Multi-Drug Cocktail Therapy Improves Survival and Neurological Function after Asphyxial Cardiac Arrest in Rodents

• Published in: Cells (Basel, Switzerland) Vol. 12; no. 11; p. 1548
• Main Authors: Choudhary, Rishabh C, Shoaib, Muhammad, Hayashida, Kei, Yin, Tai, Miyara, Santiago J, d'Abramo, Cristina, Heuser, William G, Shinozaki, Koichiro, Kim, Nancy, Takegawa, Ryosuke, Nishikimi, Mitsuaki, Li, Timmy, Owens, Casey, Molmenti, Ernesto P, He, Mingzhu, Vanpatten, Sonya, Al-Abed, Yousef, Kim, Junhwan, Becker, Lance B
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05.06.2023; MDPI
• Subjects: Antioxidants; Asphyxia; Bioenergetics; brain injury; Brain research; Cardiac arrest; cardiopulmonary bypass resuscitation; cardiopulmonary resuscitation; cell death; Cerebral blood flow; Complications and side effects; Degeneration; Disease; Drug delivery; Drug dosages; Drug therapy; Drug therapy, Combination; Heart; Hypothermia; Inflammation; Ischemia; ischemic damage; Metabolic pathways; Metabolism; Metabolites; Nervous system diseases; Neurological diseases; Neuroprotection; Neuroprotective agents; Oxidation; Oxidative stress; Prevention; Reperfusion; Sodium; Testing; Traumatic brain injury; Vitamin C; United States; Canada; St Louis Missouri; Ann Arbor Michigan; United States > US; multi-drug cocktail; brain injury; cardiopulmonary resuscitation; cell death; return of spontaneous circulation; neuroprotection; neurodegeneration; ischemic damage; cardiac arrest; cardiopulmonary bypass resuscitation
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12111548

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-reperfusion 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. 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; = 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. 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.