Therapeutic potential of targeting hydrogen peroxide metabolism in the treatment of brain ischaemia

Abstract

For many years after its discovery, hydrogen peroxide (H2O2) was viewed as a toxic molecule to human tissues; however, in light of recent findings, it is being recognized as an ubiquitous endogenous molecule of life as its biological role has been better elucidated. Indeed, increasing evidence suggests that H2O2 may act as a second messenger with a pro-survival role in several physiological processes. In addition, our group has recently demonstrated neuroprotective effects of H2O2 on in vitro and in vivo ischaemic models through a catalase (CAT) enzyme-mediated mechanism. Therefore, the present review summarizes experimental data supporting a neuroprotective potential of H2O2 in ischaemic stroke that has been principally achieved by means of pharmacological and genetic strategies that modify either the activity or the expression of the superoxide dismutase (SOD), glutathione peroxidase (GPx) and CAT enzymes, which are key regulators of H2O2 metabolism. It also critically discusses a translational impact concerning the role played by H2O2 in ischaemic stroke. Based on these data, we hope that further research will be done in order to better understand the mechanisms underlying H2O2 functions and to promote successful H2O2 signalling based therapy in ischaemic stroke. Abbreviations3-AT, 3-amino-1,2,4-triazole; ACSF, artificial cerebral spinal fluid; BSO, buthionine sulfoximine; CAT, catalase; DA, dopamine; DHE, dihydroethidium; fEPSP, field excitatory postsynaptic potential; GPx, glutathione peroxidase; HIF, hypoxia-inducible factor; IPC, ischaemic preconditioning; IR, ischaemia-reperfusion; KATP, ATP-sensitive K + channel; MCAo, middle cerebral artery occlusion; MCS, mercaptosuccinate; mTOR, mammalian target of rapamycin; NF, nuclear factor; NOS, nitric oxide synthase; O2, molecular oxygen; · O2 -, superoxide anion; OGD, oxygen/glucose-deprivation; •OH, hydroxyl radical; PGC1a, PPARg coactivator1a; PI3K, phosphatidylinositol 3-kinase; PPARg, peroxisome proliferator-activated receptorg; Prx, peroxiredoxin; ROS, reactive oxygen species; SNc, substantia nigra pars compacta; SOD, superoxide dismutase; TDP, thiolate-dependent phosphatase; Tg(CAT), transgenic mouse over-expressing catalase; TRP, transient receptor potential; WT, wild-type NomenclatureThe drug/molecular target nomenclature used in this review conforms to the British Journal of Pharmacology's Guide to Receptors and Channels (Alexander et al., 2011), where applicable. Historical notesThe history of H2O2 began in 1818 when it was discovered by Thénard who named it eau oxygénée (Thénard, 1818). Since the mid-1800s, H2O2 has been marketed for a wide variety of uses, including non-polluting bleaching, oxidizing agent, BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2012 (Wolffenstein, 1894). In 1888, the first medical use of H2O2 was described by Love as efficacious in treating numerous diseases, including scarlet fever, diphtheria, nasal catarrh, acute coryza, whooping cough, asthma hay fever and tonsillitis (Love, 1888). Similar...

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