A Review of the Regulatory Role of Nicotinamide on Pro- and Anti-apoptotic Proteins in Neuronal Cells

Mukherjee, Suman; Sonee, Manisha; Adams, James D.

doi:10.2174/157018005774479177

Cited by 10 publications

(2 citation statements)

References 54 publications

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“…Moreover, nicotinamide attenuates apoptotic cell death by modulation proand anti-apoptotic proteins in neuronal cells [21]. The results of this study clearly confirm that nicotinamide reduces the volume of the infarct region and protects neuronal cells against ischemic brain injury through the inhibition of apoptotic cell death.…”

Section: Discussionsupporting

confidence: 75%

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: Discussionsupporting

confidence: 75%

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

2012

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“…Parvalbumin levels were 0.58 ± 0.02 in the glutamate-treated group, and 0.79 ± 0.03 and 0.89 ± 0.01 in the nicotinamide-treated groups (0.1 and 1 mM, respectively). Nicotinamide attenuates apoptotic cell death in the brain by modulating apoptosis related proteins [11,12]. In our current report [7], the MCAO injury induces decrease of parvalbumin and rise of intracellular calcium levels [7].…”

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confidence: 48%

Nicotinamide Restores the Reduction of Parvalbumin in Cerebral Ischemic Injury

Koh

2013

The Journal of Veterinary Medical Science

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ABSTRACT. The aim of this study investigated whether nicotinamide affects parvalbumin expression in focal cerebral ischemic injury. Rats were treated with vehicle or nicotinamide (500 mg/kg) 2 hr after middle cerebral artery occlusion (MCAO), and cerebral cortex tissues were collected 24 hr after MCAO. Nicotinamide significantly decreases the volume of infarct areas in the cerebral cortex. A proteomic approach revealed that MCAO induces decreases of parvalbumin levels, while nicotinamide treatment prevents injury-induced decreases in parvalbumin. RT-PCR and Western blot analyses demonstrated that nicotinamide restores injury-induced decreases in parvalbumin. Moreover, immunohistochemical staining confirmed that the numbers of parvalbumin-positive cells were decreased in vehicle-treated animals with MCAO, and that nicotinamide averted this decrease. In cultured hippocampal cells, nicotinamide treatment prevents the glutamate exposure-induced increase in intracellular Ca 2+ concentration and decrease in parvalbumin expression. These results suggest the fact that the maintenance of parvalbumin expression is mediated to the neuroprotective function of nicotinamide against ischemic brain injury. Nicotinamide is an essential precursor of nicotinamide adenine dinucleotide (NAD+) that acts as a poly-ADP ribose polymerase (PARP) inhibitor. Nicotinamide protects against oxidative stress and neurotoxicity, and exerts neuroprotective effects in neurodegenerative conditions such as Alzheimer's disease and stroke [1,6]. Nicotinamide attenuates infarct volumes following focal cerebral ischemia and prevents neuronal cell death by enhancing survival pathways and inhibiting apoptotic signaling pathways [8,17].Parvalbumin, a calcium sensor protein, is predominately expressed in brain tissues including the hippocampus, cortex and cerebellum [2,3]. Parvalbumin is involved in intracellular calcium buffering by binding to Ca 2+ molecules released into the cytoplasm [3,4]. Parvalbumin plays an important role in modulating calcium homeostasis of the central nervous system [4]. Increases in intracellular Ca 2+ concentration induce neuronal cell death and result in nervous system disorders [15]. Therefore, parvalbumin is considered to mediate neuroprotective function by attenuating increases of intracellular Ca 2+ . Although previous studies elucidated the neuroprotective mechanism of nicotinamide, more information is needed to understand its neuroprotective effects. This study hypothesizes that nicotinamide contributes to the regulation of parvalbumin in cerebral ischemia. However, few data are available regarding the effects of nicotinamide on parvalbumin expression in ischemic brain injury. The present paper describes the effect of nicotinamide on parvalbumin during focal cerebral ischemia.All experimental procedures for animals were approved by Institutional Animals Care and Use Committee at Gyeongsang National University. Sprague-Dawley rats (male, 220-230 g, n=60) were randomly divided into four groups, vehicle + sham group, nicotin...

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Protective Function of Nicotinamide Against Ketamine-induced Apoptotic Neurodegeneration in the Infant Rat Brain

Ullah

Lee

et al. 2011

J Mol Neurosci

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During development, anesthetics activate neuroapoptosis and produce damage in the central nervous system that leads to several types of neurological disorders. A single dose of ketamine (40 mg/kg) during synaptogenesis in a 7-day-old rat brain activated the apoptotic cascade and caused extensive neuronal cell death in the forebrain. In this study, we investigated the protective effect of nicotinamide against ketamine-induced apoptotic neurodegeneration. After 4 h, neuronal cell death induced by ketamine was associated with the induction of Bax, release of cytochrome c into the cytosol, and activation of caspase-3. One single dose of 1 mg/g nicotinamide was administered to a developing rat and was found to inhibit ketamine-induced neuroapoptosis by downregulating Bax, inhibiting cytochrome c release from mitochondria into cytosol, and inhibiting the expression of activated caspase-3. TUNEL and immunohistochemical analyses showed that ketamine-induced cell death occurred through apoptosis and that it was inhibited by nicotinamide. Fluoro-Jade-B staining demonstrated an increased number of dead cells in the cortex and thalamus after ketamine treatment; treatment with nicotinamide reduced the number of dead cells in these brain regions. Our findings suggest that nicotinamide attenuated ketamine-induced neuronal cell loss in the developing rat brain and is a promising therapeutic and neuroprotective agent for the treatment of neurodevelopmental disorders.

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A Review of the Regulatory Role of Nicotinamide on Pro- and Anti-apoptotic Proteins in Neuronal Cells

Cited by 10 publications

References 54 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

Nicotinamide Restores the Reduction of Parvalbumin in Cerebral Ischemic Injury

Protective Function of Nicotinamide Against Ketamine-induced Apoptotic Neurodegeneration in the Infant Rat Brain

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