Proteomic identification of proteins differentially expressed by nicotinamide in focal cerebral ischemic injury

Sung, Jin-Hee; Kim, M.-O.; Koh, Phil-Ok

doi:10.1016/j.neuroscience.2010.11.021

Cited by 11 publications

(21 citation statements)

References 36 publications

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“…Several growth factors or mitogens sequentially activate a protein kinase cascade including Raf, MEK, and ERK. A proteomics approach demonstrated that ischemic brain injury reduces MAPK and MAPK kinase proteins, but nicotinamide prevents these proteins reductions [25]. In this study, the phosphorylation of MAPK upstream proteins including Raf and MEK was decreased with ischemic brain injury, while nicotinamide attenuates these ischemia-induced decreases.…”

Section: Discussionmentioning

confidence: 48%

Nicotinamide Prevents the Down-Regulation of MEK/ERK/p90RSK Signaling Cascade in Brain Ischemic Injury

2012

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ABSTRACT. Nicotinamide attenuates neuronal cell death related to focal cerebral ischemic injury. This study investigated whether nicotinamide exerts a neuroprotective effect through the activation of Raf-mitogen-activated protein kinase kinase (MEK)-ERK and its downstream targets, including p90 ribosomal S6 kinase (p90RSK) and Bad. Adult male Sprague-Dawley rats were treated with nicotinamide (500 mg/kg) or vehicle 2 hr after the onset of middle cerebral artery occlusion (MCAO). Brains were collected 24 hr after MCAO. In the present study, nicotinamide significantly reduces the volume of infarct regions and decreases the number of positive cells by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining in the cerebral cortex. Nicotinamide prevents injury-induced decrease in Raf-1, MEK1/2, and ERK1/2 phosphorylation. As part of the downstream cascade, nicotinamide inhibits the injury-induced decrease in p90RSK and Bad phosphorylation. Moreover, nicotinamide prevents the injury-induced increase in cleaved caspase-3 levels. These findings suggest that nicotinamide protects neuronal cells against cerebral ischemic injury and that MEK-ERK-p90RSK cascade activation by nicotinamide contributes to these neuroprotective effects. Ischemic brain injury leads to serious cellular damage through the imbalance of energy metabolism and the generation of oxidative stress 1, 4, 15. Nicotinamide, vitamin B3 amide form, is the precursor for NAD+ and is the necessary factor for cellular function and energy metabolism 27. Nicotinamide reduces the generation of reactive oxygen species (ROS) and attenuates cell damage from cerebral ischemic injury [2,13,20,23]. Nicotinamide prevents necrosis and apoptosis by inhibiting DNA destruction [28]. Moreover, nicotinamide exerts a cytoprotective effect in neurodegenerative diseases such as Alzheimer's disease and traumatic brain injury [3,6,12].Mitogen-activated protein (MAP) kinases (MAPKs, Erk1/2) are members of the serine and threonine protein kinase family involved in many cellular programs including cell differentiation, proliferation, survival, and cell death [22]. In the presence of growth factor or mitogen, MAPKs are phosphorylated and activated by MAPK-kinase (MAPKK, Raf-1), which in turn are phosphorylated and activated by MAPKK-kinase (MAPKKK, MEK1/2). The up-stream enzymes of MAPK are Raf and MEK. While, down-stream targets of MAPK are 90 kDa ribosomal S6 kinase (p90RSK) and transcription factor 18,22]. ERK1/2 leads to the phosphorylation of p90RSK, which then leads to the phosphorylation of the pro-apoptotic bcl-2 family, Bad [5,11,24]. The Raf-MEK-ERK signal cascade attenuates apoptotic cell death through the phosphorylation of the downstream targets, p90RSK and Bad. Previous studies reported that nicotinamide exerts a neuroprotective effect by activation of cellular survival signaling pathway including protein kinase B/Akt [7,8]. Although previous studies have demonstrated the neuroprotective effect of nicotinamide, little data is available regarding th...

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Section: Discussionmentioning

confidence: 48%

Nicotinamide Prevents the Down-Regulation of MEK/ERK/p90RSK Signaling Cascade in Brain Ischemic Injury

2012

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“…54 We also hypothesize that PP2A up-regulators, such as ITH12246, could present a beneficial effect on focal cerebral ischemic injury, as PP2A activity is decreased in these situations. 17 In these experiments, upon administration of Rose Bengal, oxygen singlet species are generated after illumination of brain cortex, causing peroxydation of endothelial cell membranes, occlusive platelet aggregation, microthrombi formation and focal cerebral ischemia. 55 Following the protocol described in the Methods section, we injected i.p.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

PP2A Ligand ITH12246 Protects against Memory Impairment and Focal Cerebral Ischemia in Mice

Lorrio

Romero

González‐Lafuente

et al. 2013

ACS Chem. Neurosci.

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ITH12246 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b] [1,8]naphthyridine-3-carboxylate) is a 1,8-naphthyridine described to feature an interesting neuroprotective profile in in vitro models of Alzheimer's disease. These effects were proposed to be due in part to a regulatory action on protein phosphatase 2A inhibition, as it prevented binding of its inhibitor okadaic acid. We decided to investigate the pharmacological properties of ITH12246, evaluating its ability to counteract the memory impairment evoked by scopolamine, a muscarinic antagonist described to promote memory loss, as well as to reduce the infarct volume in mice suffering phototrombosis. Prior to conducting these experiments, we confirmed its in vitro neuroprotective activity against both oxidative stress and Ca 2+ overload-derived excitotoxicity, using SH-SY5Y neuroblastoma cells and rat hippocampal slices. Using a predictive model of blood-brain barrier crossing, it seems that the passage of ITH12246 is not hindered. Its potential hepatotoxicity was observed only at very high concentrations, from 0.1 mM. ITH12246, at the concentration of 10 mg/kg i.p., was able to improve the memory index of mice treated with scopolamine, from 0.22 to 0.35, in a similar fashion to the well-known Alzheimer's disease drug galantamine 2.5 mg/kg. On the other hand, ITH12246, at the concentration of 2.5 mg/kg, reduced the phototrombosis-triggered infarct volume by 67%. In the same experimental conditions, 15 mg/kg melatonin, used as control standard, reduced the infarct volume by 30%. All of these findings allow us to consider ITH12246 as a new potential drug for the treatment of neurodegenerative diseases, which would act as a multifactorial neuroprotectant.

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“…In cerebral ischemia, this approach has been used to uncover key molecular events using a cerebral ischemic model. [24][25][26] However, there have been no studies of pain-associated regions such as the spinal cord or sciatic nerve using cerebral ischemic animal models.…”

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confidence: 99%

Withdrawal: Proteomic Profiling in the Spinal Cord and Sciatic Nerve in a Global Cerebral Ischemia-Induced Mechanical Allodynia Mouse Model

Harada

Matsuura

Takano

et al. 2016

Biological & Pharmaceutical Bulletin

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Central post-stroke pain (CPSP) is one of the complications of cerebral ischemia and neuropathic pain syndrome. At present, there are few studies of pain in regions such as the spinal cord or sciatic nerve in cerebral ischemic animal models. To identify proteomic changes in the spinal cord and sciatic nerve in global cerebral ischemic model mice, in the present study we performed an investigation using proteomic methods. In a comparison between the intensity of protein spots obtained from a sham and that from a bilateral carotid artery occulusion (BCAO) in spinal cord and sciatic nerve, the levels of 10 (spinal cord) and 7 (sciatic nerve) protein spots were altered. The protein levels in the spinal cord were significantly increased in N G ,N Gdimethylarginine dimethylaminohydrolase 1 (DDAH1), 6-phosphogluconolactonase isoform 1, and precursor apoprotein A-I and decreased in dihydropyrimidinase-related protein 2 (CRMP-2), enolase 1B, rab guanosine 5′-diphosphate (GDP) dissociation inhibitor beta, septin-2 isoform a, isocitrate dehydrogenase subunit alpha, cytosolic malate dehydrogenase, and adenosine triphosphate synthase. The protein levels in the sciatic nerve were significantly increased in a mimecan precursor, myosin light chain 1/3, and myosin regulatory light chain 2 (MLC2), and decreased in dihydropyrimidinase-related protein 3 (CRMP-4), protein disulfideisomerase A3, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1, and B-type creatine kinase. In addition, CRMP-2 and CRMP-4 protein levels were decreased, and DDAH1 and MLC2 protein levels were increased on day 1 after BCAO using Western blotting. These results suggested that changes in these proteins may be involved in the regulation of CPSP.Key words global ischemia; pain; spinal cord; sciatic nerve; proteome Cerebral stroke remains one of the leading causes of death and disability worldwide.1) Recent insights into the basic mechanism involved in ischemic stroke indicate that endothelial dysfunctions along with oxidative stress and neuroinflammation are key elements in the occurrence and development of ischemic brain damage that results in cell damage and death.2,3) Many clinical symptoms can manifest after strokes, including motor deficits, cognitive dysfunction, language problems, emotional disturbances, social maladjustment, somatosensory dysfunction, and central pain. 4,5) Cerebral stroke occasionally induces central post-stroke pain (CPSP) that manifests as burning pain, throbbing pain, aching pain, slashing pain, allodynia, and hyperalgesia, either continuously or intermittently on the affected side.6,7) CPSP is known to be one of the neuropathic pain.8) Neuropathic pain is defined as "pain initiated or caused by a primary lesion or dysfunction of the nervous system." It can be a debilitating and difficult condition to treat and is often resistant to simple analgesics, requiring additional analgesic treatment. 9)Some hypotheses of the pathophysiological mechanisms of somatosensory dysfunction have been proposed to explain CPSP symptoms, such as the ...

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Proteomic identification of proteins differentially expressed by nicotinamide in focal cerebral ischemic injury

Cited by 11 publications

References 36 publications

Nicotinamide Prevents the Down-Regulation of MEK/ERK/p90RSK Signaling Cascade in Brain Ischemic Injury

Nicotinamide Prevents the Down-Regulation of MEK/ERK/p90RSK Signaling Cascade in Brain Ischemic Injury

PP2A Ligand ITH12246 Protects against Memory Impairment and Focal Cerebral Ischemia in Mice

Withdrawal: Proteomic Profiling in the Spinal Cord and Sciatic Nerve in a Global Cerebral Ischemia-Induced Mechanical Allodynia Mouse Model

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