An important “sensors” protein that captures specific metabolic information after SAH and transforms it into an appropriate response is Kelch-like ECH-associated protein 1 (Keap1), which contains reactive cysteine residues that collectively respond to ROS resulting from heme. Covalent modification of Keap1 leads to reduce ubiquitination and accumulates Nrf2 (Bollong et al., 2018). It is combined with a given DNA site, the antioxidant response element, modulating the transcription of a series of antioxidant enzymes (Zolnourian et al., 2019). Lots of researches on stroke models have substantiated that Nrf2 levels lift soon after the stroke. It first appears within 3 h and peaks within 24 h post insult, with the peri-infarct area markedly increasing (Yang et al., 2009; Tanaka et al., 2011). The study indicated that Nrf2 expression is significantly activated in neurons, astrocytes, leukocytes, microglia, endothelin cells, smooth muscle cells, and adventitial cells after SAH-induced brain insult (Wang et al., 2010). Wang et al., found that the Nrf2-ARE pathway is upregulated in rat models with experimental SAH in the time course at 12, 24, and 48 h (Chen et al., 2011). Since then, lots of known activators of the Keap1-Nrf2-ARE pathway were overwhelmingly carried out in the study. Although controversial conclusions are sometimes achieved due to pleiotropic and primary mechanisms, more effective inducers with less crossing activation of other pathways are identified and reach favorable outcomes.

In addition to the agents summarized by former researchers, such as sulforaphane, astaxanthin, curcumin, lycopene, tetra-butyl hydroquinone, dimethyl fumarate, melatonin, and erythropoietin, there are also many other experimental studies conducted more recently. Efforts to target the Nrf2 signaling pathway therapeutically have largely focused on covalent small molecule agonists of Keap1. Mitoquinone (MitoQ), effective in the prevention of mitochondrial dysfunction, restrained OS-related neuronal death by stimulating mitophagy through Keap1/Nrf2/PHB2 pathway after SAH in rats (Zhang T. et al., 2019). In the endovascular perforation mice SAH model, MitoQ treatment reduced OS, both short term and long term. Another activator of Nrf2, RTA 408, a new second-generation semisynthetic oleanane triterpenoid, manifested an antioxidant and anti-inflammatory phenotype (Reisman et al., 2014). After administrated intraperitoneally, vasospasm was reversed by RTA 408 through growth in Nrf2 and reduction in NF-κB (Tsai et al., 2020).

Intriguingly, performing as a downstream molecule in the Keap1-Nrf2-ARE pathway, heme oxygenase-1 (HO-1), also known as HSP32, could be induced by upregulating expression of Nrf2 (Wang and Doré, 2007; Jiang et al., 2020). After SAH, vasospasm and lipid peroxidation can be weakened by HO-1 through the improvement of clearance. Post-hemorrhagic administration of Nrf2 activator, tetramethylpyrazine nitrone (Wu et al., 2019), aloperine (Song et al., 2018), milk fat globule-epidermal growth factor 8 (MFGE8) (Liu et al., 2014, 2015), tumor necrosis factor-alpha stimulated gene-6 (Li et al., 2020), ursolic acid (UA) (Zhang et al., 2014a,b; Ding et al., 2017), gastrodin (Wang et al., 2019), tert-Butylhydroquinone (Wang et al., 2014), promotes posttranscriptional augment of both Nrf2 and HO-1, attenuates OS, and then reduces early brain damage, including brain edema, BBB damage, and cognitive impairment following SAH in animal models. Moreover, an additional NRF family member, namely, Nrf1 (Qian et al., 2019), responsible for ROS detoxification, participates in an effective treatment to moderate SAH-elicited EBI. Researchers concluded that HSP22 played a part in neuroprotective effects by regulating TFAM/Nrf1-triggered mitochondrial biogenesis with positive feedback, further attenuating OS and EBI (Fan et al., 2021).

Shortly after the induction of SAH, EBI triggers mitochondrial disorder, in which many signaling molecules communicate with each other to control OS (Prentice et al., 2015). Thus, another pivotal key in alleviating EBI is discovering new options to keep normal mitochondrial activity by attenuating OS. The mechanisms for ROS generated by mitochondria are under the consensus that the production of ROS is maximal when the ingredients of the electron transport chains (ETCs) are superlatively impaired (Murphy et al., 1999; Moro et al., 2005). Particularly interacting with autophagy and apoptosis, activation of autophagic pathways attenuates EBI after SAH in rats (Jing et al., 2012; Shi et al., 2020; Xu W. et al., 2021). Among the mounts of antioxidant agents, docosahexaenoic acid (DHA), the so-called omega-3 fatty acid, reduces OS through enhancing mitochondrial dynamics in EBI (Zhang T. et al., 2018). Concretely, DHA reduced the number of ROC-positive cells, improved cell viability, attenuated malondialdehyde levels, and superoxide dismutase (SOD) stress. Furthermore, a metabolite of DHA, namely, resolvin D2 (RvD2), helps to defend EBI, especially in the cortex and hypothalamus (Zhang T. et al., 2021). The p38 mitogen-activated protein kinase (MAPK) is a major player in mitochondrial dysfunction after SAH (Sasaki et al., 2004; Yatsushige et al., 2007; Guo et al., 2016; Han et al., 2017a; Tomar et al., 2017; Lu et al., 2019). Recently, a p38 inhibitor, DJ-1, protects mitochondrial dysfunction by induction of translocation (Huang et al., 2018). Another selective inhibitor of Drp1, Mdivi-1, exerts neuroprotective effects against mitochondrial fission and OS (Fan et al., 2017; Wu P. et al., 2017). More recently, SS31 cell-membrane permeating mitochondria has been shown to exert potential neuroprotective effects (Petri et al., 2006). Via suppressing Bax translocation and cytochrome c release, SS31 ameliorated OS by inhibiting the mitochondrial pathway (Shen et al., 2020).

The number of data accumulated till now concerning the protective action of melatonin against OS is preponderant (Galano et al., 2011; Wu H. J. et al., 2017; Luo et al., 2019; Shao et al., 2020). Melatonin, a lipophilic amino acid that originated from tryptophan, N-acetyl-5-methoxytryptamine, is synthesized in the pineal gland and other organs and exhibits both direct and indirect antioxidant effects. Melatonin first reported the antioxidative function in preventing focal regions of injury via inducing HO-1 expression following a rat SAH model in 2002 (Martinez-Cruz et al., 2002). Before the post-clazosentan era, studies regarding the EBI experiments were still broadly focused on delayed brain injury, such as setting the assessment point at day 5 (Fang et al., 2009). Although melatonin shows no improvement in neurologic scores, the phenomenon is settled by large doses with immensely lessened mortality (Ayer et al., 2008a,b). However, the latest study shows that patients with higher serum melatonin concentrations are more likely to have a poor prognosis (Zhan et al., 2021). The increased concentrations of serum melatonin correlate with admission WFNS scores and mFS and serum melatonin appears as an independent predictor for poor 6-month prognosis after aSAH, with a high discriminatory ability for the risk of the poor outcome under the ROC curve, indicating that serum melatonin might serve as a promising prognostic biomarker for aSAH (Zhan et al., 2021). In vivo experiments exhibit that melatonin supplied protection from the effects of EBI after SAH by adjusting the expression of murine SIRT3 (one of the members of the sirtuin family) (Yang S. et al., 2018). Another two recent studies also denoted that melatonin plays a neuroprotective role by increasing the expression of NRF2-mitophagy and ER stress via inducing antioxidant, LC3-II/LC3-I, and Atg 5-mediated autophagy, NLRP3 inflammasome-mediated anti-inflammatory effects, and detoxifying enzymes post-SAH (Wang et al., 2012; Dong et al., 2016; Wu H. J. et al., 2017; Sun et al., 2018). Melatonin may reduce neurobehavioral dysfunction in the SAH model through the TRL4 pathway (Wang et al., 2013). Furthermore, melatonin reduces the EBI by influencing NLRP3 inflammasome-associated apoptosis (Dong et al., 2016) and inhibiting NF-κB activation and attenuating HO-1, NQO-1, and c-GCLC expressions (Jumnongprakhon et al., 2015). The mechanism of these antiapoptosis effects was linked to the improvement of autophagy through a mitochondrial pathway (Chen et al., 2014b). Melatonin inhibits the disruption of tight junction proteins possibly linked to the adjustment of proinflammatory cytokines (Chen et al., 2014a). Taken together, these results demonstrate that regulation of melatonin attenuates symptomatic dysfunction (Chen et al., 2015).

Sirtuins (SIRTs), including the seven SIRTs identified, are a family of deacetylases with homology. Lines of studies showed that SIRTs could modulate diverse biological functions, Sirtuin 1 (SIRT1) with antioxidative properties particularly. Demonstrating that sequential inhibition of forkhead transcription factors of the O class-, NF-κ B-, and p53-induced oxidative pathways, SIRT1 enhanced the neuroprotective role against EBI in rats (Zhang et al., 2016). A well-recognized antioxidant, astaxanthin, mitigates SAH-induced EBI by increasing SIRT1 and suppressing the TLR4 signaling pathway (Wu et al., 2014; Zhang et al., 2014; Zhang X. et al., 2019). Interestingly, derived from seaweeds, fucoxanthin (Fx) mitigates SAH-induced oxidative damage via the SIRT1-dependent pathway (Zhang X. S. et al., 2020). The activation of melanocortin 1 receptor with BMS-470539 immensely reduced EBI after SAH by restraining OS, apoptosis, and mitochondrial fission via the AMPK/SIRT1/PGC-1α signaling pathway (Xu W. et al., 2021). Modulated by SIRT1 activation, salvianolic acid B protects against SAH-triggered oxidative damage by upregulating the Nrf2 antioxidant signaling pathway (Zhang X. et al., 2018). Salvianolic acid homolog A also presented antioxidative, antiapoptotic, and anti-inflammatory properties (Gu et al., 2017; Zhang X. et al., 2018).

Other members of the SIRT family are increasingly studied recently. SIRT3, a type of NAD-dependent deacetylase, remarkedly activated in vivo and in vitro following SAH, is involved in the PGC-1a/SIRT3 pathway attenuating OS (Zhang K. et al., 2020). Drawing on the successful experience of the SIRT6 protective role of the heart from I/R injury via upregulating antioxidants and suppressing OS, the activation of RXR ameliorated neurological deficits after SAH at least partially via adjusting the PPARγ/SIRT6/FoxO3a pathway (Zuo Y. et al., 2019).

Hydrogen sulfide (H₂S), a neuromodulator, which can be generated in the CNS from L-cysteine by cystathionine-β-synthase (CBS), may prove protective effects in experimental SAH (Xiong et al., 2020). The hypothesis that signaling through hydrogen sulfide may mediate protection from DCI clinically in patients with SAH was proposed in 2011 (Grobelny et al., 2011) and further demonstrated by Yu et al. (2014). Afterward, hydrogen sulfide attenuated brain edema formation and promoted the secretion of inflammatory cytokines (Cui et al., 2016). Soon after the proinflammation demonstrated in EBI after SAH, exogenous hydrogen sulfide functioning as an antioxidant and antiapoptotic mediator, donated by NaSH and L-cysteine, could significantly reduce EBI (Cui et al., 2016; Li et al., 2017; Xiong et al., 2020). Inspired by inhaled hydrogen gas markedly decreasing OS on ischemia/reperfusion injury and stroke in rats (Ohsawa et al., 2007), hydrogen gas therapy was conducted, and the rate of survival and neurological deficits were improved in a pilot study as expected (Camara et al., 2019). Mechanistically, the above advantageous effects might be linked to the suppression of the ROS/NLRP3 axis (Zhuang et al., 2019). Similarly, hydrogen-rich saline exhibited the satisfying outcome of alleviating EBI through alleviating OS following experimental SAH in both rabbit and rat models (Zhuang et al., 2012; Shao et al., 2016). Furthermore, sodium/hydrogen exchanger 1 participates in EBI activated by SAH via mediating OS (Song et al., 2019). As abovementioned earlier, a recent study shows that postconditioning with hydrogen gas ameliorated SAH-induced neuronal pyroptosis (Zhang C. S. et al., 2021). Produced endogenously through HO, carbon oxide (CO) minimizes neurobehavioral deficits, indicating that posttreatment with CO gas or CO-donors can be further tested as a potential therapy against SAH (Kamat et al., 2019).

Peaking onset age between 50 and 60 years, many patients with aSAH have modifiable hypertension, dyslipidemia, diabetes mellitus, cardiovascular diseases, and so on (de Rooij et al., 2007; Zhang L. et al., 2017; Macdonald and Schweizer, 2017). To control the clinical status, they are recommended with antihypertensive drugs, statins, and so on, part of whom demonstrate the antioxidative effect in the laboratory, for example, telmisartan, ameliorates OS, and SAH-induced CVS (Erdi et al., 2016). One of the L-type calcium channel blockers, verapamil, can inhibit vasospasm, OS, and apoptosis following experimental SAH (Akkaya et al., 2019). Rosuvastatin, commonly used clinically, ameliorates EBI after SAH through restraining SOD formation and NF-κB activation in rats. Moreover, 3,4-dihydroxyphenylethanol may be a powerful agent in the treatment of EBI after SAH because of its free radical scavenging capacity and modulating the Akt and NF-κB signaling pathway (Zhong et al., 2016; Fu and Hu, 2016). In addition to the intervening abovementioned diseases, other drugs commonly used clinically, such as heparin (Hayman et al., 2017), albumin (Deng et al., 2021), and propofol (Zhang H. B. et al., 2019), all projected an antioxidative role. Some authors believe that preconditioning would provide the greatest chance of benefit but is obviously not effective (Mayor et al., 2013; Zolnourian et al., 2019; Ruan et al., 2020; Otsuka et al., 2021). Given the sophistication of brain damage after aSAH, therapeutic multimodality is promising. Supported by the evidence shown above, we suppose that the regular drug taken with high adherence may benefit favorable outcomes after aneurysm rupture than those who do not.