J Stroke.  2024 May;26(2):203-230. 10.5853/jos.2023.04329.

Neuroprotective Approaches for Brain Injury After Cardiac Arrest: Current Trends and Prospective Avenues

• Marasini S
• Jia X

• KMID: 2556042
• DOI: http://doi.org/10.5853/jos.2023.04329

Abstract

With the implementation of improved bystander cardiopulmonary resuscitation techniques and public-access defibrillation, survival after out-of-hospital cardiac arrest (OHCA) has increased significantly over the years. Nevertheless, OHCA survivors have residual anoxia/reperfusion brain damage and associated neurological impairment resulting in poor quality of life. Extracorporeal membrane oxygenation or targeted temperature management has proven effective in improving post-cardiac arrest (CA) neurological outcomes, yet considering the substantial healthcare costs and resources involved, there is an urgent need for alternative treatment strategies that are crucial to alleviate brain injury and promote recovery of neurological function after CA. In this review, we searched PubMed for the latest preclinical or clinical studies (2016–2023) utilizing gas-mediated, pharmacological, or stem cell-based neuroprotective approaches after CA. Preclinical studies utilizing various gases (nitric oxide, hydrogen, hydrogen sulfide, carbon monoxide, argon, and xenon), pharmacological agents targeting specific CA-related pathophysiology, and stem cells have shown promising results in rodent and porcine models of CA. Although inhaled gases and several pharmacological agents have entered clinical trials, most have failed to demonstrate therapeutic effects in CA patients. To date, stem cell therapies have not been reported in clinical trials for CA. A relatively small number of preclinical stem-cell studies with subtle therapeutic benefits and unelucidated mechanistic explanations warrant the need for further preclinical studies including the improvement of their therapeutic potential. The current state of the field is discussed and the exciting potential of stem-cell therapy to abate neurological dysfunction following CA is highlighted.

Keyword

Neuroprotection; Cardiac arrest; Pharmacological approach; Gases; Stem cells

Figure

• 

  Figure 1. Schematic representation for the reported neuroprotective mechanisms of gases in CA. Red arrows indicate downregulatory effects, whereas green indicates the upregulatory effects for respective signaling mechanisms. Gases suppress oxidative stress, inflammation, and apoptosis while upregulating the neuroprotective mechanisms in the CA brain. CA, cardiac arrest; NO, nitric oxide; CO, carbon monoxide; CO2, carbon dioxide; H2, hydrogen; H2S, hydrogen-sulfide; Xe, xenon; Ar, argon; ROS, reactive oxygen species; NMDAR, N-methyl-D-aspartate receptor; cGMP: cyclic guanosine 3’,5’-monophosphate; GSNO, S-nitrosoglutathione; BDNF, brain-derived neurotrophic factor; SOD, superoxide dismutase; TLR, toll-like receptor; AKT, protein kinase B; CREB, cyclic adenosine 3,5-monophosphate-response element-binding protein; HO1, heme-oxygenase-1; IRAK, interleukin-1 receptor associated kinase; Nrf2, nuclear factor erythroid 2–related factor-2; CAT, catalase; GPX1, glutathione peroxidase; GST, glutathione S-transferase; NFκB, nuclear factor kappa B; ERK, extracellular signalregulated kinase; P38, P38 kinase; hsp90, heat shock protein 90; TRκβ, tyrosine kinase β.

• 

  Figure 2. Possible neuroprotective mechanisms of pharmacological agents used for cardiac arrest. Drugs included beneath the box represent respective pathophysiological processes such as anti-inflammation, anti-apoptosis, antioxidant, and multiple pleiotropic mechanisms which suppress the ongoing pathophysiology to confer neuroprotection thus mitigating neuronal cell death. LPC-DHA, lysophosphatidylcholine containing docosahexaenoic acid; DCA, dichloroacetate; DMM, dimethyl malonate; D-NAC, dendrimer N-acetyl cysteine; ROS, reactive oxygen species; NO, nitric oxide; OH, hydroxyl radical; HMGB1, high mobility group box-1; NBP, DL-3-n-butylphthalide.

• 

  Figure 3. Diagram illustrating the proposed mechanisms of therapeutic efficacy for exogenous stem cell therapy in cardiac arrest. Stem cells can provide beneficial therapeutic effects via directly differentiating into functional neurons and by possessing pleiotropic paracrine effects such as angiogenesis, neurogenesis, synaptogenesis, anti-fibrosis, anti-apoptosis, and anti-inflammation through secretion of growth factors. VEGF, vascular endothelial growth factor; HGF, hepatocyte growth factor; FGF, fibroblast growth factor; BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; GDNF, glial cell line-derived neurotrophic factor.

Reference

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