title: Combined NADPH and the NOX inhibitor apocynin provides greater anti-inflammatory and neuroprotective effects in a mouse model of stroke.
abstract: Our previous study has reported that the pentose phosphate pathway product nicotinamide adenine dinucleotide phosphate (NADPH) protected neurons against ischemia/reperfusion-induced brain injury. NADPH can either act as a co-enzyme to produce GSH or a substrate of NADPH oxidase (NOX) to generate ROS. This study was designed to elucidate the effects of co-treatment with NADPH and NOX inhibitor apocynin on ischemia/reperfusion-induced brain inflammation and neuronal injury. The results showed that both NADPH and apocynin markedly attenuated ischemia/reperfusion-induced increases in the levels of NOX2, NOX4 and ROS. NADPH and apocynin significantly inhibited the phosphorylation and degradation of IκBα, NF-κBp65 nuclear localization, and the expression of NF-κB target gene cyclooxygenase (COX2) and inducible nitric oxide synthase (iNOS). Furthermore, both NADPH and apocynin suppressed the expression of inflammasome proteins including NLRP3 ASC, caspase-1, interleukin (IL)-1β and IL-18 in the ischemic cortex as revealed by Western blot analysis and immunofluorescence. Moreover, all these effects were greatly amplified by combination of NADPH and apocynin. Both NADPH and apocynin significantly reduced infarct volume, improved post-stroke survival, and recovery of neurological functions in mouse model of stroke. Consistently, the combination of NADPH and apocynin produced greater beneficial effects in against ischemic brain damage. These studies suggest that, beyond anti-oxidative effects, NADPH may also have anti-inflammatory effects and combination of NADPH and NOX inhibitors could produce a greater neuroprotective effect in ischemic stroke.
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China; Department of Pharmacy, Suzhou Hospital of Traditional Chinese Medicine, Suzhou 215009, Jiangsu Province, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Qin
authors.affiliation: Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Feng
authors.affiliation: Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Pharmacy, Suzhou Hospital of Traditional Chinese Medicine, Suzhou 215009, Jiangsu Province, China.
authors.forename: Xi-Kui
authors.initials: XK
authors.lastname: Shen
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.
authors.forename: Jieyu
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Sheng
authors.affiliation: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, College of Pharmacy, Zhejiang University, Hangzhou 310058, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Han
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China. Electronic address: qinzhenhong@suda.edu.cn.
authors.forename: Zheng-Hong
authors.initials: ZH
authors.lastname: Qin
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009249:NADP / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000098:Acetophenones; D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009249:NADP; C056165:acetovanillone; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases
keywords: Apocynin; Inflamasome; NADPH; NOX; Stroke