TABLE 1.

Studies on intervention of UPR in cerebral ischemia.

UPR	Intervention	Related protein changes	Ischemia model	Effects	References
PERK pathway	Hes1 knockdown	Activating the PERK/eIF2α/ATF4/CHOP signaling pathway	tMCAO	Knockdown of Hes1 increased cerebral infarction, worsened nervous system prognosis, and promoted ER stress-induced apoptosis.	Li L. et al., 2020
	PERK-cKO by cross-breeding Camk2a-CreERT2 with Perkf/f mice	Decreasing the expression of p-eIF2α and p-perk	tMCAO/BCAO	Decreased neurological scores and increased infarct volume in PERK-cKO mice.	Wang et al., 2020
	Overexpression of ATF4 induced by adeno-associated virus	Increasing the expression of ATF4	MCAO	Overexpressed ATF4 reduced cerebral infarction volume, lowered neurological score and improves HE and Nissl staining.	He et al., 2019
	Giving mice a subcutaneous injection of G-CSF (50 μg/kg) for 4 days	Decreasing the expression of ATF4, CHOP, capase-12	BCAO	G-CSF can’t only reduce acute neuronal degeneration, but also increase long-term plasticity after cerebral ischemia, and maintain cell homeostasis by reducing pro-apoptotic proteins and increasing anti-apoptotic proteins.	Modi et al., 2020
	ATF4 silencing	Decreasing the expression of PARK2 and PARK2-dependent mitophagy	tMCAO	The silencing of ATF4 gave rise to the disappearance of the neuroprotective effects where the volume of cerebral infarction decreases and the absorption rate of glucose in ischemic tissue increases induced by tunicamycin and thapsigargin.	Zhang X. et al., 2014
	Continuous injection of chrysophanol (0.1 mg/kg) for 14 days	Decreasing the expression of CHOP, GRP78, p-eIF2α, caspase-12 and increasing the expression of anti-inflammatory factor IκB-α	MCAO	CHR exerted anti-inflammatory effects by inhibiting ER stress response after I/R while reducing neuronal apoptosis.	Zhao et al., 2018
	Hypothermia (31°C)	Decreasing the expression of CHOP and Ero1-α	MCAO	Hypothermia inhibited apoptosis of stroke cells induced by endoplasmic reticulum stress.	Poone et al., 2015
	Salubrinal	Increasing the expression of p-eIF2α and GADD34	MCAO	Salubrinal played a neuroprotective effect by reducing CA1 cell death and blood-brain barrier damage.	Nakka et al., 2010; Anuncibay-Soto et al., 2016
IRE1 pathway	Overexpression of XBP1s induced by adenovirus transduction	Increasing the expression of XBP1s	ODG/R of primary rat hippocampal neurons	Overexpression of XBP1s suppressed cell death induced by OGD/R stress.	Ibuki et al., 2012
	Give Icariin to microglia and hippocampal neurons 1 h before OGD	Decreasing the ratio of p-IRE1α/IRE1α, the expression of XBP1s and IL-β, IL-6, TNF-α	ODG/R of primary microglia and cortical neurons	Increased viability of primary cortical neuron cells treated with Icariin.	Shaulian and Karin, 2002
	Using melatonin (5 mg/kg) at the beginning of reperfusion	Suppressing the PERK/eIF2α/ATF4/CHOP signaling pathway	MCAO	The infarct volume and individual skin lesion size of melatonin-treated mices were significantly reduced, and the number of surviving neurons increased.	Lin et al., 2018
	Melatonin pretreatment before cerebral ischemia	Decreasing the expression of p-perk and p-IRE1	tMCAO	Melatonin pretreatment markly relieved cerebral infarction, cerebral edema, neuronal apoptosis and nervous system defects.	Feng et al., 2017
ATF6 pathway	ATF6 pharmacological activation by a compound called 147	Increasing the expression of GRP78 and catalase	MCAO	The pharmacological activation of ATF6 stabilized the reprogramming protein, reduces damage and preserves brain function.	Blackwood et al., 2019
	Taurine	Downregulating the ratio of cleaved ATF6, full-length ATF6, p-IRE1, caspase-12, CHOP and Bax	MCAO ODG/R of primary cortical neurons	Taurine not only caused neuroprotection through the ATF6 and IRE1 pathways, but also reduces apoptosis and cerebral infarction volume in these model.	Gharibani et al., 2013