Reduced Nicotinamide Adenine Dinucleotide Phosphate, a Pentose Phosphate Pathway Product, Might Be a Novel Drug Candidate for Ischemic Stroke
Background and Purpose—Our previous study has defined a role of TP53-induced glycolysis and apoptosis regulator in neuroprotection against ischemic injury through increasing the flow of pentose phosphate pathway. We hypothesized that the pentose phosphate pathway product nicotinamide adenine dinucleotide phosphate (NADPH) could be a novel drug for treatment of ischemic stroke.
Methods—The NADPH was given before, at the onset, or after stroke onset with single or repeated intravenous (mice and rats) or intraperitoneal injections (monkey). The short- and long-term therapeutic effects of NADPH were evaluated in male adult ICR mice (total=614) with transient middle cerebral artery occlusion, in male adult Sprague–Dawley rats (total=114) with permanent middle cerebral artery occlusion, and in male adult rhesus monkey (total=12) with thrombotic middle cerebral artery occlusion.
Results—Administration of NADPH led to a dramatic increase in the levels of ATP and reduced form of glutathione, whereas it decreased the levels of reactive oxygen species. NADPH significantly reduced infarct volume, improved poststroke survival, and recovery of neurological functions in mouse and rat models of stroke. Robust neuroprotection of a single dose of NADPH was seen when it was administered within 5 hours after reperfusion; however, repeat administration of NADPH twice a day for 7 days starting 24 hours after the onset of stroke also offered therapeutic effects. Pretreatment with NADPH also significantly improved the outcome of stroke insult.
Conclusions—Administration of exogenous NADPH significantly protected neurons against ischemia/reperfusion-induced injury in 2 rodent stroke models. Thus, NADPH might be a promising drug candidate for treatment of ischemic stroke.
- Received May 13, 2015.
- Revision received October 10, 2015.
- Accepted October 16, 2015.
- © 2015 American Heart Association, Inc.