Mei Li1, Zhi-Peng Zhou1, Meiling Sun1, Lijuan Cao1, Jieyu Chen1, Yuan-Yuan Qin1, Jin-Hua Gu1, Feng Han1, Rui Sheng1, Jun-Chao Wu1, Yuqiang Ding2, Zheng-Hong Qin2. 1. From the Laboratory of Aging and Nervous Diseases, Department of Pharmacology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, China (M.L., M.S., L.C., J.C., Y.-Y.Q., R.S., J.-C.W., Z.-H.Q.); Department of Radiology, Affiliated Hospital of Guilin Medical College, Guilin, China (Z.-P.Z.); Department of Pathophysiology, Nantong University School of Medicine, Nantong, China (J.-H.G.); Institute of Pharmacology and Toxicology, Zhejiang University School of Pharmaceutical Science, Hangzhou, China (F.H.); and Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai, China (Y.D.). 2. From the Laboratory of Aging and Nervous Diseases, Department of Pharmacology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, China (M.L., M.S., L.C., J.C., Y.-Y.Q., R.S., J.-C.W., Z.-H.Q.); Department of Radiology, Affiliated Hospital of Guilin Medical College, Guilin, China (Z.-P.Z.); Department of Pathophysiology, Nantong University School of Medicine, Nantong, China (J.-H.G.); Institute of Pharmacology and Toxicology, Zhejiang University School of Pharmaceutical Science, Hangzhou, China (F.H.); and Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai, China (Y.D.). qinzhenhong@suda.edu.cn dingyuqiang@gmail.com.
Abstract
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.
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.