Cargando…

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

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 th...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10253071/
https://www.ncbi.nlm.nih.gov/pubmed/37296668
http://dx.doi.org/10.3390/cells12111548
_version_ 1785056319998263296
author 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.
author_facet 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.
author_sort Choudhary, Rishabh C.
collection PubMed
description 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–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. 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.
format Online
Article
Text
id pubmed-10253071
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-102530712023-06-10 Multi-Drug Cocktail Therapy Improves Survival and Neurological Function after Asphyxial Cardiac Arrest in Rodents 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. Cells Article 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–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. 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. MDPI 2023-06-05 /pmc/articles/PMC10253071/ /pubmed/37296668 http://dx.doi.org/10.3390/cells12111548 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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.
Multi-Drug Cocktail Therapy Improves Survival and Neurological Function after Asphyxial Cardiac Arrest in Rodents
title Multi-Drug Cocktail Therapy Improves Survival and Neurological Function after Asphyxial Cardiac Arrest in Rodents
title_full Multi-Drug Cocktail Therapy Improves Survival and Neurological Function after Asphyxial Cardiac Arrest in Rodents
title_fullStr Multi-Drug Cocktail Therapy Improves Survival and Neurological Function after Asphyxial Cardiac Arrest in Rodents
title_full_unstemmed Multi-Drug Cocktail Therapy Improves Survival and Neurological Function after Asphyxial Cardiac Arrest in Rodents
title_short Multi-Drug Cocktail Therapy Improves Survival and Neurological Function after Asphyxial Cardiac Arrest in Rodents
title_sort multi-drug cocktail therapy improves survival and neurological function after asphyxial cardiac arrest in rodents
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10253071/
https://www.ncbi.nlm.nih.gov/pubmed/37296668
http://dx.doi.org/10.3390/cells12111548
work_keys_str_mv AT choudharyrishabhc multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT shoaibmuhammad multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT hayashidakei multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT yintai multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT miyarasantiagoj multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT dabramocristina multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT heuserwilliamg multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT shinozakikoichiro multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT kimnancy multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT takegawaryosuke multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT nishikimimitsuaki multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT litimmy multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT owenscasey multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT molmentiernestop multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT hemingzhu multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT vanpattensonya multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT alabedyousef multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT kimjunhwan multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents
AT beckerlanceb multidrugcocktailtherapyimprovessurvivalandneurologicalfunctionafterasphyxialcardiacarrestinrodents