Neuroprotective Role of the Nrf2 Pathway in Subarachnoid Haemorrhage and Its Therapeutic Potential

Table 2

Animal studies published in English, investigating Nrf2 activators in experimental SAH.

Agent	Study	Animal SAH model	Time of doses	Method of administration	Animal dose	Time of tissue evaluation	Time of clinical assessment	Biochemical effect	Clinical effect	Other effects	Vasospasm
Curcumin	Wakade et al. 2009 [165]	Mouse	0, 1, 3, & 24 h	IP	150/300 mg/kg	72 & 96 h	Days 0, 1, 2, & 3	Attenuation of COX-2, IL-1, IL-6, iNOS, TNF-α, ICAM-1, & VCAM-1; reduced lipid peroxidation; & superoxide production	No effect	Reduced cerebral infraction	Reduced vasospasm
	Kuo et al. 2011 [167]	Rat	3 h & then once daily for 6 days	IP	20 mg/kg	Day 7	6 h, days 1, 3, 5, & 7	Lower glutamate & MDA levels, preserved SOD, & catalase level	Reduced mortality & improved functional outcomes	None	Reduced vasospasm
	Aydin et al. 2017 [166]	Rat	Single dose	IP	150/300/600 mg/kg	Blood at 1 h, brain extraction unclear	None	Reduced IL-1, TNF-α, & IL-6	Not done	None	Reduced vasospasm
Astaxanthin	Zhang et al. 2014 [172]	Rat; Rabbit	30 min IT, 3 h Oral	IT, PO	IT 0.01-0.1 mmol/l, PO 25/75 mg/kg	24 & 72 h	0, 24, 48, & 72 h	SOD & GSH levels reduced, MDA levels elevated	Neurological improvement only at 24 & 48 h	Reduced BBB permeability, cerebral oedema, & apoptosis and reduced caspase-3 expression	Not assessed
	Wu et al. 2014 [171]	Rat	30 min	IT	T 0.01-0.1 mmol/l	24 h	24 h	Increased expression of Nrf2, GST-α1, HO-1, & NQO-1, reduced MDA levels	Better performance at 24 h	Reduced BBB permeability, cerebral oedema, & apoptosis	Not assessed
Lycopene	Wu et al. 2015 [176]	Rat	2 h	IP	40 mg/kg	24 h	24 h	Downregulation of TNF-α, IL-1β, & ICAM-1	Improved neurological function	Lessened oedema, disruption of BBB, & cortical apoptosis	Not assessed
Tetra-butyl hydroquinone	Wang and Theeuwes 2014 [177]	Rat	2, 12, 24, & 36 h	PO	12.5 mg/kg	48 h	Days 0, 2, 3, 4, 5, 6, 7, & 8	Increased Keap1, Nrf2, & HO-1 expression; upregulation of GST-α1, HO-1, & NQO-1; reduced MDA levels; increased GSH-P & SOD levels	Improved performance & learning deficits on days 4 & 5	Reduced BBB permeability, cerebral oedema, & apoptosis	Not assessed
	Li et al. 2015 [178]	Mouse	0, 8, & 16 h	IP	50 mg/kg	24 h	24 h	Increased expression of Beclin-1 & the LC3-II to LC3-I ratio	Improvement in neurological deficits	BBB permeability, cerebral oedema, & neuronal degeneration were reduced	Not assessed
Dimethyl fumarate	Liu et al. 2015 [183]	Rat	Twice daily for 2 days	PO	15 mg/kg	48 h	Days 2, 3, 4, & 5	Decreased IL-1β, TNF-α, IL-6, SOD, MDA & GSH-P, HO-1, NQO1 & GST-α1 upregulated	Reduction of learning deficits	Brain oedema, cortical apoptosis & necrosis decreased	Not assessed
Melatonin	Aydin et al. 2005 [186]	Rabbit	0, 2, 12, 24, 36, & 48 h	IP	5 mg/kg	48 h	None	Reduced endothelial cellular apoptosis	Not assessed	Reduced cellular apoptosis	Reduced vasospasm
	Ayer et al. 2008 [188]	Rat	2 h	IP	15/150 mg/kg	24 h	24 h	No effect on MDA	Reduced mortality only	Cerebral oedema reduced	Not assessed
	Ersahin et al. 2009 [187]	Rat	0, 24, & 48 h	IP	10 mg/kg	48 h	48 h	Myeloperoxidase activity decreased, chemiluminescence values decrease, MDA decreased, & GSH was preserved	Improved neurological score	Cerebral oedema & BBB permeability reduced	Reduced vasospasm
Erythropoietin	Alafaci et al. 2000 [194]	Rabbit	5 min, 8, 16, & 24 h	IP	1000 IU/kg	24 h	None	Increased CSF EPO levels	Not assessed	Decreased neuronal damage	Not assessed
	Buemi et al. 2000 [196]	Rabbit	0	IP	1000 IU/kg	72 h	24, 48, & 72 h	No significant increase in CSF EPO concentration	Reduced mortality rate	None	Not assessed
	Grasso et al. 2002 [193]	Rabbit	5 min	IP	1000 IU/kg	72 h	72 h	Increase in CSF EPO concentration	Improved neurological score	Reduced ischaemic neuronal damage	Reduced vasospasm
	Springborg et al. 2002 [192]	Rat	0	SC	400 IU/kg	48 h	None	No biochemical effect assessed	Not assessed	Normalised autoregulation of cerebral blood flow	Not assessed
	Grasso et al. 2002 [195]	Rabbit	5 min, 8, 16, 24, 32, 40, 48, 56, 64, & 72 h	IP	1000 IU/kg	72 h	72 h	Lower S-100 protein concentration in CSF	Improved neurological function	Reduced neuronal damage	Not assessed
	Murphy et al. 2008 [191]	Rabbit	Days 0, 2, 4, & 6	IV	500/1500 IU/kg	24 h	Days 0, 2, 4, 7, 9, & 16	Increased haematocrit values	Reduced mortality rate	Improved cerebra blood flow, reduced cellular apoptosis	No change
	Zhang et al. 2010 [190]	Rat	15 min, 7, 16, 24, 32, 40, & 48 h	IP	1000 IU/kg	48 h	Not assessed	Increased Nrf2 & HO-1 expression, and upregulation of GST-α1, HO-1, & NQO-1	Not assessed	Reduced impairment of cerebral oedema, cortical apoptosis, & BBB permeability	Not assessed
Sulforaphane	Chen et al. 2011 [138]	Rat	30 min and 12 & 36 h	IP	5 mg/kg	12, 24, & 48 h	Not assessed	Increased Nrf2 & HO-1 expression and upregulation of GST-α1, HO-1, & NQO-1	Improved function at 48 h	Decreased cerebral oedema, BBB permeability, & cortical apoptosis	Not assessed
	Zhao et al. 2016 [144]	Rat	30 min and 24, 48, & 72 h	IP	5 mg/kg	72 h	72 h	Increased Nrf2 & HO-1 expression; upregulation of GST-α1, HO-1, & NQO1; and decreased IL-1β, TNF-α, & IL-6	Reduced behavioural deficits	None	Reduced vasospasm