TABLE 1.
Clinical and experimental studies overview of OS in EBI after SAH.
| Method/animal | Numbers (all/groups) | Drug/agent | Pathway | Effect | References | |
| KEAP1-NRF2-ARE pathway | Injection/rat | 30/2 | – | Nrf2-ARE | Nrf2 expression is upregulated in the cerebral artery of rats after experimental SAH | Wang et al., 2010 |
| Injection/rat | 72/4 | Sulforaphane | Nrf2-ARE | Nrf2-ARE pathway is activated in the brain after SAH, playing a beneficial role in EBI development, possibly through inhibiting cerebral oxidative stress by inducing antioxidant and detoxifying enzymes | Chen et al., 2011 | |
| Perforation/rat | 163/5 | MitoQ/ML385 | Keap1/Nrf2/PHB2 | MitoQ inhibited oxidative stress related neuronal death by activating mitophagy via Keap1/Nrf2/PHB2 pathway | Zhang T. et al., 2019 | |
| Injection/rat | 60/5 | RTA 408 | Nrf2 and NF-κB | RTA 408 attenuated SAH-induced vasospasm through its reversal of SAH-induced changes in Nrf2, NF-κB, and iNOS | Tsai et al., 2020 | |
| Injection/rabbit Perforation/rabbit | 40/6 | Tetramethyl- pyrazine nitrone (TBN) | Nrf2/HO-1 | TBN ameliorated SAH-induced cerebral vasospasm and neuronal damage, attributed to its anti-oxidative stress effect and upregulation of Nrf2/HO-1 | Wu et al., 2019 | |
| Injection/rat | 150/5 | Aloperine (ALO) | Nrf2-ARE | ALO can ameliorate oxidative damage against EBI following SAH, most likely via the Nrf2-ARE survival pathway | Song et al., 2018 | |
| Perforation/rat | 210/4 | Recombinant MFGE8 | Integrinβ3/Nrf2/HO | Recombinant MFGE8 attenuated oxidative stress that may be mediated by integrin β3/nuclear factor erythroid 2–related factor 2/HO pathway after SAH | Liu et al., 2014 | |
| Perforation/rat | 221/4 | TSG-6 | NF-κB and HO-1 | TSG-6 attenuated oxidative stress and apoptosis in EBI after SAH partly by inhibiting NF-κB and activating HO-1 pathway in brain tissue | Li et al., 2020 | |
| Perforation/rat | 96/4 | Ursolic acid | TLR4/NF-κB | UA alleviated EBI by its anti-inflammatory properties, and the therapeutic benefit of post-SAH UA administration is due to its effect on inhibiting the activation of the TLR4/NF-κB signaling pathway | Zhang et al., 2014a | |
| Perforation/rat | 132/3 | Gastrodin | Nrf2/HO-1 | The administration of gastrodin provides neuroprotection against early brain injury after experimental SAH | Wang et al., 2019 | |
| Injection/rat | 160/4 | tert-Butylhy- droquinone (tBHQ) | Keap1/Nrf2/ARE | The administration of tBHQ abated the development of EBI and cognitive dysfunction in this SAH model for activation of the Keap1/Nrf2/ARE pathway | Wang et al., 2014 | |
| Mitochondrial pathway | Perforation/rat | 76/4 | – | – | Enhanced autophagy plays a protective role in early brain injury after SAH | Jing et al., 2012 |
| Perforation/rat | 93/5 | TT01001 | – | mitoNEET activation with TT01001 reduced oxidative stress injury and neuronal apoptosis by improving mitochondrial dysfunction in EBI after SAH | Shi et al., 2020 | |
| Perforation/rat | 132/5 | Docosahexaenoic acid | – | Prevent oxidative stress-based apoptosis after SAH, further improve mitochondrial dynamics-related signaling pathways | Zhang T. et al., 2018 | |
| Perforation/rat | 135/8 | Resolvin D2 | RvD2/GPR18 | Upregulating GPR18 by RvD2 may improve neurological functions in different brain regions via multiple mechanisms | Zhang T. et al., 2021 | |
| Perforation/rat | 238/4 | Lipoxin A4 (LXA4) | FPR2/p38 | Exogenous LXA4 inhibited inflammation by activating FPR2 and inhibiting p38 after SAH | Guo et al., 2016 | |
| Perforation/rat | 32/4 | Naringin | MAPK | Reduced the oxidant damage and apoptosis by inhibiting the activation of MAPK signaling pathway | Han et al., 2017a | |
| Injection/rat | 232/4 | Peroxiredoxin 1/2 | ASK1/p38 | Early expression of Prx1/2 may protect the brain from oxidative damage after SAH and may provide a novel target for treating SAH | Lu et al., 2019 | |
| Perforation/rat | 275/3 | Mdivi-1 | PERK/eIF2α/CHOP | Inhibition of Drp1 by Mdivi-1 attenuated early brain injury after SAH probably via the suppression of inflammation-related blood–brain barrier disruption and endoplasmic reticulum stress-based apoptosis | Fan et al., 2017 | |
| Injection/rat | 192/4 | SS31 | Mitochondrial apoptotic | SS31 could alleviate EBI after SAH through its antioxidant property and ability in inhibiting neuronal apoptosis, likely by modulating the mitochondrial apoptotic pathway | Shen et al., 2020 | |
| Other Pathway | Perforation/rat | 165/10 | ReOX40 | OX40-OX40L/PI3K/AKT | ReOX40 attenuates neuronal apoptosis through OX40-OX40L/PI3K/AKT pathway in EBI after SAH | Wu et al., 2020 |
| Perforation/rat | 249/5 | Aggf1 | PI3K/Akt/NF-κB | Exogenous Aggf1 treatment attenuated neuroinflammation and BBB disruption, improved neurological deficits after SAH in rats, at least in part through the PI3K/Akt/NF-κB pathway | Zhu et al., 2018 | |
| Perforation/rat | 196/11 | Kisspeptin-54 (KP54) | GPR54/ARRB2/AKT/GSK3β | Administration of KP54 attenuated oxidative stress, neuronal apoptosis and neurobehavioral impairments through GPR54/ARRB2/AKT/GSK3β signaling pathway after SAH in rat | Huang et al., 2021 | |
| Perforation/mouse | 168/4 | Apolipoprotein E | JAK2/STAT3/NOX2 | apoE and apoE-mimetic peptide have whole-brain protective effects that may reduce EBI after SAH via M1 microglial quiescence | Pang et al., 2018 | |
| Injection/rat | 32/4 | SC79 | Iron accumulation | Disrupted iron homeostasis could contribute to EBI and Akt activation may regulate iron metabolism to relieve iron toxicity, further protecting neurons from EBI after SAH | Hao et al., 2016 | |
| Injection/rat | 319/4 | SC79 | Akt/GSK3β | SC79 exerts its neuroprotective effect likely through the dual activities of anti-oxidation and antiapoptosis | Zhang et al., 2016a | |
| Perforation/rat | 84/4 | Scutellarin (SCU) | Erk5-KLF2-eNOS | SCU could attenuate vasospasm and neurological deficits via modulating the Erk5-KLF2-eNOS pathway after SAH | Li Q. et al., 2016 | |
| Injection/rat | 120/3 | Purmorphamine (PUR) | Sonic hedgehog | PUR exerts neuroprotection against SAH-evoked injury in rats, mediated in part by antiapoptotic and antioxidant mechanism, upregulating phospho-ERK levels, mediating Shh signaling molecules in the PFC | Hu et al., 2016 | |
| Perforation/rat | 199/5 | TGR5/INT-777 | cAMP/PKCε/ALDH2 | The activation of TGR5 with INT-777 attenuated oxidative stress and neuronal apoptosis via the cAMP/PKCε/ALDH2 signaling pathway | Zuo G. et al., 2019 | |
| Perforation/rat | 196/5 | AVE 0991 | Mas/PKA/p-CREB/UCP-2 | Mas activation with AVE reduces oxidative stress injury and neuronal apoptosis through Mas/PKA/p-CREB/UCP-2 pathway after SAH | Mo et al., 2019 | |
| Melatonin | Injection/rabbit | 48/4 | Melatonin | – | Post-SAH melatonin administration may attenuate inflammatory response and oxidative stress in the spasmodic artery | Fang et al., 2009 |
| Human | 169/2 | Melatonin | – | Patients with higher serum melatonin concentrations are more likely to have a poor prognosis | Zhan et al., 2021 | |
| Perforation/mouse | –/3 | Melatonin | Sirt3/SOD2 and Bax/Bcl-2/CC3 | Melatonin provided protection from the effects of EBI following SAH by regulating the expression of murine SIRT3 | Yang S. et al., 2018 | |
| Perforation/mouse | –/3 | Melatonin | NRF2 and mitophagy | By increasing the expression of NRF2, the mitophagy induced by melatonin provided protection against brain injury post-SAH | Sun et al., 2018 | |
| Injection/rat | 72/4 | Melatonin | Nrf2-ARE | Through activating Nrf2-ARE pathway and modulating cerebral oxidative stress by inducing antioxidant and detoxifying enzymes | Wang et al., 2012 | |
| Injection/rat | 80/4 | Melatonin | TLR4 | Post-SAH melatonin administration might be due to its salutary effect on modulating TLR4 signaling pathway | Dong et al., 2016 | |
| Perforation/rat | 56/3 | Melatonin | Mitochondrial | The mechanism of these antiapoptosis effects was related to the enhancement of autophagy, which ameliorated cell apoptosis via a mitochondrial pathway | Chen et al., 2014b | |
| Perforation/rat | 77/3 | Melatonin | Tight junction and pro-inflammatory | Melatonin prevents disruption of tight junction proteins which might play a role in attenuating brain edema secondary to BBB dysfunctions by repressing the inflammatory response in EBI after SAH | Chen et al., 2014a | |
| Sirtuins | Injection/rat | 262/4 | Activator 3 | SIRT1 | SIRT1 plays an important role in endogenous neuroprotection by deacetylation and subsequent inhibition of FoxOs-, NF-κ B-, and p53-induced oxidative, inflammatory and apoptotic pathways | Zhang et al., 2016 |
| Injection/rat Injection/mouse | 422/8 | Astaxanthin (ATX) | SIRT1/TLR4 | ATX treatment inhibits TLR4-mediated inflammatory injury by increasing SIRT1 expression after SAH | Zhang X. et al., 2019 | |
| Injection/rat | 96/4 | Astaxanthin (ATX) | Nrf2-ARE | ATX treatment alleviated EBI in SAH model, possibly through activating the Nrf2-ARE pathway by inducing antioxidant and detoxifying enzymes | Wu et al., 2014 | |
| Injection/rat Injection/rabbit | 325/8 20/4 | Astaxanthin (ATX) | – | ATX administration could alleviate EBI after SAH, potentially through its powerful antioxidant property | Zhang et al., 2014 | |
| Injection/rat Injection/mouse | 213/5 – | Fucoxanthin (Fx)/EX527 | Sirt1 | Fx provided protection against SAH-induced oxidative insults by inducing Sirt1 signaling | Zhang X. S. et al., 2020 | |
| Injection/rat Injection/mouse | 159/6 57/2 | Salvianolic acid B | SIRT1 and Nrf2 | SalB provides protection against SAH-triggered oxidative damage by upregulating the Nrf2 antioxidant signaling pathway, which may be modulated by SIRT1 activation | Zhang X. et al., 2018 | |
| Perforation/rat | 68/4 | Salvianolic acid A | ERK/P38/Nrf2 | SalA also modulated Nrf2 signaling, and the phosphorylation of ERK and P38 MAPK signaling in SAH rats | Gu et al., 2017 | |
| Injection/mouse | 132/4 | LV-shPGC-1a | PGC-1a/SIRT3 | The detrimental PGC-1a/SIRT3 pathway, involving regulation of the endogenous antioxidant activity against neuronal damage | Zhang K. et al., 2020 | |
| Perforation/rat | 200/5 | Bexarotene | PPARγ/SIRT6/FoxO3a | The anti-neuroinflammatory effect was at least partially through regulating PPARγ/SIRT6/FoxO3a pathway | Zuo Y. et al., 2019 | |
| Hydrogen sulfide | Injection/rat | 96/4 | Hydrogen sulfide | – | NaSH as an exogenous H2S donor could significantly reduce EBI induced by SAH | Cui et al., 2016 |
| Injection/rat | 134/5 | L-cysteine | CBS/H2S | L-cysteine may play a neuroprotective role in SAH by inhibiting cell apoptosis, upregulating CREB-BDNF expression, and promoting synaptic structure via the CBS/H2S pathway | Li et al., 2017 | |
| Perforation/rat | 35/3 | Hydrogen gas | – | The first report demonstrating that high dose hydrogen gas therapy reduces mortality and improves outcome after SAH | Camara et al., 2019 | |
| Perforation/rat | 182/5 | Hydrogen gas | ROS/NLRP3 | Hydrogen inhalation can ameliorate oxidative stress related endothelial cells injury in the brain and improve neurobehavioral outcomes in rats following SAH related to the inhibition of activation of ROS/NLRP3 axis | Zhuang et al., 2019 | |
| Injection/rabbit | 72/4 | Hydrogen-rich saline (HS) | – | Treatment with hydrogen in experimental SAH rabbits could alleviate brain injury via decreasing the oxidative stress injury and brain edema | Zhuang et al., 2012 | |
| Perforation/rat | 129/4 | Hydrogen-rich saline (HS) | NF-κB | HS may inhibit inflammation in EBI and improve neurobehavioral outcome after SAH, partially via inactivation of NF-κB pathway and NLRP3 inflammasome | Shao et al., 2016 | |
| Injection/rat | 244/8 | Sodium/hydrogen exchanger 1 (NHE1) | – | NHE1 participates in EBI induced by SAH through mediating inflammation, oxidative stress, behavioral and cognitive dysfunction, BBB injury, brain edema, and promoting neuronal degeneration and apoptosis | Song et al., 2019 | |
| Perforation/mouse | –/5 | CO | – | First report to demonstrate that CO minimizes delayed SAH-induced neurobehavioral deficits | Kamat et al., 2019 | |
| Modifiable factors | Injection/rat | 120/5 | Gp91ds-tat/GKT137831/apocynin | – | Nox4 should contribute to the pathological processes in SAH-induced EBI, and there was not an overlay effect of Nox2 inhibition and Nox4 inhibition on preventing SAH-induced EBI | Zhang L. et al., 2017 |
| Injection/rabbit | 40/5 | Telmisartan | Trx/TrxR | Downregulation of TXNIP and upregulation of Trx/TrxR | Erdi et al., 2016 | |
| Injection/rat | 24/3 | Verapamil | Antioxidant and antiapoptotic | Intrathecal verapamil can prevent vasospasm, oxidative stress, and apoptosis after experimental subarachnoid hemorrhage | Akkaya et al., 2019 | |
| Perforation/rat | 21/3 | 3,4-dihydroxyphenylethanol (DOPET) | – | Free radical scavenging capacity | Zhong et al., 2016 | |
| Perforation/rat | 40/4 | 3,4-dihydroxyphenylethanol (DOPET) | Akt and NF-κB | DOPET attenuates apoptosis in a rat SAH model through modulating oxidative stress and Akt and NF-κB signaling pathways | Fu and Hu, 2016 | |
| Perforation/rat | 80/4 | Propofol/LY294002 | PI3K/Akt | Propofol attenuates SAH-induced EBI by inhibiting inflammatory reaction and oxidative stress, which might be associated with the activation of PI3K/Akt signaling pathway | Zhang H. B. et al., 2019 | |
| Perforation/rat | 248/10 | Wnt-3a | Frz-1/aldolase C/PPAN | Intranasal administration of wnt-3a alleviates neuronal apoptosis through Frz-1/aldolase C/PPAN pathway in the EBI of SAH rats | Ruan et al., 2020 | |
| Perforation/rat | 48/3 | Preconditioning exercise | Nrf2/HO-1 14–3-3γ/p-β-catenin Ser37/Bax/caspase-3 | Preconditioning exercise ameliorates EBI after SAH | Otsuka et al., 2021 |