{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T16:29:53Z","timestamp":1789921793002,"version":"4.0.1"},"reference-count":75,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,6,5]],"date-time":"2023-06-05T00:00:00Z","timestamp":1685923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"United Therapeutics"},{"name":"North Shore University Hospital, Northwell Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Cardiac arrest (CA) can lead to neuronal degeneration and death through various pathways, including oxidative, inflammatory, and metabolic stress. However, current neuroprotective drug therapies will typically target only one of these pathways, and most single drug attempts to correct the multiple dysregulated metabolic pathways elicited following cardiac arrest have failed to demonstrate clear benefit. Many scientists have opined on the need for novel, multidimensional approaches to the multiple metabolic disturbances after cardiac arrest. In the current study, we have developed a therapeutic cocktail that includes ten drugs capable of targeting multiple pathways of ischemia\u2013reperfusion injury after CA. We then evaluated its effectiveness in improving neurologically favorable survival through a randomized, blind, and placebo-controlled study in rats subjected to 12 min of asphyxial CA, a severe injury model. Results: 14 rats were given the cocktail and 14 received the vehicle after resuscitation. At 72 h post-resuscitation, the survival rate was 78.6% among cocktail-treated rats, which was significantly higher than the 28.6% survival rate among vehicle-treated rats (log-rank test; p = 0.006). Moreover, in cocktail-treated rats, neurological deficit scores were also improved. These survival and neurological function data suggest that our multi-drug cocktail may be a potential post-CA therapy that deserves clinical translation. Conclusions: Our findings demonstrate that, with its ability to target multiple damaging pathways, a multi-drug therapeutic cocktail offers promise both as a conceptual advance and as a specific multi-drug formulation capable of combatting neuronal degeneration and death following cardiac arrest. Clinical implementation of this therapy may improve neurologically favorable survival rates and neurological deficits in patients suffering from cardiac arrest.<\/jats:p>","DOI":"10.3390\/cells12111548","type":"journal-article","created":{"date-parts":[[2023,6,5]],"date-time":"2023-06-05T04:34:51Z","timestamp":1685939691000},"page":"1548","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Multi-Drug Cocktail Therapy Improves Survival and Neurological Function after Asphyxial Cardiac Arrest in Rodents"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1080-7516","authenticated-orcid":false,"given":"Rishabh C.","family":"Choudhary","sequence":"first","affiliation":[{"name":"Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"},{"name":"Department of Emergency Medicine, Northwell Health, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7686-2817","authenticated-orcid":false,"given":"Muhammad","family":"Shoaib","sequence":"additional","affiliation":[{"name":"Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"},{"name":"Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY 11549, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2287-3318","authenticated-orcid":false,"given":"Kei","family":"Hayashida","sequence":"additional","affiliation":[{"name":"Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"},{"name":"Department of Emergency Medicine, Northwell Health, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai","family":"Yin","sequence":"additional","affiliation":[{"name":"Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"},{"name":"Department of Emergency Medicine, Northwell Health, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago J.","family":"Miyara","sequence":"additional","affiliation":[{"name":"Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"},{"name":"Elmezzi Graduate School of Molecular Medicine, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"d\u2019Abramo","sequence":"additional","affiliation":[{"name":"Litwin-Zucker Center for Research in Alzheimer\u2019s Disease, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7588-9105","authenticated-orcid":false,"given":"William G.","family":"Heuser","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Northwell Health, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichiro","family":"Shinozaki","sequence":"additional","affiliation":[{"name":"Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"},{"name":"Department of Emergency Medicine, Northwell Health, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9470-636X","authenticated-orcid":false,"given":"Nancy","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY 11549, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3565-359X","authenticated-orcid":false,"given":"Ryosuke","family":"Takegawa","sequence":"additional","affiliation":[{"name":"Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"},{"name":"Department of Emergency Medicine, Northwell Health, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2342-7245","authenticated-orcid":false,"given":"Mitsuaki","family":"Nishikimi","sequence":"additional","affiliation":[{"name":"Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"},{"name":"Department of Emergency Medicine, Northwell Health, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4351-7256","authenticated-orcid":false,"given":"Timmy","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY 11549, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey","family":"Owens","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY 11549, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto P.","family":"Molmenti","sequence":"additional","affiliation":[{"name":"Department of Surgery, Northwell Health, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhu","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonya","family":"Vanpatten","sequence":"additional","affiliation":[{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousef","family":"Al-Abed","sequence":"additional","affiliation":[{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"},{"name":"Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY 11549, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1162-8616","authenticated-orcid":false,"given":"Junhwan","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"},{"name":"Department of Emergency Medicine, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY 11549, USA"},{"name":"Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY 11549, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance B.","family":"Becker","sequence":"additional","affiliation":[{"name":"Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"},{"name":"Department of Emergency Medicine, Northwell Health, Manhasset, NY 11030, USA"},{"name":"Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY 11549, USA"},{"name":"Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY 11549, USA"},{"name":"Emergency Medicine, Feinstein Institutes for Medical Research, Northwell Health, 350 Community Dr., Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e56","DOI":"10.1161\/CIR.0000000000000659","article-title":"Heart disease and stroke statistics-2019 update: A report from the American Heart Association","volume":"139","author":"Benjamin","year":"2019","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e254","DOI":"10.1161\/CIR.0000000000000950","article-title":"Heart disease and stroke statistics-2021 update: A report from the American Heart Association","volume":"143","author":"Virani","year":"2021","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ncl.2005.10.008","article-title":"Cerebral Resuscitation: State of the Art, Experimental Approaches and Clinical Perspectives","volume":"24","author":"Popp","year":"2006","journal-title":"Neurol. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"636651","DOI":"10.3389\/fmed.2021.636651","article-title":"Pharmacological Approach for Neuroprotection After Cardiac Arrest\u2014A Narrative Review of Current Therapies and Future Neuroprotective Cocktail","volume":"8","author":"Choudhary","year":"2021","journal-title":"Front. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s12640-009-9110-5","article-title":"Endoplasmic Reticulum Stress Plays Critical Role in Brain Damage After Cerebral Ischemia\/Reperfusion in Rats","volume":"17","author":"Nakka","year":"2010","journal-title":"Neurotox. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S447","DOI":"10.1097\/CCM.0b013e31818a8a51","article-title":"Early mitochondrial dysfunction in electron transfer activity and reactive oxygen species generation after cardiac arrest","volume":"36","author":"Han","year":"2008","journal-title":"Crit. Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/sj.jcbfm.9600234","article-title":"Normoxic resuscitation after cardiac arrest protects against hippocampal oxidative stress, metabolic dysfunction, and neuronal death","volume":"26","author":"Vereczki","year":"2006","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"192769","DOI":"10.1155\/2014\/192769","article-title":"Impaired Cerebral Mitochondrial Oxidative Phosphorylation Function in a Rat Model of Ventricular Fibrillation and Cardiopulmonary Resuscitation","volume":"2014","author":"Jiang","year":"2014","journal-title":"BioMed. Res. Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3892\/br.2016.677","article-title":"Inflammatory mechanisms involved in brain injury following cardiac arrest and cardiopulmonary resuscitation","volume":"5","author":"Xiang","year":"2016","journal-title":"Biomed. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e012809","DOI":"10.1161\/JAHA.119.012809","article-title":"Tissue-Specific Metabolic Profiles After Prolonged Cardiac Arrest Reveal Brain Metabolome Dysfunction Predominantly After Resuscitation","volume":"8","author":"Choi","year":"2019","journal-title":"J. Am. Heart Assoc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19707","DOI":"10.1038\/s41598-020-76401-x","article-title":"Plasma metabolomics supports the use of long-duration cardiac arrest rodent model to study human disease by demonstrating similar metabolic alterations","volume":"10","author":"Shoaib","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1093\/ehjcvp\/pvv047","article-title":"Drug therapy in cardiac arrest: A review of the literature","volume":"2","author":"Lundin","year":"2016","journal-title":"Eur. Heart J. Cardiovasc. Pharmacother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"a007161","DOI":"10.1101\/cshperspect.a007161","article-title":"HIV-1 Antiretroviral Drug Therapy","volume":"2","author":"Arts","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Preissner, S., Dunkel, M., Hoffmann, M.F., Preissner, S.C., Genov, N., Rong, W.W., Preissner, R., and Seeger, K. (2012). Drug Cocktail Optimization in Chemotherapy of Cancer. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0051020"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.resuscitation.2015.04.009","article-title":"Effect of a pharmacologically induced decrease in core temperature in rats resuscitated from cardiac arrest","volume":"92","author":"Katz","year":"2015","journal-title":"Resuscitation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/j.ajem.2016.02.066","article-title":"Protective effects of cyclosporine A and hypothermia on neuronal mitochondria in a rat asphyxial cardiac arrest model","volume":"34","author":"Liu","year":"2016","journal-title":"Am. J. Emerg. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1007\/s12035-017-0470-1","article-title":"Combination Treatment with Methylene Blue and Hypothermia in Global Cerebral Ischemia","volume":"55","author":"Li","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.1161\/01.CIR.0000146894.45533.C2","article-title":"Coenzyme Q10 combined with mild hypothermia after cardiac arrest: A preliminary study","volume":"110","author":"Damian","year":"2004","journal-title":"Circulation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8892","DOI":"10.1073\/pnas.95.15.8892","article-title":"Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects","volume":"95","author":"Matthews","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","first-page":"25","article-title":"Edaravone (Radicava): A Novel Neuroprotective Agent for the Treatment of Amyotrophic Lateral Sclerosis","volume":"43","author":"Cruz","year":"2018","journal-title":"P T"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1016\/j.ajem.2016.06.084","article-title":"Edaravone improves survival and neurological outcomes after CPR in a ventricular fibrillation model of rats","volume":"34","author":"Qin","year":"2016","journal-title":"Am. J. Emerg. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12950-020-00255-3","article-title":"N-acetylcysteine alleviates post-resuscitation myocardial dysfunction and improves survival outcomes via partly inhibiting NLRP3 inflammasome induced-pyroptosis","volume":"17","author":"He","year":"2020","journal-title":"J. Inflamm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1080\/14734220601142878","article-title":"N-acetylcysteine and neurodegenerative diseases: Basic and clinical pharmacology","volume":"6","author":"Arakawa","year":"2007","journal-title":"Cerebellum"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e023787","DOI":"10.1161\/JAHA.121.023787","article-title":"Vitamin C Improves the Outcomes of Cardiopulmonary Resuscitation and Alters Shedding of Syndecan-1 and p38\/MAPK Phosphorylation in a Rat Model","volume":"11","author":"Xiao","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"ref_25","first-page":"1405","article-title":"Reversible Blockade of Electron Transport during Ischemia Protects Mitochondria and Decreases Myocardial Injury following Reperfusion","volume":"319","author":"Chen","year":"2006","journal-title":"Experiment"},{"key":"ref_26","first-page":"406","article-title":"Inhibited mitochondrial respiration by amobarbital during cardiac ischaemia improves redox state and reduces matrix Ca2+ overload and ROS release","volume":"77","author":"Aldakkak","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gazmuri, R.J., Radhakrishnan, J., and Ayoub, I.M. (2019). Sodium-Hydrogen Exchanger Isoform-1 Inhibition: A Promising Pharmacological Intervention for Resuscitation from Cardiac Arrest. Molecules, 24.","DOI":"10.3390\/molecules24091765"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/sj.bjp.0705749","article-title":"Cardioprotective efficacy of zoniporide, a potent and selective inhibitor of Na+\/H+ exchanger isoform 1, in an experimental model of cardiopulmonary bypass","volume":"142","author":"Sutherland","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Pille, J.A., and Riess, M.L. (2021). Potential Effects of Poloxamer 188 on Rat Isolated Brain Mitochondria after Oxidative Stress In Vivo and In Vitro. Brain Sci., 11.","DOI":"10.3390\/brainsci11010122"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.jacbts.2016.04.001","article-title":"Intracoronary Poloxamer 188 Prevents Reperfusion Injury in a Porcine Model of ST-Segment Elevation Myocardial Infarction","volume":"1","author":"Bartos","year":"2016","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.abb.2018.10.013","article-title":"Cardiolipin-targeted peptides rejuvenate mitochondrial function, remodel mitochondria, and promote tissue regeneration during aging","volume":"660","author":"Szeto","year":"2018","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.hlc.2018.01.008","article-title":"Increased Survival Time With SS-31 After Prolonged Cardiac Arrest in Rats","volume":"28","author":"Zhang","year":"2019","journal-title":"Heart Lung Circ."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1111\/bph.12461","article-title":"First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics","volume":"171","author":"Szeto","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S0304-3940(02)00588-8","article-title":"Use of an adenosine triphosphate-based \u2018cocktail\u2019 early in reperfusion substantially improves brain protein synthesis after global ischemia in rats","volume":"331","author":"Paskitti","year":"2002","journal-title":"Neurosci. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1093\/eurheartj\/ehq112","article-title":"Inhibition of mitochondrial permeability transition to prevent the post-cardiac arrest syndrome: A pre-clinical study","volume":"32","author":"Cour","year":"2011","journal-title":"Eur. Heart J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1089\/neu.2018.5706","article-title":"Neuroprotective Effects of Cyclosporine in a Porcine Pre-Clinical Trial of Focal Traumatic Brain Injury","volume":"36","author":"Karlsson","year":"2018","journal-title":"J. Neurotrauma"},{"key":"ref_37","first-page":"658","article-title":"Metformin: Current knowledge","volume":"19","author":"Nasri","year":"2014","journal-title":"J. Res. Med. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e22307","DOI":"10.1096\/fj.202200121R","article-title":"Metformin-mediated mitochondrial protection post-cardiac arrest improves EEG activity and confers neuroprotection and survival benefit","volume":"36","author":"Shoaib","year":"2022","journal-title":"FASEB J."},{"key":"ref_39","first-page":"9349063","article-title":"Role of the Synthetic B1 Vitamin Sulbutiamine on Health","volume":"2020","author":"Bettendorff","year":"2020","journal-title":"J. Nutr. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1248\/bpb.34.1759","article-title":"Evidence for Neuroprotective Effect of Sulbutiamine against Oxygen-Glucose Deprivation in Rat Hippocampal CA1 Pyramidal Neurons","volume":"34","author":"Kwag","year":"2011","journal-title":"Biol. Pharm. Bull."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1002\/jps.20744","article-title":"Dose-Independent Pharmacokinetics of Metformin in Rats: Hepatic and Gastrointestinal First-Pass Effects","volume":"95","author":"Choi","year":"2006","journal-title":"J. Pharm. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1097\/FJC.0000000000000320","article-title":"Intravenous Treatment With Coenzyme Q10 Improves Neurological Outcome and Reduces Infarct Volume After Transient Focal Brain Ischemia in Rats","volume":"67","author":"Belousova","year":"2016","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/acem.12335","article-title":"Combination of Intravenous Ascorbic Acid Administration and Hypothermia After Resuscitation Improves Myocardial Function and Survival in a Ventricular Fibrillation Cardiac Arrest Model in the Rat","volume":"21","author":"Tsai","year":"2014","journal-title":"Acad. Emerg. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"A148","DOI":"10.1161\/circ.130.suppl_2.148","article-title":"Abstract 148: Zoniporide Combined with \u03b1-Methylnorepinephrine Appears Highly Effective for Resuscitation from Cardiac Arrest in a Rat Model of Ventricular Fibrillation","volume":"130","author":"Lamoureux","year":"2014","journal-title":"Circulation"},{"key":"ref_45","first-page":"1192","article-title":"Poloxamer-188 Reduces Muscular Edema After Tourniquet-Induced Ischemia-Reperfusion Injury in Rats","volume":"70","author":"Walters","year":"2011","journal-title":"J. Trauma: Inj. Infect. Crit. Care"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e002206","DOI":"10.1161\/CIRCHEARTFAILURE.115.002206","article-title":"Chronic Therapy With Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs With Advanced Heart Failure","volume":"9","author":"Sabbah","year":"2016","journal-title":"Circ. Heart Fail."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0304-3940(00)01420-8","article-title":"Evidence for a modulatory effect of sulbutiamine on glutamatergic and dopaminergic cortical transmissions in the rat brain","volume":"292","author":"Trovero","year":"2000","journal-title":"Neurosci. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Levine, B.S., and Kerrigan, S. (2020). Principles of Forensic Toxicology, Springer Nature. [5th ed.].","DOI":"10.1007\/978-3-030-42917-1"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.resuscitation.2009.09.018","article-title":"A rodent model of emergency cardiopulmonary bypass resuscitation with different temperatures after asphyxial cardiac arrest","volume":"81","author":"Han","year":"2010","journal-title":"Resuscitation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/0300-9572(94)00827-3","article-title":"Epinephrine and sodium bicarbonate during CPR following asphyxial cardiac arrest in rats","volume":"29","author":"Neumar","year":"1995","journal-title":"Resuscitation"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.resuscitation.2007.08.014","article-title":"Improving neurological outcomes post-cardiac arrest in a rat model: Immediate hypothermia and quantitative EEG monitoring","volume":"76","author":"Jia","year":"2008","journal-title":"Resuscitation"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/1479-5876-9-115","article-title":"Combination therapy: The next opportunity and challenge of medicine","volume":"9","author":"Ascierto","year":"2011","journal-title":"J. Transl. Med."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"(2017). Rationalizing combination therapies. Nat. Med., 23, 1113.","DOI":"10.1038\/nm.4426"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/nyas.14507","article-title":"A walk through the progression of resuscitation medicine","volume":"1507","author":"Shoaib","year":"2020","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1007\/s10753-016-0395-2","article-title":"Inhibiting High-Mobility Group Box 1 (HMGB1) Attenuates Inflammatory Cytokine Expression and Neurological Deficit in Ischemic Brain Injury Following Cardiac Arrest in Rats","volume":"39","author":"Xu","year":"2016","journal-title":"Inflammation"},{"key":"ref_56","first-page":"7468738","article-title":"Neuroprotective Effect of the Inhibitor Salubrinal after Cardiac Arrest in a Rodent Model","volume":"2020","author":"Zhang","year":"2020","journal-title":"Oxidat. Med. Cell Longev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"586229","DOI":"10.3389\/fmed.2020.586229","article-title":"Inhaled Gases as Therapies for Post\u2013Cardiac Arrest Syndrome: A Narrative Review of Recent Developments","volume":"7","author":"Hayashida","year":"2020","journal-title":"Front. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"390","DOI":"10.3109\/10903127.2015.1086848","article-title":"Blinded Evaluation of Combination Drug Therapy for Prolonged Ventricular Fibrillation Using a Swine Model of Sudden Cardiac Arrest","volume":"20","author":"Mader","year":"2016","journal-title":"Prehospital Emerg. Care"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e008389","DOI":"10.1161\/JAHA.117.008389","article-title":"Metformin Improves Neurologic Outcome via AMP-Activated Protein Kinase\u2013Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation","volume":"7","author":"Zhu","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1097\/SHK.0000000000000357","article-title":"Evaluation of Cyclosporine a as a Cardio- and Neuroprotective Agent after Cardiopulmonary Resuscitation in a Rat Model","volume":"43","author":"Knapp","year":"2015","journal-title":"Shock"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.resuscitation.2016.04.024","article-title":"Thiamine as a neuroprotective agent after cardiac arrest","volume":"105","author":"Ikeda","year":"2016","journal-title":"Resuscitation"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Marcos, M.A., Cabaleiro, D., Guimarey, M.J.G., Comu\u00f1as, M.J.P., Fedele, L., Fern\u00e1ndez, J., and Lugo, L. (2017). PEG 400-Based Phase Change Materials Nano-Enhanced with Functionalized Graphene Nanoplatelets. Nanomaterials, 8.","DOI":"10.3390\/nano8010016"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"27642","DOI":"10.1038\/srep27642","article-title":"Cardiac arrest triggers hippocampal neuronal death through autophagic and apoptotic pathways","volume":"6","author":"Cui","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1615\/CritRevNeurobiol.v18.i1-2.150","article-title":"Inflammation in Ischemic Brain Injury: Timing Is Important","volume":"18","author":"Kriz","year":"2006","journal-title":"Crit. Rev. Neurobiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1038\/aps.2013.89","article-title":"Inflammatory responses in hypoxic ischemic encephalopathy","volume":"34","author":"Liu","year":"2013","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"S232","DOI":"10.1038\/sj.bjp.0706400","article-title":"The role of inflammation in CNS injury and disease","volume":"147","author":"Lucas","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"193","DOI":"10.2174\/1566524043479185","article-title":"Astrocyte Influences on Ischemic Neuronal Death","volume":"4","author":"Swanson","year":"2004","journal-title":"Curr. Mol. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/092986708783330665","article-title":"Modulation of neuro-inflammation and vascular response by oxidative stress following cerebral ischemia-reperfusion injury","volume":"15","author":"Wong","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1038\/nm.2399","article-title":"The immunology of stroke: From mechanisms to translation","volume":"17","author":"Iadecola","year":"2011","journal-title":"Nat. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1523\/JNEUROSCI.5505-08.2009","article-title":"Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor","volume":"29","author":"Lambertsen","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/jnc.13008","article-title":"Rapid mitochondrial dysfunction mediates TNF-alpha-induced neurotoxicity","volume":"132","author":"Doll","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1615\/CritRevImmunol.v21.i5.20","article-title":"Interleukin-10 in the brain","volume":"21","author":"Strle","year":"2001","journal-title":"Crit. Rev. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1046\/j.1460-9568.2000.00090.x","article-title":"Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage","volume":"12","author":"Grilli","year":"2000","journal-title":"Eur. J. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1161\/01.CIR.0000155622.68580.DC","article-title":"Postischemic Gene Transfer of Interleukin-10 Protects Against Both Focal and Global Brain Ischemia","volume":"111","author":"Ooboshi","year":"2005","journal-title":"Circulation"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/sj.embor.7400236","article-title":"Accelerating drug discovery","volume":"5","author":"Kraljevic","year":"2004","journal-title":"EMBO Rep."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/11\/1548\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:48:24Z","timestamp":1760125704000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/11\/1548"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,5]]},"references-count":75,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["cells12111548"],"URL":"https:\/\/doi.org\/10.3390\/cells12111548","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,5]]}}}