Neuroscience Letters (NEUROSCI LETT)

Publications in this journal

• Article: A comparison of neuroplastic responses to non-invasive brain stimulation protocols and motor learning in healthy adults.

  Ann-Maree Vallence, Lisa Kurylowicz, Michael C Ridding
  [show abstract] [hide abstract]
  ABSTRACT: Non-invasive brain stimulation (NBS) techniques can induce neuroplastic changes similar to those associated with motor learning and there is evidence for the involvement of common mechanisms. Whether there are correlations between the changes induced by NBS and those associated with motor learning remains unclear. We investigated whether there was any relationship between an individual's neuroplastic responses to several different NBS protocols (continuous theta-burst stimulation (cTBS); intermittent theta-burst stimulation (iTBS); facilitatory paired associative stimulation (PAS: inter-stimulus interval 25ms)) and whether these responses correlated with the neuroplastic response associated with a motor training (MT) task involving repeated fast-as-possible thumb abductions. Changes in motor evoked potential (MEP) amplitude were used to assess the neuroplastic response to each protocol. MEP amplitude decreased significantly following cTBS, however there was no significant change in MEP amplitude following iTBS, PAS or MT. There were no significant correlations between individuals' neuroplastic responses to any of the NBS protocols tested or between individuals' neuroplastic responses to the NBS protocols and motor learning. These results provide no support for an association between individuals' neuroplastic responses to several plasticity-inducing protocols. Although there is evidence for involvement of common mechanisms in the neuroplastic changes induced by NBS and motor learning, the results of this study suggest (1) the mechanisms mediating TBS-, PAS-, and MT-induced plasticity may only partially overlap, and (2) additional factors, including large intra and inter-subject response variability, may make the demonstration of associations between neuroplastic responses to the various protocols difficult.
  Neuroscience Letters 06/2013;
• Article: Meta-analysis confirms a functional polymorphism (5-HTTLPR) in the serotonin transporter gene conferring risk of bipolar disorder in European populations.

  Hong-Yan Jiang, Fei Qiao, Xiu-Feng Xu, Yuan Yang, Yan Bai, Ling-Ling Jiang
  [show abstract] [hide abstract]
  ABSTRACT: The serotonin transporter (5-HTT) is a candidate risk gene for bipolar disorder, and a functional polymorphism of 44-bp insertion/deletion (5-HTTLPR) located in the promoter region of this gene has been investigated for the association with the illness extensively among worldwide populations, but overall results were inconsistent and its role in the disorder remains unclear. The present study attempts to find its potential association with bipolar disorder using meta-analyzes that maximize the statistical power. We applied meta-analysis techniques by combining all available case-control studies of 5-HTTLPR and bipolar disorder in samples of European ancestry (with a total of 3778 cases and 4997 controls), and we assessed the evidence for allelic associations, heterogeneity among different studies, influence of each single study, and potential publication bias. The short allele (S allele) of 5-HTTLPR showed a significant association with bipolar disorder in our meta-analysis (odds ratio=1.10, p-value=0.005), suggesting it is likely a risk polymorphism for the illness, and the observed OR is consistent with other susceptibility loci identified through recent large-scale genetic association studies on bipolar disorder, which could be regarded simply as a small but detectable effects.
  Neuroscience Letters 06/2013;
• Article: C-terminals in the mouse branchiomotor nuclei originate from the magnocellular reticular formation.

  Toshiyasu Matsui, Yu Hongo, Yoshinori Haizuka, Kenichi Kaida, George Matsumura, Donna M Martin, Yasushi Kobayashi
  [show abstract] [hide abstract]
  ABSTRACT: Large cholinergic synaptic boutons called "C-terminals" contact motoneurons and regulate their excitability. C-terminals in the spinal somatic motor nuclei originate from cholinergic interneurons in laminae VII and X that express a transcription factor Pitx2. Cranial motor nuclei contain another type of motoneuron: branchiomotor neurons. Although branchiomotor neurons receive abundant C-terminal projections, the neural source of these C-terminals remains unknown. In the present study, we first examined whether cholinergic neurons express Pitx2 in the reticular formation of the adult mouse brainstem, as in the spinal cord. Although Pitx2-positive cholinergic neurons were observed in the magnocellular reticular formation and region around the central canal in the caudal medulla, none was present more rostrally in the brainstem tegmentum. We next explored the origin of C-terminals in the branchiomotor nuclei by using biotinylated dextran amine (BDA). BDA injections into the magnocellular reticular formation of the medulla and pons resulted in the labeling of numerous C-terminals in the branchiomotor nuclei: the ambiguous, facial, and trigeminal motor nuclei. Our results revealed that the origins of C-terminals in the branchiomotor nuclei are cholinergic neurons in the magnocellular reticular formation not only in the caudal medulla, but also at more rostral levels of the brainstem, which lacks Pitx2-positive neurons.
  Neuroscience Letters 06/2013;
• Article: Culture and its neurofunctional correlates when death is in mind.

  Verena Graupmann, Isabella Peres, Tonia Michaely, Thomas Meindl, Dieter Frey, Maximilian Reiser, Ernst Pöppel, Kai Fehse, Evgeny Gutyrchik
  [show abstract] [hide abstract]
  ABSTRACT: The human fear of death is marked by specific psychological reactions that affirm cultural belonging. Terror management theory explains this phenomenon with the symbolic immortality provided by collective meaning in culture. This coping has also been explained with the motive of maintaining a meaningful representation of the world. Here we show that neural patterns of activations corresponding to cultural worldview defense processes differed when images that affirmed participants' cultural heritage were preceded by death-related verbal primes versus verbal primes threatening meaning. Cultural content was drawn upon distinctly on a neural basis when facing death-related cognitions. The neural representation of cultural coping sheds light on the immediate mechanisms in compensating the human fear of death.
  Neuroscience Letters 06/2013;
• Article: Dietary whey protein stimulates mitochondrial activity and decreases oxidative stress in mouse female brain.

  Howard G Shertzer, Mansi Krishan, Mary Beth Genter
  [show abstract] [hide abstract]
  ABSTRACT: In humans and experimental animals, protein-enriched diets are beneficial for weight management, muscle development, managing early-stage insulin resistance and overall health. Previous studies have shown that in mice consuming a high fat diet, whey protein isolate (WPI) reduced hepatosteatosis and insulin resistance due in part to an increase in basal metabolic rate. In the current study, we examined the ability of WPI to increase energy metabolism in mouse brain. Female C57BL/6J mice were fed a normal AIN-93M diet for 12 weeks, with (WPI group) or without (Control group) 100g WPI/L drinking water. In WPI mice compared to controls, the oxidative stress biomarkers malondialdehyde and 4-hydroxyalkenals were 40% lower in brain homogenates, and the production of hydrogen peroxide and superoxide were 25-35% less in brain mitochondria. Brain mitochondria from WPI mice remained coupled, and exhibited higher rates of respiration with proportionately greater levels of cytochromes a+a3 and c+c1. These results suggested that WPI treatment increased the number or improved the function of brain mitochondria. qRT-PCR revealed that the gene encoding a master regulator of mitochondrial activity and biogenesis, Pgc-1alpha (peroxisome proliferator-activated receptor-gamma coactivator-1alpha) was elevated 2.2-fold, as were the PGC-1alpha downstream genes, Tfam (mitochondrial transcription factor A), Gabpa/Nrf-2a (GA-binding protein alpha/nuclear respiratory factor-2a), and Cox-6a1 (cytochrome oxidase-6a1). Each of these genes had twice the levels of transcript in brain tissue from WPI mice, relative to controls. There was no change in the expression of the housekeeping gene B2mg (beta-2 microglobulin). We conclude that dietary whey protein decreases oxidative stress and increases mitochondrial activity in mouse brain. Dietary supplementation with WPI may be a useful clinical intervention to treat conditions associated with oxidative stress or diminished mitochondrial activity in the brain.
  Neuroscience Letters 06/2013;
• Article: Mammal retinal distribution of ENKergic amacrine cells and their neurochemical features: Evidence from the PPE-GFP transgenic mice.

  Jing Chen, Yan Lin, Jing Huang, Wen Wang, Yan-Yan Wei, Yun-Qing Li, Takeshi Kaneko, Sheng-Xi Wu
  [show abstract] [hide abstract]
  ABSTRACT: The neuroactive peptide enkephalin (ENK) has been postulated to play important roles in modulating visual information. The retinal presence of ENKergic cells has been revealed with conventional morphological protocols targeting ENK molecule especially in avian, however, the detailed distribution of ENKergic cells and their specific neurochemical features in the mammal retina remain unclear because of the difficulties in visualizing ENKergic cells efficiently and reliably. To address this question, we took advantage of the preproenkephalin-green fluorescent protein (PPE-GFP) transgenic mice previously generated and identified in our group, and identified the neurochemical characteristics of retinal ENKergic cells. The majority of ENKergic cells occupied the proximal inner nuclear layer with a few displaced in the ganglion cell layer. Further double labeling revealed that most of these ENKergic amacrine cells used inhibitory glycine or gamma-aminobutyric acid as the primary neurotransmitter. However, some of them also utilized excitatory glutamate as the primary neurotransmitter. The present findings suggest that the retinal ENKergic cells fall into a subpopulation of amacrine cells and show predominantly inhibitory as well as less dominantly excitatory neurochemical features. Our findings offered comprehensive morphological evidence for the function of ENKergic amacrine cells of mammal species.
  Neuroscience Letters 06/2013;
• Article: Caspr interaction with Amyloid Precursor Protein reduces amyloid-β generation in vitro.

  Liang-Feng Fan, De-En Xu, Wei-Hua Wang, Ke Yan, Hao Wu, Xue-Qin Yao, Ru-Xiang Xu, Chun-Feng Liu, Quan-Hong Ma
  [show abstract] [hide abstract]
  ABSTRACT: Contactin associated protein (Caspr), an adhesion molecule, plays roles in formation of paranodal junctions in myelinated axons, neurite outgrowth, synaptic plasticity in nervous system. Here we have shown a novel function of Caspr in pathogenesis of Alzheimer's disease (AD). Caspr distributes around amyloid plaques in APP/PS1 mice. Levels of Caspr increase in the cerebral cortex of 7-month-old APP/PS1 mice comparing to wild-type littermates. Caspr decreased protein levels of APP in both HEK-293 cells stably transfected with Indiana mutant APP (V717F; HEK-APP) and CHO cells which express endogenous APP, while it did not alter mRNA levels of APP. Furthermore, Caspr co-localizes and interacts with APP. Amyloid-β (Aβ) 40 and Aβ42 generation were also reduced in HEK-APP cells by Caspr overexpression.
  Neuroscience Letters 06/2013;
• Article: Resveratrol Induced Neuroprotection Is Mediated Via Both Estrogen Receptor Subtypes, Erα And Erβ

  Monique C Saleh, Barry J Connell, Tarek M Saleh
  [show abstract] [hide abstract]
  ABSTRACT: Resveratrol, a dietary polyphenol with antioxidant and anti-inflammatory activity has been shown to provide neuroprotection in models of ischemia. However, the mechanism of action of resveratrol-induced neuroprotection remains unclear. Previous work in our laboratory has provided evidence that acute, systemic administration of resveratrol is neuroprotective in a permanent model of cerebral ischemia, an effect that was blocked when animals received the non-selective estrogen receptor antagonist, ICI, 182,780. The present study was designed to investigate whether the source of neuroprotection afforded by resveratrol action within the cerebral cortex itself is mediated preferentially via selective activation of either α or β estrogen receptor subtype. Intracortical injection of resveratrol (0.1 and 1.0μM) 10minutes prior to 30minutes of ischemia followed by 5.5hours of reperfusion significantly reduced infarct volume in the prefrontal cortex. This neuroprotective effect was significantly attenuated when resveratrol injection (1.0μM) was preceded by injection of a selective estrogen receptor α antagonist, 1,3-Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1N-pyrozole dihydrochloride (MPP) or a selective estrogen receptor beta (ERβ) antagonist, 4-[2-phenyo- 5,7-bis(trifluoromrthyl) pyrazolo(1,5-a)pyrimidin-3-yl)phenol (PHTPP). These results provide evidence for rapidly induced neuroprotection mediated by resveratrol activation of either estrogen receptor subtype within the ischemic cortex of rats.
  Neuroscience Letters 06/2013;
• Article: Abnormal cytoplasmic calcium dynamics in central neurons of a dystonia mouse model.

  Sadahiro Iwabuchi, Yasuhiro Kakazu, Jin-Young Koh, N Charles Harata
  [show abstract] [hide abstract]
  ABSTRACT: Increased activities of cytoplasmic calcium and the excitatory neurotransmitter glutamate have been independently implicated in dystonia pathophysiology. However, cellular-level evidence linking these two features is not available. Here we show that glutamate-dependent changes in neuronal calcium dynamics occur in a knock-in mouse model of DYT1 dystonia, the most common hereditary form of this disorder. Fluorescence-based analysis of the dynamics of cytoplasmic calcium concentration ([Ca(2+)]c) in cultured hippocampal neurons shows that electrical stimulation depolarizes the neurons and increases the dendritic [Ca(2+)]c, which then decays slowly to the pre-stimulus level. Whereas the peak amplitude of [Ca(2+)]c was not affected, the decay period was prolonged in neurons of heterozygous mice whose genotype reflects the human condition. We found that this effect was blocked by the antagonists of ionotropic glutamate receptors, and confirmed that glutamate receptors are present in these neurons. As the [Ca(2+)]c is readout and regulator of neuronal excitability, its abnormality represents an important cellular phenotype of dystonia.
  Neuroscience Letters 06/2013;
• Article: Chronic Treatment with DCPCX, an Adenosine A1 Antagonist, Worsens Long-Term Memory.

  Craig Vollert, Gloria S Forkuo, Richard A Bond, Jason L Eriksen
  [show abstract] [hide abstract]
  ABSTRACT: Alzheimer's disease is characterized by progressive cognitive disturbances and neurotransmitter dysfunction. Previous studies targeting the adrenergic A1 pathway suggest that this plays a role in cognitive impairment in Alzheimer's disease. Previous studies have reported that acute treatment with A1 antagonists appears to improve behavioral deficits in rodent models of memory and behavioral impairment. In this study, we addressed whether the chronic administration of 8-cyclopentyl-1,3-dipropylxanthine, a potent and selective adenosine A1 antagonist, could reverse the memory deficits found in aged APPswe/PS1dE9 mice. Chronic treatment did not improve memory in the APPswe/PS1dE9 mouse model and resulted in reduced exploratory behavior, suggestive of reduced anxiety, and a worsening of long-term memory in nontransgenic mice. These results have important implications for understanding the mechanisms of A1 receptor modulation as a target in Alzheimer's disease therapy.
  Neuroscience Letters 06/2013;
• Article: An efficient and non-enzymatic method for isolation and culture of endothelial cells from the nidus of human cerebral arteriovenous malformations.

  Hai-Feng Zhang, Guo-Biao Liang, Ming-Guang Zhao, Zhen-Quan Song, Zai-Hua Xu
  [show abstract] [hide abstract]
  ABSTRACT: In this report, we describe an efficient and non-enzymatic method for isolating and culturing endothelial cells (ECs) from the nidus of surgically resected arteriovenous malformation (AVM) specimens. These cultured cells possessed typical phenotypic markers (i.e., von Willebrand factor and CD34), as well as morphological and ultrastructural characteristics of ECs. However, they had activated Notch-1 signaling, which plays a critical role in the development of AVM. The present study suggests that hypoxic endothelial cells from the nidus of human cerebral arteriovenous malformation (CAVMECs) have angiogenic potentials, as our data showed that VEGF gene expression and cell proliferation were more evident with prolonged hypoxia. In our study, we successfully used the vascular tissue explants adherent method to isolate and culture CAVMECs with high purity. This may prove to be a useful tool for studying the molecular mechanisms that mediate abnormal vessel development and maintenance in AVM.
  Neuroscience Letters 06/2013;
• Article: Proteinase 3 induces oxidative stress-mediated neuronal death in rat primary cortical neuron.

  Kyoung Ja Kwon, Kyu Suk Cho, Jung Nam Kim, Min Kyeong Kim, Eun Joo Lee, Soo Young Kim, Se Jin Jeon, Ki Chan Kim, Jeong Eun Han, Young Sun Kang, Soohyun Kim, Hahn Young Kim, Seol-Heui Han, Geonho Bahn, Ji Woong Choi, Chan Young Shin
  [show abstract] [hide abstract]
  ABSTRACT: The recruitment of neutrophils into the cerebral microcirculation occurs, especially, in acute brain diseases like a focal cerebral ischemia and plays important role in pathological processes. Proteinases 3 is one of the three major proteinases expressed in neutrophils but no reports are available whether proteinase 3 can modulate neuronal survival. In this study, treatment of cultured rat primary cortical neuron with proteinase 3 induced overt reactive oxygen species production and decreased total glutathione contents as well as disruption of mitochondrial transmembrane potential. Proteinase 3 induced neuronal cell death as evidenced by MTT analysis as well as propidium iodide staining, which was prevented by pretreatment with an antioxidant, N-acetyl cysteine. Proteinase 3 increased activation of procaspase-3 and altered expression level of apoptotic regulator proteins, such as Bcl-2, Bax, and Bcl-xL. Similar to in vitro data, a direct microinjection of proteinase 3 into striatum of rat brain induced neuronal death, which was mediated by reactive oxygen species. These results suggest that proteinase 3 is new essential regulator of neuronal cell death pathway in a condition of excess neutrophil encounter in neuroinflammatory conditions.
  Neuroscience Letters 06/2013;
• Article: CA-074Me, a cathepsin B inhibitor, decreases APP accumulation and protects primary rat cortical neurons treated with okadaic acid.

  Kwangmin Cho, Seung Yong Yoon, Jung Eun Choi, Hoe Jin Kang, He Yoon Jang, Dong-Hou Kim
  [show abstract] [hide abstract]
  ABSTRACT: Upregulation of the lysosomal system has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). But the exact role of this system remains unknown. Okadaic acid (OA), a protein phosphatase-2A inhibitor, increases tau phosphorylation, β-amyloid deposition, and neuronal cell death, which are the pathological hallmarks of AD. To investigate the role of lysosomal activation in AD brain cells, cultured neurons were treated with OA and assessed lysosomal morphology and enzyme activity and the protective effect of cathepsin B, D, or L inhibitors. It was found that although it induced lysosomal swelling and enzyme activation, OA did not induce lysosomal rupture. While inhibition of cathepsin D and L failed to protect neurons from OA-induced cell death, CA074-Me, a cathepsin B inhibitor, conferred a protective effect. Interestingly, CA-074Me reduced amyloid precursor protein (APP) accumulation and α-spectrin cleavage, similar to the effect of calpain inhibition.
  Neuroscience Letters 06/2013;
• Article: Mu-opioidergic modulation differs in deep and superficial wide-dynamic range dorsal horn neurons in mice.

  Qian Xu, Wei-Yan Li, Yun Guan
  [show abstract] [hide abstract]
  ABSTRACT: The spinal cord dorsal horn is an important action site for morphine analgesia. Wide-dynamic range (WDR) neurons in the dorsal horn are essential to spinal pain transmission and show increased excitability after repetitive noxious drive (windup). In light of differences in mu-opioid receptor distribution and neurophysiological properties of WDR neurons between deep and superficial dorsal horn, we recorded extracellular single-unit activity of WDR neurons from deep (350-700μm) and superficial (<350μm) dorsal horn in C57BL/6 mice and compared their responses to spinal superfusion of morphine (0.5mM, 30μl) and naloxone (1mM, 30μl). The windup level to repetitive electrical stimulation of 1.0Hz (16 pulses, suprathreshold for C-fiber activation, 2.0ms) was significantly decreased by morphine in deep (n=8), but not superficial (n=11), WDR neurons. However, the steady C-component response to graded intra-cutaneous electrical stimuli (0.01-5.0mA, 2ms) was significantly depressed by morphine only in superficial neurons. In separate experiments, spinal administration of naloxone facilitated the development of windup to 0.2Hz stimulation in deep (n=10), but not superficial (n=8), WDR neurons. Accordingly, morphine and naloxone modulation of neuronal activity may be related to a specific effect on neuronal sensitization/plasticity in deep WDR neurons, whereas morphine inhibition may depress acute noxious inputs to superficial WDR neurons. Our study suggests that mu-opioidergic modulation may be different in deep and superficial WDR neurons.
  Neuroscience Letters 06/2013;
• Article: A method for selective ablation of neurons in C. elegans using the phototoxic fluorescent protein, KillerRed.

  Junya Kobayashi, Hisashi Shidara, Yuma Morisawa, Maki Kawakami, Yuta Tanahashi, Kohji Hotta, Kotaro Oka
  [show abstract] [hide abstract]
  ABSTRACT: Specific neuron ablation with laser microbeam has been used in behavioral analysis of Caenorhabditis elegans. However, this method is hard to acquire many ablated worms, and is unable to compare behavioral changes just before and after ablation. Here, we developed an ablation method by using genetically encoded photosensitizer protein, KillerRed, which produces reactive oxygen species by green light irradiation. Ablation of AWA sensory neurons abolished the chemotaxis to AWA specific sensitive attractant, diacetyl, and no functional effect on the other sensory neuron, AWC, which senses benzaldehyde. This ablation method can be useful for analyzing neural circuit in situ.
  Neuroscience Letters 06/2013;
• Article: Pre-attentive auditory processing of non-scale pitch in absolute pitch possessors.

  Ayasa Matsuda, Keiko Hara, Satsuki Watanabe, Masato Matsuura, Katsuya Ohta, Eisuke Matsushima
  [show abstract] [hide abstract]
  ABSTRACT: Absolute pitch (AP) refers to the ability to identify the pitch of sound without reference. To clarify the neurophysiological characteristics of AP, we compared mismatch negativity (MMN) elicited by scale and non-scale notes between AP possessors and non-AP individuals. Eight individuals who were able to identify pitch with perfect accuracy were defined as AP possessors. Eighteen participants who failed to achieve perfect accuracy were included in the non-AP group. We presented participants with two tone pairs, in a scale condition and a non-scale condition. The frequency ratios of the two pairs were the same. MMN over the frontal region in the non-scale condition was larger in the AP group than the non-AP group. In contrast, no such difference was observed between the two groups in the scale condition. The results suggest that pre-attentive processing of non-scale note sounds in the auditory cortex is a salient neurophysiological characteristic of AP.
  Neuroscience Letters 06/2013;
• Article: Intraperitoneal melatonin is not neuroprotective in the G93ASOD1 transgenic mouse model of familial ALS and may exacerbate neurodegeneration.

  Efthimios Dardiotis, Elena Panayiotou, Marianne L Feldman, Andreas Hadjisavvas, Stavros Malas, Ilia Vonta, Georgios Hadjigeorgiou, Kyriakos Kyriakou, Theodoros Kyriakides
  [show abstract] [hide abstract]
  ABSTRACT: In amyotrophic lateral sclerosis (ALS) reactive oxygen species and apoptosis are implicated in disease pathogenesis. Melatonin with its anti-oxidant and anti-apoptotic properties is expected to ameliorate disease phenotype. The aim of this study was to assess possible neuroprotection of melatonin in the G93A-Copper/Zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. Four groups of mice, 14 animals each, were injected intraperitoneally with 0mg/kg, 0.5mg/kg, 2.5mg/kg and 50mg/kg of melatonin from age 40 days. The primary end points were; disease onset, disease duration, survival and rotarod performance. No statistically significant difference in disease onset between the four groups was found. Survival was significantly reduced with the 0.5mg/kg and 50mg/kg doses and tended to be reduced with the 2.5mg/kg dose. Histological analysis of spinal cords revealed increased motoneuron loss in melatonin treated mice. Melatonin treated animals were associated with increased oxidative stress as assessed with 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation. Histochemistry and western blot data of spinal cord from melatonin treated mice revealed upregulation of human SOD1 compared to untreated mice. In addition, real-time PCR revealed a dose dependent upregulation of human SOD1 in melatonin treated animals. Thus, intraperitoneal melatonin, at the doses used, does not ameliorate and perhaps exacerbates phenotype in the G93ASOD1 mouse ALS model. This is probably due to melatonin's effect on upregulating gene expression of human toxic SOD1. This action presumably overrides any of its direct anti-oxidant and anti-apoptotic properties.
  Neuroscience Letters 06/2013;
• Article: An ASK1-p38 signalling pathway mediates hydrogen peroxide-induced toxicity in NG108-15 neuronal cells.

  Koji Nomura, Mercede Lee, Christina Banks, Graham Lee, Brian J Morris
  [show abstract] [hide abstract]
  ABSTRACT: Reactive oxygen species (ROS) are believed to be involved in many forms of neurodegeneration, including ischaemic infarct damage and Alzheimer's disease. Despite the known involvement of p38 and JNK MAP kinases in mediating apoptosis and cell death in a variety of cell types, the details of the signalling pathways activated in neuronal cells by ROS are poorly-characterised. Recently TAK1 (MAP3K7), a kinase upstream of JNK and p38, has attracted attention as a possible mediator of ischaemic cell death. This study tested the hypothesis that hydrogen peroxide (H2O2), which produces ROS, induces apoptosis in the NG108-15 neuronal cell line via activation of either TAK1 or the related kinase ASK1 (MAP3K5). H2O2 caused a concentration-dependent reduction in cell viability associated caspase 3 activation. Loss of cell viability was inhibited by a selective caspase 3 inhibitor, and by the p38 inhibitor SB203580, but was not affected by the JNK inhibitor SP600125. The selective TAK1 inhibitor 5Z-7-oxozeaenol (5Z-7) exacerbated the loss of cell viability, whereas the ASK1 inhibitor NQDI-1 completely prevented caspase activation and cell death. These results show that pharmacological inhibition of ASK1 is neuroprotective, implicating an ASK1-p38 signalling pathway in ROS-induced apoptosis in neurones. The results also imply that the role of TAK1 may be neuroprotective rather than pro-degenerative.
  Neuroscience Letters 06/2013;
• Article: Different modifications of phosphorylated Smad3C and Smad3L through TGF-β after spinal cord injury in mice.

  Masahiro Joko, Koji Osuka, Nobuteru Usuda, Kimie Atsuzawa, Masahiro Aoyama, Masakazu Takayasu
  [show abstract] [hide abstract]
  ABSTRACT: Transforming growth factor-β (TGF-β) is an anti-inflammatory cytokine and is expressed in the injured spinal cord. TGF-β signals through receptors to activate Smad proteins, which translocate into the nucleus. In the present study, we investigated the chronological alterations and cellular locations of the TGF-β/Smad signaling pathway following spinal cord injury (SCI) in mice. ELISA analysis showed that the concentration of interleukin-6 (IL-6) in injured spinal cords significantly increases immediately after SCI, while the concentration of TGF-β gradually increased after SCI, peaked at 2 days, and then gradually decreased. Immunohistochemical studies revealed that Smad3 was mainly expressed in neurons of the spinal cord. Phosphorylated Smad3 at the C-terminus (p-Smad3C) was stained within the motor neurons in the anterior horn, while phosphorylated Smad3 at the linker regions (p-Smad3L) was expressed in astrocytes within gray matter. These findings suggest that SCI induces gradual increases in TGF-β and induces different activation of p-Smad3C and p-Smad3L. Phosphorylated Smad3C might be involved in neuronal degeneration after SCI, and p-Smad3L may play a role in glial scar formation by astrocytes.
  Neuroscience Letters 05/2013;
• Article: Suppression of cytochrome P450 reductase expression promotes astrocytosis in subventricular zone of adult mice.

  Yunyi Yao, Senyan Liu, Yue Wang, Weiping Yuan, Xinxin Ding, Tao Cheng, Qin Shen, Jun Gu
  [show abstract] [hide abstract]
  ABSTRACT: The aim of this study was to determine the role of NADPH-cytochrome P450 reductase (CPR) and CPR-dependent enzymes in neural stem cell (NSC) genesis in the brain. A mouse model with globally suppressed Cpr gene expression (Cpr-low mouse) was studied for this purpose. Cpr-low and wild-type (WT) mice were compared immunohistochemically for the expression of markers of cell proliferation (Ki67), immature neurons (doublecortin, DCX), oligodendrocytes (oligodendrocyte transcription factor 2, OLIG2), and astrocytes (glial fibrillary acidic protein, GFAP) in the SVZ, and for the in vitro capability of their SVZ cells to form neurospheres and differentiate into astrocytes. We found that the abundance of SVZ cells that are positive for Ki67 or GFAP expression, but not the abundance of SVZ cells that are positive for DCX and OLIG2 expression, was significantly increased in Cpr-low mice, at various ages, compared with WT mice. Furthermore, extents of astrocyte differentiation and growth, but not neurosphere formation, from SVZ cells of the Cpr-low mice were significantly increased, compared with WT mice. These results suggest that CPR and CPR-dependent enzymes play a role in suppressing astrocytosis in the SVZ of adult mice.
  Neuroscience Letters 05/2013;