Journal of Neuroscience Research (J Neurosci Res)

Publications in this journal

• Article: Parkinson's disease cybrids, differentiated or undifferentiated, maintain morphological and biochemical phenotypes different from those of control cybrids.

  T A Appukuttan, N Ali, M Varghese, A Singh, D Tripathy, M Padmakumar, P K Gangopadhyay, K P Mohanakumar
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  ABSTRACT: SH-SY5Y, control, and Parkinson's disease (PD) cybrids prepared from an Indian population were differentiated using retinoic acid (RA) for understanding their dopaminergic characteristics and neuritogenesis. Undifferentiated control and PD cybrids exhibited higher levels of TH mRNA, but lower c-RET expression, short neurites, low neuritic density, and low proportion of cells with neurites compared with the undifferentiated parent cell line, SH-SY5Y. The expression levels of DAT and Ptx3 were similar to SH-SY5Y. PD cybrids showed poor viability and lower differentiating potency than SH-SY5Y or control cybrids. RA treatment for 6 days elevated c-RET expression and corrected the neuritic morphology of the control, but not of PD cybrids. Cell viability was found to be reduced in differentiated control and PD cybrids. TH expression level was significantly elevated in SH-SY5Y following RA treatment, but not in both the cybrids. In differentiated control and PD cybrids, the TH immunofluorescence intensity was significantly lower compared with SH-SY5Y cells. MitoTracker Green fluorescence intensity of the mitochondria was higher in differentiated PD cybrids. Dopamine released into the medium was unaffected in the differentiated SH-SY5Y or in the control cybrids but was significantly elevated in PD cybrids. These results suggest that PD cybrids, differentiated or undifferentiated, maintained morphological and biochemical phenotypes significantly different from those of the control cybrids, or the differentiated SH-SY5Y cells, and therefore could be an ideal cellular model of the disease for pharmacological screening of drugs and for investigation of the pathophysiology of PD. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 05/2013;
• Article: Roles of T helper 17 cells and interleukin-17 in neuroautoimmune diseases with emphasis on multiple sclerosis and Guillain-Barré syndrome as well as their animal models.

  Xu Wang, Chi Ma, Jiang Wu, Jie Zhu
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  ABSTRACT: The identification of T helper 17 (Th17) cells challenges the Th1/Th2 paradigm of the immune response and invites intensive exploration of their mechanisms and functions in the field of autoimmune diseases, host defense, allergy, etc. The collective data have shown that transforming growth factor-β (TGF-β), interleukin (IL)-6, IL-1β, IL-21, and IL-23 are involved in the differentiation program of Th17 cells. The transcription factors RORγT, STAT3, RORγ, RORα, and IRF4 exert regulatory effects on the development of Th17 cells. Among the Th17-related effector cytokines, such as IL-17, IL-17F, IL-21, and IL-22, IL-17 is regarded as a key cytokine to induce inflammatory responses. This review outlines the cytokines and transcription factors involved in the differentiation of Th17 cells and their effector functions, with specific focus on the roles of Th17 cells and IL-17 in neuroautoimmune diseases, especially in multiple sclerosis and Guillain-Barré syndrome, as well as in their animal models, experimental autoimmune encephalomyelitis and experimental autoimmune neuritis. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 05/2013;
• Article: Blocking central galanin receptors attenuates insulin sensitivity in myocytes of diabetic trained rats.

  Le Bu, Zhimin Liu, Junjie Zou, Xiang Gao, Yi Bao, Shen Qu
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  ABSTRACT: Galanin (Gal), a bioactive neuropeptide, is widely distributed throughout the central nervous system and has diverse modulatory effects. To understand the central effect of this training-stimulatory peptide on insulin sensitivity, its antagonist M35 was injected into the cerebral ventricle in type 2 diabetic rats. A treadmill running of the rats was used to stimulate circulating Gal secretion and central Gal mRNA expression. The results showed that M35 significantly decreased glucose infusion rates in euglycemic-hyperinsulinemic clamp tests as well as 2-deoxy-[(3) H]D-glucose uptake and peroxisome proliferator-activated receptor-α expression levels in skeletal muscles. M35 also attenuated glucose transporter 4 (GLUT4) concentration in plasma membranes and total cell membranes of myocytes, and the ratios of the GLUT4 contents in the former to the latter in M35 groups were lower than those of each diabetic control. These results imply that endogenous Gal, acting through its central receptor, may facilitate GLUT4 translocation from cytoplasm vesicles to cellular surface of myocytes to accelerate glucose uptake and to enhance insulin sensitivity in healthy and type 2 diabetic rats. Gal and its relative agents are potential targets for treatment of type 2 diabetes mellitus and its complications. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 05/2013;
• Article: Glycogen function in adult central and peripheral nerves.

  Richard D Evans, Angus M Brown, Bruce R Ransom
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  ABSTRACT: We studied the roles of glycogen in axonal pathways of the central nervous system (CNS) and peripheral nervous system (PNS). By using electrophysiological recordings, in combination with biochemical glycogen assay, it was possible to determine whether glycogen was crucial to axon function under different conditions. Glycogen was present both in mouse optic nerve (MON) and in mouse sciatic nerve (MSN). Aglycemia caused loss of the compound action potential (CAP) in both pathways after a latency of 15 min (MON) and 120 min for myelinated axons (A fibers) in the MSN. With the exception of unmyelinated axons (C fibers) in the MSN, CAP decline began when usable glycogen was exhausted. Glycogen was located in astrocytes in the MON and in myelinating Schwann cells in the MSN; it was absent from the Schwann cells surrounding unmyelinated C fibers. In MON, astrocytic glycogen is metabolized to lactate and "shuttled" to axons to support metabolism. The ability of lactate to support A fiber conduction in the absence of glucose suggests a common pathway in both the CNS and the PNS. Lactate is released from MON and MSN in substantial quantities. That lactate levels fall in MSN in the presence of diaminobenzidine, which inhibits glycogen phosphorylase, strongly suggests that glycogen metabolism contributes to lactate release under resting conditions. Glycogen is a "backup" energy substrate in both the CNS and the PNS and, beyond sustaining excitability during glucose deprivation, has the capacity to subsidize the axonal energy demands during times of intense activity in the presence of glucose. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 04/2013;
• Article: Conditioned medium from human amniotic epithelial cells may induce the differentiation of human umbilical cord blood mesenchymal stem cells into dopaminergic neuron-like cells.

  Shu Yang, Hai-Mei Sun, Ji-Hong Yan, Hong Xue, Bo Wu, Fang Dong, Wen-Shuai Li, Feng-Qing Ji, De-Shan Zhou
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  ABSTRACT: Dopaminergic (DA) neuron therapy has been established as a new clinical tool for treating Parkinson's disease (PD). Prior to cell transplantation, there are two primary issues that must be resolved: one is the appropriate seed cell origin, and the other is the efficient inducing technique. In the present study, human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) were used as the available seed cells, and conditioned medium from human amniotic epithelial cells (ACM) was used as the inducing reagent. Results showed that the proportion of DA neuron-like cells from hUCB-MSCs was significantly increased after cultured in ACM, suggested by the upregulation of DAT, TH, Nurr1, and Pitx3. To identify the process by which ACM induces DA neuron differentiation, we pretreated hUCB-MSCs with k252a, the Trk receptor inhibitor of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), and found that the proportion of DA neuron-like cells was significantly decreased compared with ACM-treated hUCB-MSCs, suggesting that NGF and BDNF in ACM were involved in the differentiation process. However, we could not rule out the involvement of other unidentified factors in the ACM, because ACM + k252a treatment does not fully block DA neuron-like cell differentiation compared with control. The transplantation of ACM-induced hUCB-MSCs could ameliorate behavioral deficits in PD rats, which may be associated with the survival of engrafted DA neuron-like cells. In conclusion, we propose that hUCB-MSCs are a good source of DA neuron-like cells and that ACM is a potential inducer to obtain DA neuron-like cells from hUCB-MSCs in vitro for an ethical and legal cell therapy for PD. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 04/2013;
• Article: Estrogen receptor-β ligand treatment after disease onset is neuroprotective in the multiple sclerosis model.

  Amy J Wisdom, Yuan Cao, Noriko Itoh, Rory D Spence, Rhonda R Voskuhl
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  ABSTRACT: Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and neurodegeneration. Current MS treatments were designed to reduce inflammation in MS rather than directly to prevent neurodegeneration. Estrogen has well-documented neuroprotective effects in a variety of disorders of the CNS, including experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model of MS. Treatment with an estrogen receptor-β (ERβ) ligand is known to ameliorate clinical disease effectively and provide neuroprotection in EAE. However, the protective effects of this ERβ ligand have been demonstrated only when administered prior to disease (prophylactically). Here we tested whether ERβ ligand treatment could provide clinical protection when treatment was initiated after onset of disease (therapeutically). We found that therapeutic treatment effectively ameliorated clinical disease in EAE. Specifically, ERβ ligand-treated animals exhibited preserved axons and myelin compared with vehicle-treated animals. We observed no difference in the number of T lymphocytes, macrophages, or microglia in the CNS of vehicle- vs. ERβ ligand-treated animals. Our findings show that therapeutically administered ERβ ligand successfully treats clinical EAE, bearing translational relevance to MS as a candidate neuroprotective agent. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 04/2013;
• Article: Impact of omega-6 polyunsaturated fatty acid supplementation and γ-aminobutyric acid on astrogliogenesis through the endocannabinoid system.

  Noriko Shinjyo, Fabiana Piscitelli, Roberta Verde, Vincenzo Di Marzo
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  ABSTRACT: Neural stem cells express cannabinoid CB1 and CB2 receptors and the enzymes for the biosynthesis and metabolism of endocannabinoids (eCBs). Here we have studied the role of neural stem cell-derived eCBs as autonomous regulatory factors during differentiation. First, we examined the effect of an indirect eCB precursor linoleic acid (LA), a major dietary omega-6 fatty acid, on the eCB system in neural stem/progenitor cells (NSPCs) cultured in DMEM/F12 supplemented with N2 (N2/DF) as monolayer cells. LA upregulated eCB system-related genes and 2-arachidonoylglycerol (2-AG), but not anandamide (AEA), levels. Glial fibrillary acidic protein (GFAP) was significantly higher under LA-enriched conditions, and this effect was inhibited by the cannabinoid receptor type-1 (CB1) antagonist AM251. Second, the levels of AEA and 2-AG, as well as of the mRNA of eCB system-related genes, were measured in NSPCs after γ-aminobutyric acid (GABA) treatment. GABA upregulated AEA levels significantly in LA-enriched cultures and increased the mRNA expression of the 2-AG-degrading enzyme monoacylglycerol lipase. These effects of GABA were reproduced under culture conditions using neurobasal media supplemented with B27, which is commonly used for neurosphere culture. GABA stimulated astroglial differentiation in this medium as indicated by increased GFAP levels. This effect was abolished by AM251, suggesting the involvement of AEA and CB1 in GABA-induced astrogliogenesis. This study highlights the importance of eCB biosynthesis and CB1 signalling in the autonomous regulation of NSPCs and the influence of the eCB system on astrogliogenesis induced by nutritional factors or neurotransmitters, such as LA and GABA. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 04/2013;
• Article: Do reductions in brain N-acetylaspartate levels contribute to the etiology of some neuropsychiatric disorders?

  Prasanth S Ariyannur, Peethambaran Arun, Erin S Barry, Brian Andrews-Shigaki, Asamoah Bosomtwi, Haiying Tang, Reed Selwyn, Neil E Grunberg, John R Moffett, Aryan M A Namboodiri
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  ABSTRACT: N-acetylaspartate (NAA) is recognized as a noninvasive diagnostic neuronal marker for a host of neuropsychiatric disorders using magnetic resonance spectroscopy (MRS). Numerous correlative clinical studies have found significant decreases in NAA levels in specific neuronal systems in an array of neuropsychiatric and substance-abuse disorders. We have recently identified the methamphetamine-induced neuronal protein known as "shati" as the NAA biosynthetic enzyme (aspartate N-acetyltransferase [Asp-NAT]; gene Nat8l). We have generated an Nat8l transgenic knockout mouse line to study the functions of NAA in the nervous system. We were unable to breed homozygous Nat8l knockout mice successfully for study and so used the heterozygous mice (Nat8l(+/-) ) for initial characterization. MRS analysis of the Nat8l(+/-) mice indicated significant reductions in NAA in cortex (-38%) and hypothalamus (-29%) compared with wild-type controls, which was confirmed using HPLC (-29% in forebrain). The level of the neuromodulator N-acetylaspartylglutamate (NAAG), which is synthesized from NAA, was decreased by 12% in forebrain as shown by HPLC. Behavioral analyses of the heterozygous animals indicated normal behavior in most respects but reduced vertical activity in open-field tests compared with age- and sex-matched wild-type mice of the same strain. Nat8l(+/-) mice also showed atypical locomotor responses to methamphetamine administration, suggesting that NAA is involved in modulating the hyperactivity effect of methamphetamine. These observations add to accumulating evidence suggesting that NAA has specific regulatory functional roles in mesolimbic and prefrontal neuronal pathways either directly or indirectly through impact on NAAG synthesis.© 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 04/2013;
• Article: Choline acetyltransferase activity in the hamster central auditory system and long-term effects of intense tone exposure.

  Donald A Godfrey, James A Kaltenbach, Kejian Chen, Omer Ilyas
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  ABSTRACT: Acoustic trauma often leads to loss of hearing of environmental sounds, tinnitus, in which a monotonous sound not actually present is heard, and/or hyperacusis, in which there is an abnormal sensitivity to sound. Research on hamsters has documented physiological effects of exposure to intense tones, including increased spontaneous neural activity in the dorsal cochlear nucleus. Such physiological changes should be accompanied by chemical changes, and those chemical changes associated with chronic effects should be present at long times after the intense sound exposure. Using a microdissection mapping procedure combined with a radiometric microassay, we have measured activities of choline acetyltransferase (ChAT), the enzyme responsible for synthesis of the neurotransmitter acetylcholine, in the cochlear nucleus, superior olive, inferior colliculus, and auditory cortex of hamsters 5 months after exposure to an intense tone compared with control hamsters of the same age. In control hamsters, ChAT activities in auditory regions were never more than one-tenth of the ChAT activity in the facial nerve root, a bundle of myelinated cholinergic axons, in agreement with a modulatory rather than a dominant role of acetylcholine in hearing. Within auditory regions, relatively higher activities were found in granular regions of the cochlear nucleus, dorsal parts of the superior olive, and auditory cortex. In intense-tone-exposed hamsters, ChAT activities were significantly increased in the anteroventral cochlear nucleus granular region and the lateral superior olivary nucleus. This is consistent with some chronic upregulation of the cholinergic olivocochlear system influence on the cochlear nucleus after acoustic trauma. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 04/2013;
• Article: Involvement of matrix metalloproteinases-2 and -9 in the formation of a lacuna-like cerebral cavity.

  Francisco S Cayabyab, Krishnamoorty Gowribai, Wolfgang Walz
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  ABSTRACT: We used a modified pial vessel disruption (PVD) protocol with adult male Wistar rats to mimic small-vessel stroke in the cerebral cortex. Within 3 weeks, this lesion develops into a single lacuna-like cavity, which is fluid-filled and encapsulated by reactive astrocytes. Minocycline treatment that commences 1 hr after lesion and continues for 6 days prevents the cavitation and causes a filling of the lesion with reactive astrocytes and no barrier. Here, we determined whether inhibition of matrix metalloproteinases-2 and -9 (MMPs) mediates this minocycline action. Confocal microscopy revealed increased punctate staining of MMPs inside the lesion sites after 2 days of PVD. Astrocytes lined the lesion border but showed sparse localization inside the lesion. In contrast, increased MMP levels inside the lesion coincided with increased ED1 or OX-42 immunostaining, suggesting that MMP elevation reflected increased secretions from microglia/macrophages. Imaging analyses also revealed that minocycline administered for 2 days before animal euthanasia, significantly decreased MMP levels within the lesion. Moreover, Western blot analysis of cortical tissue extracts showed a significant 30-40% upregulation of MMPs 2 days after lesion. Minocycline administered 2 hr before the lesion significantly inhibited both MMP-9 and MMP-2 levels by ∼40%. In contrast, minocycline administered 1 hr after the lesion only decreased MMP-9 levels by ∼30%. Because MMP inhibition with batimastat injection also prevented cavity formation at 21 days, we conclude that minocycline prevented the creation of a lacuna-like cyst in the cerebral cortex by inhibiting the MMP secretion from microglia in the affected tissue. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 04/2013;
• Article: Presynaptic protein synaptotagmin1 regulates the activity-induced remodeling of synaptic structures in cultured hippocampal neurons.

  Yuriko Inoue, Masaaki Takayanagi, Hiroyuki Sugiyama
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  ABSTRACT: Activity-dependent reorganizations of central neuronal synapses are thought to play important roles in learning and memory. Although the precise mechanisms of how neuronal activities modify synaptic connections in neurons remain to be clarified, the activity-induced neuronal presynaptic proteins such as synaptotagmin1 may contribute to the onset of synaptic remodeling. To understand better the physiological roles of synaptotagmin1, we first examined the prolonged effects of neuronal stimulation capable of inducing synaptotagmin1 on the distribution of a postsynaptic proteins (PSD) protein Homer1c by immunostaining. Previously we found that glutamate stimulation induced other postsynaptic proteins, such as postsynaptic density-95 (PSD95), a biphasic change with an initially diffuse distribution after 30 min to 1 hr, followed by reassembly to more than the original level after 4-8 hr, suggesting that glutamate stimulation induces a global biphasic alteration in synaptic structures. To dissect further the functions of synaptotagmin1 in the activity-induced synaptic remodeling, short hairpin RNA (shRNA) vectors that specifically block the expression of endogenous synaptotagmin1 were constructed. When the shRNA of synaptotagmin1 was introduced to the neurons, the activity-induced changes were almost completely suppressed. We found that synaptotagmin1 contributes to the postsynaptic remodeling in a retrograde manner. Our data indicate that synaptotagmin1 regulates the activity-induced biphasic changes of post- and presynaptic sites. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 04/2013;
• Article: Acute inflammation alters adult hippocampal neurogenesis in a multiple sclerosis mouse model.

  A Giannakopoulou, N Grigoriadis, C Bekiari, A Lourbopoulos, I Dori, A S Tsingotjidou, H Michaloudi, G C Papadopoulos
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  ABSTRACT: Neural precursor cells (NPCs) located in the subgranular zone (SGZ) of the dentate gyrus (DG) give rise to thousands of new cells every day, mainly hippocampal neurons, which are integrated into existing neuronal circuits. Aging and chronic degenerative disorders have been shown to impair hippocampal neurogenesis, but the consequence of inflammation is somewhat controversial. The present study demonstrates that the inflammatory environment prevailing in the brain of experimental autoimmune encephalomyelitis (EAE) mice enhances the proliferation of NPCs in SGZ of the dorsal DG and alters the proportion between radial glial cells and newborn neuroblasts. The injection protocol of the cell cycle marker bromodeoxyuridine and the immunohistochemical techniques that were employed revealed that the proliferation of NPCs is increased approximately twofold in the SGZ of the dorsal DG of EAE mice, at the acute phase of the disease. However, although EAE animals exhibited significant higher percentage of newborn radial-glia-like NPCs, the mean percentage of newborn neuroblasts rather was decreased, indicating that the robust NPCs proliferation is not followed by a proportional production of newborn neurons. Significant positive correlations were detected between the number of proliferating cells in the SGZ and the clinical score or degree of brain inflammation of diseased animals. Finally, enhanced neuroproliferation in the acute phase of EAE was not found to trigger compensatory apoptotic mechanisms. The possible causes of altered neurogenesis observed in this study emphasize the need to understand more precisely the mechanisms regulating adult neurogenesis under both normal and pathological conditions. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 04/2013;
• Article: Ventral posterolateral deep brain stimulation treatment for neuropathic pain shortens pain response after cold stimuli.

  Jinhyung Kim, Sung Eun Lee, Kyou Sik Min, Hyun Ho Jung, Ji Eun Lee, Sung June Kim, Jin Woo Chang
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  ABSTRACT: Neuropathic pain is often severe. Deep brain stimulation (DBS) is a treatment method for neuropathic pain, but its mechanism of action remains unclear. Patients with neuropathic pain are affected by various stimulations, such as mechanical and cold stimuli, but studies of cold allodynia showed the associated pain to be less than that caused by mechanical stimuli. This study focused on the effects of DBS on cold allodynia in rats. To observe the effects of DBS, we established three groups: a normal group (normal), a neuropathic pain group (pain), and a DBS with neuropathic pain group (DBS). The stimulation target was the ventral posterolateral nucleus (VPL). We observed differences in the degree of cold allodynia elicited between a conventional method that measured the number of pain responses and our altered novel method that measured the duration of pain responses. Cold allodynia after DBS did not differ when conventional analysis was applied, but the pain response duration was decreased. We suggest that VPL DBS was partially effective in cold allodynia, implicating complex pathways of pain signaling. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 04/2013;
• Article: Changes in tau phosphorylation in hibernating rodents.

  Gonzalo León-Espinosa, Esther García, Vega García-Escudero, Félix Hernández, Javier Defelipe, Jesús Avila
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  ABSTRACT: Tau is a cytoskeletal protein present mainly in the neurons of vertebrates. By comparing the sequence of tau molecule among different vertebrates, it was found that the variability of the N-terminal sequence in tau protein is higher than that of the C-terminal region. The N-terminal region is involved mainly in the binding of tau to cellular membranes, whereas the C-terminal region of the tau molecule contains the microtubule-binding sites. We have compared the sequence of Syrian hamster tau with the sequences of other hibernating and nonhibernating rodents and investigated how differences in the N-terminal region of tau could affect the phosphorylation level and tau binding to cell membranes. We also describe a change, in tau phosphorylation, on a casein kinase 1 (ck1)-dependent site that is found only in hibernating rodents. This ck1 site seems to play an important role in the regulation of tau binding to membranes. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 04/2013;
• Article: Reduced extracellular zinc levels facilitate glutamate-mediated oligodendrocyte death after trauma.

  Joshua T Johnstone, Paul D Morton, Arumugam R Jayakumar, Valerie Bracchi-Ricard, Erik Runko, Daniel J Liebl, Michael D Norenberg, John R Bethea
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  ABSTRACT: Spinal cord injury results in irreversible paralysis, axonal injury, widespread oligodendrocyte death, and white matter damage. Although the mechanisms underlying these phenomena are poorly understood, previous studies from our laboratory indicate that inhibiting activation of the nuclear factor-κB transcription factor in astrocytes reduces white matter damage and improves functional recovery following spinal cord injury. In the current study, we demonstrate that activation of the nuclear factor-κB transcription factor within astrocytes results in a significant increase in oligodendrocyte death following trauma by reducing extracellular zinc levels and inducing glutamate excitotoxicity. By using an ionotropic glutamate receptor antagonist (CNQX), we show that astroglial nuclear factor-κB-mediated oligodendrocyte death is dependent on glutamate signaling despite no change in extracellular glutamate concentrations. Further analysis demonstrated a reduction in levels of extracellular zinc in astrocyte cultures with functional nuclear factor-κB signaling following trauma. Cotreatment of oligodendrocytes with glutamate and zinc showed a significant increase in oligodendrocyte toxicity under low-zinc conditions, suggesting that the presence of zinc at specific concentrations can prevent glutamate excitotoxicity. These studies demonstrate a novel role for zinc in regulating oligodendrocyte excitotoxicity and identify new therapeutic targets to prevent oligodendrocyte cell death in central nervous system trauma and disease. © 2012 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 03/2013;
• Article: Sulfiredoxin-1 protects PC12 cells against oxidative stress induced by hydrogen peroxide.

  Qiong Li, Shanshan Yu, Jingxian Wu, Yanyang Zou, Yong Zhao
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  ABSTRACT: Oxidative stress results in protein oxidation and is implicated in cerebral disease, such as Parkinson's disease, Alzheimer's disease, and ischemic stroke. Sulfiredoxin-1 (Srxn1) is an endogenous antioxidant protein that has neuroprotective effects. The mechanisms of Srxn1 in oxidative stress have not been well studied, however. This study used 180 μM H2 O2 exposure for 24 hr to model oxidative stress. This experimental design allowed us to explore the protective effects and underlying mechanisms of Srxn1 in PC12 cells. To investigate Srxn1's role in oxidative stress protection, transient knockdowns of Srxn1 in PC12 cells were performed prior to treatment with 180 μM H2 O2 for 24 hr. Knockdown of Srxn1 resulted in decreased cell viability and increased cellular damage as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and lactate dehyrogenase analysis, respectively. Intracellular superoxide dismutase and glutathione are important indexes of oxidative stress; these were reduced in Srxn1 knockdown PC12. We further found that the decreased Srxn1 correlated with a reduction in 2-Cys Prdxs activity. Moreover, 2-Cys Prdxs protein levels were increased in the H2 O2 -dosed cells, as measured by RT-PCR and immunoblot analysis. These results suggested that Srxn1 can protect PC12 cells from H2 O2 -induced oxidative stress and are involve in Prdxs activity. Srxn1 play a protective role against oxidative injury and demonstrates potential as a target for neuroprotective intervention in oxidative stress. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 03/2013;
• Article: Microsomal prostaglandin E synthase-1 is induced in alzheimer's disease and its deletion mitigates alzheimer's disease-like pathology in a mouse model.

  Yoshiharu Akitake, Yoshihito Nakatani, Daisuke Kamei, Masato Hosokawa, Hiroyasu Akatsu, Satoshi Uematsu, Shizuo Akira, Ichiro Kudo, Shuntaro Hara, Mitsuo Takahashi
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  ABSTRACT: Epidemiological studies have suggested that long-term use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX) activity can moderate the onset or progression of Alzheimer's disease (AD). Thus it has been suggested that prostaglandin E2 (PGE2 ), a major end-product of COX, may play a pathogenic role in AD, but the involvement of PGE synthase (PGES), a terminal enzyme downstream from COX, has not been fully elucidated. Here we found that, among three PGES enzymes, only microsomal PGES-1 (mPGES-1) is induced, and its expression is associated with β-amyloid (Aβ) plaques in the cerebral cortex in human AD patients and in Tg2576 mice, a transgenic AD mouse model. Furthermore, to investigate whether mPGES-1 contributes to AD-like pathology, we bred mPGES-1-deficient mice with Tg2576 mice. We found that mPGES-1 deletion reduced the accumulation of microglia around senile plaques and attenuated learning impairments in Tg2576 mice. These results indicated that mPGES-1 is induced in the AD brain and thus plays a role in AD pathology. Blockage of mPGES-1 could form the basis for a novel therapeutic strategy for patients with AD. Inc. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 03/2013;
• Article: Protein kinase CK2 enhances Mcl-1 gene expression through the serum response factor-mediated pathway in the rat hippocampus.

  Chia-Ming Chang, Chih Chang Chao
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  ABSTRACT: The protein kinase CK2 (casein kinase 2) is a ubiquitous serine/threonine protein kinase that suppresses apoptosis. CK2 is composed of catalytic and regulatory subunits, and CK2-dependent phosphorylation is a global mechanism in the inhibition of caspase signaling pathways. The serum response factor (SRF) is an important regulator of cell growth and differentiation. Although CK2 has been shown to phosphorylate SRF in vitro, the biological relevance of this interaction remains largely unclear. We observed increased SRF phosphorylation and increased Mcl-1 gene expression in hippocampal CA1 neurons following transfection with a plasmid expressing the wild-type CK2α (CK2αWT) protein, whereas transfection with a plasmid expressing a catalytically inactive mutant of CK2α (CK2α156A) reduced Mcl-1 gene expression. Cotransfection with a plasmid expressing the inactive SRF99A mutant inhibited the CK2αWT-induced upregulation of Mcl-1 gene expression. The expression of either the CK2α156A or the SRF99A mutant also inhibited the glutamate-induced upregulation of Mcl-1 protein expression in PC12 cells. Our results suggest that CK2-mediated signaling represents a cellular mechanism that may aid in the development of alternative therapeutic strategies to attenuate apoptosis in hippocampal neurons. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 03/2013;
• Article: 2-Phenylethynyl-butyltellurium attenuates amyloid-β peptide(25-35)-induced learning and memory impairments in mice.

  Ana Cristina Guerra Souza, Marcel Henrique Marcondes Sari, Simone Pinton, Cristiane Luchese, José Sebastião Santos Neto, Cristina Wayne Nogueira
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  ABSTRACT: Our previous study demonstrated that 2-phenylethynyl-butyltellurium (PEBT), an organotellurium compound, enhances memory in mice. In this study, the effects of PEBT on cognitive impairment induced by Aβ25-35 were assessed by Morris water maze and step-down inhibitory avoidance tasks. Mice received a single intracerebroventricular injection of Aβ25-35 (3 nmol/3 μl/per site) and a daily oral administration of PEBT (1 mg/kg, for 10 days). PEBT significantly improved Aβ-induced learning deficits on the training session in the Morris water maze. At the probe trial session, PEBT significantly decreased the escape latency and increased the number of crossings in the platform local compared with the Aβ-treated group. PEBT significantly improved Aβ-induced memory impairment in the step-down inhibitory avoidance task. General locomotor activity was similar in all groups. This study showed that PEBT ameliorated the impairments of spatial and nonspatial long-term memory evaluated on Morris water maze and step-down inhibitory avoidance tasks, respectively. The results suggest that PEBT could be considered a candidate for the prevention of memory deficits such as those observed in Alzheimer's disease. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 03/2013;
• Article: Preischemic exercise reduces brain damage by ameliorating metabolic disorder in ischemia/reperfusion injury.

  David Dornbos, Nathan Zwagerman, Miao Guo, Jamie Y Ding, Changya Peng, Fatema Esmail, Chaitanya Sikharam, Xiaokun Geng, Murali Guthikonda, Yuchuan Ding
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  ABSTRACT: Physical exercise preconditioning is known to ameliorate stroke-induced injury. In addition to several other mechanisms, the beneficial effect of preischemic exercise following stroke is due to an upregulated capacity to maintain energy supplies. Adult male Sprague-Dawley rats were used in exercise and control groups. After 1-3 weeks of exercise, several enzymes were analyzed as a gauge of the direct effect of physical exercise on cerebral metabolism. As a measure of metabolic capacity, an ADP/ATP ratio was obtained. Glucose transporters (GLUT1 and GLUT3) were monitored to assess glucose influx, and phosphofructokinase (PFK) was measured to determine the rate of glycolysis. Hypoxia-induced factor-1α (HIF-1α) and 5'AMP-activated protein kinase (AMPK) levels were also determined. These same analyses were performed on preconditioned and control rats following an ischemic/reperfusion (I/R) insult. Our results show that GLUT1, GLUT3, PFK, AMPK, and HIF-1α were all increased following 3 weeks of exercise training. In addition, the ADP/ATP ratio was chronically elevated during these 3 weeks. After I/R injury, HIF-1α and AMPK were significantly higher in exercised rats. The ADP/ATP ratio was reduced in preconditioned rats in the acute phase after stroke, suggesting a lower level of metabolic disorder. GLUT1 and GLUT3 were also increased in the acute phase in exercise rats, indicating that these rats were better able to increase rates of metabolism immediately after ischemic injury. In addition, PFK expression was increased in exercise rats showing an enhanced glycolysis resulting from exercise preconditioning. Altogether, exercise preconditioning increased the rates of glucose metabolism, allowing a more rapid and more substantial increase in ATP production following stroke. © 2013 Wiley Periodicals, Inc.
  Journal of Neuroscience Research 03/2013;