor 23 (chemR23), phosphorylated calmodulin-dependent protein kinase kinase 2 (CAMKK2), as well as phosphorylated adenosine monophosphate-activated protein kinase (AMPK). Specific inhibition of chemR23, CAMKK2, and AMPK abolished the anti-apoptotic effects of rh-chemerin at 24 h after HIE, demonstrating that rh-chemerin ameliorated neuronal apoptosis partially via activating chemR23/CAMKK2/AMPK signaling pathway. Neuronal apoptosis is a well-established contributing factor of pathological changes and the neurological impairment after HIE. These results revealed mechanisms of neuroprotection by rh-chemerin, and indicated that activation of chemR23 might be harnessed to protect from neuronal apoptosis in HIE. FAU - Zhang, Yixin AU - Zhang Y AD - Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China. AD - Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA. FAU - Xu, Ningbo AU - Xu N AUID- ORCID: 0000-0001-9055-3597 AD - Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA. FAU - Ding, Yan AU - Ding Y AD - Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA. FAU - Doycheva, Desislava Met AU - Doycheva DM AD - Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA. FAU - Zhang, Yiting AU - Zhang Y AD - Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA. FAU - Li, Qian AU - Li Q AD - Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA. FAU - Flores, Jerry AU - Flores J AD - Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA. FAU - Haghighiabyaneh, Mina AU - Haghighiabyaneh M AD - Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA. FAU - Tang, Jiping AU - Tang J AD - Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA. FAU - Zhang, John H AU - Zhang JH AUID- ORCID: 0000-0002-4319-4285 AD - Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA. johnzhang3910@yahoo.com. AD - Departments of Anesthesiology, Neurosurgery and Neurology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA. johnzhang3910@yahoo.com. LA - eng GR - R01 NS104083/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190204 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Chemokines) RN - 0 (Cmklr1 protein, rat) RN - 0 (Neuroprotective Agents) RN - 0 (RARRES2 protein, human) RN - 0 (Rarres2 protein, rat) RN - 0 (Reactive Oxygen Species) RN - 0 (Receptors, Chemokine) RN - 0 (bcl-2-Associated X Protein) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 3.4.22.- (Caspase 3) SB - IM MH - AMP-Activated Protein Kinases/metabolism MH - Animals MH - Animals, Newborn MH - Apoptosis/*drug effects MH - Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism MH - Caspase 3/metabolism MH - Chemokines/metabolism/*therapeutic use MH - Humans MH - Hypoxia-Ischemia, Brain/*drug therapy/metabolism/pathology MH - In Situ Nick-End Labeling MH - Infant, Newborn MH - Neurons/*drug effects/metabolism MH - Neuroprotective Agents/therapeutic use MH - Phosphorylation MH - Rats MH - Rats, Sprague-Dawley MH - Reactive Oxygen Species/metabolism MH - Receptors, Chemokine/*metabolism MH - Signal Transduction/drug effects MH - bcl-2-Associated X Protein/metabolism PMC - PMC6362229 COIS- The authors declare that they have no conflict of interest. EDAT- 2019/02/06 06:00 MHDA- 2020/04/09 06:00 PMCR- 2019/02/04 CRDT- 2019/02/06 06:00 PHST- 2018/05/12 00:00 [received] PHST- 2019/01/07 00:00 [accepted] PHST- 2018/12/12 00:00 [revised] PHST- 2019/02/06 06:00 [entrez] PHST- 2019/02/06 06:00 [pubmed] PHST- 2020/04/09 06:00 [medline] PHST- 2019/02/04 00:00 [pmc-release] AID - 10.1038/s41419-019-1374-y [pii] AID - 1374 [pii] AID - 10.1038/s41419-019-1374-y [doi] PST - epublish SO - Cell Death Dis. 2019 Feb 4;10(2):97. doi: 10.1038/s41419-019-1374-y.