A Meta-analysis of Animal Studies Evaluating the Effect of Hydrogen Sulfide on Ischemic Stroke: is the Preclinical Evidence Sufficient to Move Forward?

Overview

Journal Naunyn Schmiedebergs Arch Pharmacol

Specialty Pharmacology

Date 2024 Jul 17

PMID 39017715

Authors

Selda Emre Aydingoz

Ariyan Teimoori

Halit Guner Orhan

Elif Demirtas

Nargiz Zeynalova

Affiliations

Soon will be listed here.

Abstract

Hydrogen sulfide (HS) is a gasotransmitter that has been studied for its potential therapeutic effects, including its role in the pathophysiology and treatment of stroke. This systematic review and meta-analysis aimed to determine the sufficiency of overall preclinical evidence to guide the initiation of clinical stroke trials with HS and provide tailored recommendations for their design. PubMed, Web of Science, Scopus, EMBASE, and MEDLINE were searched for studies evaluating the effect of any HS donor on in vivo animal models of regional ischemic stroke, and 34 publications were identified. Pooling of the effect sizes using the random-effect model revealed that HS decreased the infarct area by 34.5% (95% confidence interval (CI) 28.2-40.8%, p < 0.0001), with substantial variability among the studies (I = 89.8%). HS also caused a 37.9% reduction in the neurological deficit score (95% CI 29.0-46.8%, p < 0.0001, I = 63.8%) and in the brain water content (3.2%, 95% CI 1.4-4.9%, p = 0.0014, I = 94.6%). Overall, the studies had a high risk of bias and low quality of evidence (median quality score 5/15, interquartile range 4-9). The majority of the included studies had a "high" or "unclear" risk of bias, and none of the studies overall had a "low" risk. In conclusion, HS significantly improves structural and functional outcomes in in vivo animal models of ischemic stroke. However, the level of evidence from preclinical studies is not sufficient to proceed to clinical trials due to the low external validity, high risk of bias, and variable design of existing animal studies.

References

Li G, Luo H, Li L, Zhang Q, Xie L, Jiang H . Dual effects of hydrogen sulphide on focal cerebral ischaemic injury via modulation of oxidative stress-induced apoptosis. Clin Exp Pharmacol Physiol. 2012; 39(9):765-71. DOI: 10.1111/j.1440-1681.2012.05731.x. View

Virani S, Alonso A, Benjamin E, Bittencourt M, Callaway C, Carson A . Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation. 2020; 141(9):e139-e596. DOI: 10.1161/CIR.0000000000000757. View

Yang K, Li W, Liu Y, Wei Y, Ren Y, Mai C . Hydrogen Sulfide Attenuates Neuroinflammation by Inhibiting the NLRP3/Caspase-1/GSDMD Pathway in Retina or Brain Neuron following Rat Ischemia/Reperfusion. Brain Sci. 2022; 12(9). PMC: 9497235. DOI: 10.3390/brainsci12091245. View

Narne P, Pandey V, Phanithi P . Role of Nitric Oxide and Hydrogen Sulfide in Ischemic Stroke and the Emergent Epigenetic Underpinnings. Mol Neurobiol. 2018; 56(3):1749-1769. DOI: 10.1007/s12035-018-1141-6. View

Vesterinen H, Sena E, Egan K, Hirst T, Churolov L, Currie G . Meta-analysis of data from animal studies: a practical guide. J Neurosci Methods. 2013; 221:92-102. DOI: 10.1016/j.jneumeth.2013.09.010. View

Schmidt A, Wellmann J, Schilling M, Strecker J, Sommer C, Schabitz W . Meta-analysis of the efficacy of different training strategies in animal models of ischemic stroke. Stroke. 2013; 45(1):239-47. DOI: 10.1161/STROKEAHA.113.002048. View

Carbone L, Austin J . Pain and Laboratory Animals: Publication Practices for Better Data Reproducibility and Better Animal Welfare. PLoS One. 2016; 11(5):e0155001. PMC: 4865140. DOI: 10.1371/journal.pone.0155001. View

Fisher M, Feuerstein G, Howells D, Hurn P, Kent T, Savitz S . Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009; 40(6):2244-50. PMC: 2888275. DOI: 10.1161/STROKEAHA.108.541128. View

Joseph C, Buga A, Vintilescu R, Balseanu A, Moldovan M, Junker H . Prolonged gaseous hypothermia prevents the upregulation of phagocytosis-specific protein annexin 1 and causes low-amplitude EEG activity in the aged rat brain after cerebral ischemia. J Cereb Blood Flow Metab. 2012; 32(8):1632-42. PMC: 3421103. DOI: 10.1038/jcbfm.2012.65. View

10.

Michael Clark J, Sanders S, Carter M, Honeyman D, Cleo G, Auld Y . Improving the translation of search strategies using the Polyglot Search Translator: a randomized controlled trial. J Med Libr Assoc. 2020; 108(2):195-207. PMC: 7069833. DOI: 10.5195/jmla.2020.834. View

11.

Mendonca B, Cardoso J, Michels M, Vieira A, Wendhausen D, Manfredini A . Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke. Intensive Care Med Exp. 2020; 8(1):13. PMC: 7145883. DOI: 10.1186/s40635-020-00300-8. View

12.

Saini V, Guada L, Yavagal D . Global Epidemiology of Stroke and Access to Acute Ischemic Stroke Interventions. Neurology. 2021; 97(20 Suppl 2):S6-S16. DOI: 10.1212/WNL.0000000000012781. View

13.

McCann S, Cramond F, Macleod M, Sena E . Systematic Review and Meta-Analysis of the Efficacy of Interleukin-1 Receptor Antagonist in Animal Models of Stroke: an Update. Transl Stroke Res. 2016; 7(5):395-406. PMC: 5014900. DOI: 10.1007/s12975-016-0489-z. View

14.

Wang L, Wang X, Li T, Zhang Y, Ji H . 8e Protects against Acute Cerebral Ischemia by Inhibition of PI3Kγ-Mediated Superoxide Generation in Microglia. Molecules. 2018; 23(11). PMC: 6278485. DOI: 10.3390/molecules23112828. View

15.

Moher D, Liberati A, Tetzlaff J, Altman D . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009; 151(4):264-9, W64. DOI: 10.7326/0003-4819-151-4-200908180-00135. View

16.

Yin W, Lan L, Huang Z, Ji J, Fang J, Wang X . Discovery of a ring-opened derivative of 3-n-butylphthalide bearing NO/H2S-donating moieties as a potential anti-ischemic stroke agent. Eur J Med Chem. 2016; 115:369-80. DOI: 10.1016/j.ejmech.2016.03.044. View

17.

Keep R, Hua Y, Xi G . Brain water content. A misunderstood measurement?. Transl Stroke Res. 2012; 3(2):263-5. PMC: 3413327. DOI: 10.1007/s12975-012-0152-2. View

18.

Macleod M, van der Worp H, Sena E, Howells D, Dirnagl U, Donnan G . Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke. 2008; 39(10):2824-9. DOI: 10.1161/STROKEAHA.108.515957. View

19.

Numagami Y, Sato S, Ohnishi S . Attenuation of rat ischemic brain damage by aged garlic extracts: a possible protecting mechanism as antioxidants. Neurochem Int. 1996; 29(2):135-43. DOI: 10.1016/0197-0186(95)00117-4. View

20.

Gheibi S, Aboutaleb N, Khaksari M, Kalalian-Moghaddam H, Vakili A, Asadi Y . Hydrogen sulfide protects the brain against ischemic reperfusion injury in a transient model of focal cerebral ischemia. J Mol Neurosci. 2014; 54(2):264-70. DOI: 10.1007/s12031-014-0284-9. View