Table 2:

Strategies by modulating NAD-consuming enzymes.

Targets	Compounds	Disease model	Effects	Ref.
Sirtuin activity modulators
SIRT1 activator	Resveratrol	Cerebral ischemia (CI)	SIRT1 activation modulates neuronal survival in aged CI mice in an Akt-dependent manner	[154]
SIRT1 activator	Sulfonamide derivatives	6-OHDA-treated neuronal cell	SIRT1 activation by sulfonamide derivatives can protect SH-SY5Y from 6-OHDA-induced cell death	[155]
SIRT1 activator	NeuroHeal	Peripheral nerve axotomy	NeuroHeal can activate the pro-survival autophagy process and protect pups from peripheral nerve axotomy by the concomitant activation of SIRT1 and the PI3K/Akt pathway	[156]
SIRT2 inhibitor	AGK2	Ischemic stroke model	SIRT2 inhibitor AGK2 or sirt2 knockout have neuroprotective effects in the transient middle cerebral artery occlusion mouse model	[157]
SIRT2 inhibitor	Thioamide 53		Thioamide 53 can promote neurite outgrowth of Neuro-2a cells	[158]
PARP inhibitors
	Olaparib	Schinzel-Giedion syndrome (SGS)	The neurodegeneration caused by inheritable DNA damage can be alleviated by PARP1 inhibition	[62]
	10e	PD	10e protects neurons from α-synuclein pre-formed fiber-mediated neurotoxicity and helps maintain normal NAD levels	[159]
	PJ34	Rat forebrain ischemia	PJ34 almost completely inhibits neuroinflammation and reduces CA1 neuronal death by 84%.	[160]
	PJ34	Rotenone-treated Drosophila	PARP1 inhibition by PJ34 reduces dSARM expression, and protects Drosophila from rotenone-induced loss of locomotor ability.	[161]
	INO1001	Aortic cross-clamping-induced ischemia/reperfusion	INO1001 markedly protects the spinal cord from aortic occlusion-induced injury.	[162]
	INO1001	Brain traumatic injury	INO1001 significantly reduces microglial activation and increases neuronal survival after TBI.	[163]
	INO1001	R6/2 mutant Huntington’s disease mouse model	INO1001 prolongs R6/2 mutant mouse survival, and reduces severe signs of neurological dysfunction compared to vehicle control	[164]
SARM1 inhibitors
	Berberine Chloride	Chronic acrylamide-induced axon destruction	Berberine treatment significantly ameliorates axonal degeneration, alleviates pathological changes in the sciatic nerve and spinal cord, and improves neurobehavioral symptoms in acrylamide-treated rats.	[165]
	DSRM-3716	Rotenone-induced axon degeneration	SARM1 inhibition by DSRM-3716 rescues rotenone-treated axons that are fated to degenerate	[166]
	NB-3	Nerve injury model Vincristine-induced neuropathy model	NB-3 is covalently conjugated with SARM1 product ADPR and exerts a potent protective effect against nerve injury	[167]
	EV-99	Vacor and vincristine-induced neuropathy	EV-99 covalently binds to C311 of SARM1, and protects axons from vincristine- and vacor-induced neurite degeneration in cultured dorsal root ganglion neurons	[168]
CD38 inhibitors
	78c	age	78c can reverse age-related NAD decline, and improve age-related physiological and metabolic parameters	[169]
	78c	age	Increases lifespan and health span of naturally aged mice	[170]
	apigenin	Diabetes, cell senescence, neuroinflammation	Apigenin has protective effects in age-related diabetes, age-related cell senescence, and LPS-induced neuroinflammation and cognitive impairment	[89, 171–173]
	MK-0159	Ischemia/reperfusion	MK-0159 shows strong protection against I/R-induced myocardial damage	[174]
Other enzymes
Phosphodiesterase (PDE)10A	papaverine	Quinolinic acid-treated primary cortical neuron	Papaverine can increase cellular NAD levels, restore mitochondrial membrane potential, reduce ROS levels, and show neuroprotective activity	[175]
PDE4	Roflumilast	Quinolinic acid-treated primary cortical neuron	Roflumilast can increase intracellular NAD content and protects primary cortical neurons from quinolinic acid-induced toxicity	[176]
PED4	Roflupram	MPP(+)-treated neuronal cells	Roflupram protects dopaminergic neurons from MPP(+)-induced apoptotic cell death via CREB/PGC1α pathways	[177]
	Roflupram	Rotenone-treated SH-SY5Y cells	Roflupram can increase the NAD/NADH levels, activate lysosome function, and reduce α-syn levels in rotenone-treated neuronal cells.	[178]