Table 1.

Summary of In Vivo Studies Involving the Genetic or Pharmacological Manipulation of Sirtuins in the Context of Cerebral Ischemia

Sirtuin modulating compound	Treatment	Injury	Method of sirtuin inhibition	Evaluation	Outcome	Targets	Ref
Multisirtuin modulation
Resveratrol (10 mg/kg), IPC (2 min BCAo w/HT)	Once 2 days prior, once 2 days prior	ACA	Sirtinol (10 μl of 1 mM) ICV	7 days post	Reduced hippocampal cell death, improved neurological score	UCP2, mitochondrial function	(36)
Curcumin (50 mg/kg)	Once/day for 5 days prior	2 h tMCAo	Sirtinol (15 mg/kg) IP	24 h post	Reduced infarct, brain edema, improved neurological score	TNFα, IL-6, mitochondrial function, Bcl-2, p53, Bax	(110)
Sirt1
Hyperbaric oxygen preconditioning (1 h 100% oxygen)	Once/day for 5 days prior	2 h tMCAo	siRNA (10 μl of 50 nM), ICV	7 days post	Reduced infarct volume ratio, improved neurobehavioral deficit	Nrf2, HO-1, SOD1	(177)
Melatonin (10 mg/kg)	Once at ischemia onset, once at reperfusion onset	30 min tMCAo	EX-527 (10 μg) 3x/day for 2 days prior, ICV	24 h post	Reduced infarct, brain edema, improved neurological score	Bcl2, Bax, mitochondrial function	(180)
NAD+–lentiviral NAMPT overexpression (0.5 μl per site of 1 × 109 TU/ml)	4 sites (cortex and hippocampus) 3 weeks prior	2 h tMCAo	Sirt1+/− mice	24 h post	Reduced infarct volume, improved neurological deficit	AMPK, LKB1	(166)
Activator 3 (10 mg/kg)	10 min, 24 h, 40 h after	pMCAo	Sirt1−/−, Sirtinol (10 mg/kg) 10 min, 24 h, 40 h after IP	48 h post	Reduced infarct volume	p53, NF-κB	(58)
Sirt1 overexpression	N/A	BCAS	N/A	28 days post	Improved histopathology, spatial working memory	eNOS, cerebral blood flow	(53)
Sirt1 overexpression	N/A	10 min BCAo	Sirtinol (1 mg/kg), IV	7 days post	less hippocampal damage	Cerebral blood flow	(54)
Sirt2
Sirt2 knockout	immediately after	45 or 1 h tMCAo	Sirt2−/−, AGK2 (0.764 mg/kg), superficial cervical vein	24 h post	Reduced infarct, improved neurological deficit	N/A	(176)
N/A	30 min after	8 min CA/CPR	AGK2, 30 min after (10 μg/kg), IV	3 days, 7 days or 30 days after	Reduced CA1 injury in males	TRPM2, long-term potentiation	(148)
Sirt2 knockout	N/A	45 min or 15 min of tMCAo	Sirt2−/−	48 h, 7 days	Improved neurological deficit, no change in stroke volume	N/A	(85)
Sirt3
Sirt3 knockout	N/A	1 h tMCAo	Sirt3−/−	24 h	Reduced infarct	Ceramide synthases, mitochondrial function, ROS	(128)
Sirt4
None
Sirt5
Sirt5 knockout	ΨɛRACK (PKCɛ activator, 0.75 mg/kg)	85 min tMCAo	Sirt5−/−	24 h	Reduced infarct	NAMPT, AMPK, mitochondrial function	(117)
Sirt6
None
Sirt7
None

ACA, asphyxial cardiac arrest; BCAS, bilateral common carotid artery stenosis; BCAo, bilateral common carotid artery occlusion; eNOS, endothelial nitric oxide synthase; ICV, intracerebroventricular; N/A, not available; PKCɛ, protein kinase C epsilon; ROS, reactive oxygen species; tMCAo, transient middle cerebral artery occlusion; TU, transduction units.