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Reactive oxygen species and resultant lipid peroxidation (LPO) have been associated with central nervous system trauma. Acrolein (2-propenal) and 4-hydroxynonenal (HNE) are the most toxic byproducts of LPO, with detrimental effects in various types of cells. In this study, we used immunoblotting techniques to detect the accumulation of protein-bound acrolein and HNE. We report that protein-bound acrolein and HNE were significantly increased in guinea pig spinal cord following a controlled compression injury. The acrolein and HNE protein-adducts increased in the damaged spinal cord as early as 4 h after injury, reached a peak at 24 h after injury, and remained at a significantly high level up to 7 days after injury. Such increase of protein adducts was also observed in the adjacent segments of the injury site beginning at 24 h post injury. These results suggest that products of lipid peroxidation, especially acrolein, may play a critical role in the secondary neuronal degeneration, which follows mechanical insults. 相似文献
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Gang Liu Gentao Fan Guodong Guo Wenbo Kang Dongsheng Wang Bin Xu Jianning Zhao 《Cellular and molecular neurobiology》2017,37(5):843-855
FK-506 (Tacrolimus) is a very commonly used immunomodulatory agent that plays important roles in modulating the calcium-dependent phosphoserine–phosphothreonine protein phosphatase calcineurin and thus inhibits calcineurin-mediated secondary neuronal damage. The biological function of FK-506 in the spinal cord has not been fully elucidated. To clarify the anti-inflammatory action of FK-506 in spinal cord injury (SCI), we performed an acute spinal cord contusion injury model in adult rats and hypoxia-treated primary spinal cord microglia cultures. This work studied the activation of NF-κB and proinflammatory cytokine (TNF-a, IL-1b, and IL-6) expression. ELISA and q-PCR analysis revealed that TNF-a, IL-1b, and IL-6 levels significantly increased 3 days after spinal cord contusion and decreased after 14 days, accompanied by the increased activation of NF-κB. This increase was reversed by an FK-506 treatment. Double immunofluorescence labeling suggested that NF-κB activation was especially prominent in microglia. Immunohistochemistry confirmed no alteration in the number of microglia. Moreover, the results in hypoxia-treated primary spinal cord microglia confirmed the effect of FK-506 on TNF-a, IL-1b, and IL-6 expression and NF-κB activation. These findings suggest that FK-506 may be involved in microglial activation after SCI. 相似文献
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Xiaoqin Zhang Guoqiang Chen Qingsheng Xue Buwei Yu 《Cellular and molecular neurobiology》2010,30(6):885-890
Injury to the peripheral nervous system can lead to spontaneous pain, hyperalgesia and allodynia. Previous studies have shown
sprouting of Aβ-fibres into lamina II of the spinal cord dorsal horn after nerve injury and the formation of new synapses
by these sprouts. β-Catenin and menin as synaptogenic factors are critically involved in synapse formation. However, the roles
of β-catenin and menin in neuropathic pain are still unclear. Using Western blot analysis we investigated the changes of β-catenin
and menin in the spinal dorsal horn after unilateral spared nerve injury (SNI). We demonstrated an increase in both β-catenin
and menin protein levels in the ipsilateral spinal dorsal horn at days 1 and 3 following spared nerve injury (P < 0.05). These increases were associated with changes in paw withdrawal threshold to mechanical stimuli and weight bearing
deficit suggestive of pain behavior and spontaneous ongoing pain respectively. However, the injury-associated increases in
β-catenins and menins levels returned to control levels at day 14. In conclusion, these results indicate that peripheral nerve
injury induces upregulation of β-catenins and menins in the dorsal horn of the spinal cord, which may contribute to the development
of chronic neuropathic pain. Antagonists of these molecules may serve as new therapeutic agents. 相似文献
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Shen A Zhou D Shen Q Liu HO Sun L Liu Y Chen J Yang J Ji Y Cheng C 《Neurochemical research》2009,34(2):333-341
The proinflammatory and lipopolysaccharide (LPS)-inducible cytokine tumor necrosis factor α (TNF-α) has been shown to enhance
primary sensory nociceptive signaling. However, the precise cellular site of TNF-α synthesis is still a matter of controversy.
Therefore, we focused our study on TNF-α protein synthesis and expression patterns in spinal dorsal horn of naives and rats
under intrathecal challenge with LPS. The enzyme-linked immunosorbent (ELISA) assay showed that the protein level of TNF-α
reached peak at 8 h. Double immunofluorescence revealed that LPS-induced expression of TNF-α exclusively located in a subpopulation
of microglia, which increased at 8 h in the rat spinal dorsal horn (the injected side). Positive staining of TNF receptor
1 (TNFR1) were also found in microglia. These observations have demonstrated the production of this proinflammatory cytokine
by central nerve glia especially microglia. Synthesized TNF-α might directly act on microglia via TNFR1, but the inherent
mechanisms remain unknown. Further studies are needed to confirm the pathogenic role of tumor necrosis factor in the early
stage of inflammation.
Aiguo Shen and Dan Zhou contributed equally to this work. 相似文献
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《Molecular cell》2014,53(1):88-100
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Background
Morphine tolerance is a common drawback of chronic morphine exposure, hindering use of this drug. Studies have shown that PKCã may play a key role in the development of morphine tolerance, although the mechanisms are not fully known.Methodology/Principal Findings
In a rat model of morphine tolerance, PKCã knockdown in the spinal cord was successfully carried out using RNA interference (RNAi) with lentiviral vector-mediated short hairpin RNA of PKCã (LV-shPKCã). Spinal cords (L4-L5) were obtained surgically from morphine-tolerant (MT) rats with and without PKCã knockdown, for comparative proteomic analysis. Total proteins from the spinal cords (L4-L5) were extracted and separated using two-dimensional gel electrophoresis (2DGE); 2D gel images were analyzed with PDQuest software. Seven differential gel-spots were observed with increased spot volume, and 18 spots observed with decreased spot volume. Among these, 13 differentially expressed proteins (DEPs) were identified with matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), comparing between MT rats with and without PKCã knockdown. The DEPs identified have roles in the cytoskeleton, as neurotrophic factors, in oxidative stress, in ion metabolism, in cell signaling, and as chaperones. Three DEPs (GFAP, FSCN and GDNF) were validated with Western blot analysis, confirming the DEP data. Furthermore, using immunohistochemical analysis, we reveal for the first time that FSCN is involved in the development of morphine tolerance.Conclusions/Significance
These data cast light on the proteins associated with the PKCã activity during morphine tolerance, and hence may contribute to clarification of the mechanisms by which PKCã influences MT. 相似文献8.
Sandra Tamosaityte Roberta Galli Ortrud Uckermann Kerim H. Sitoci-Ficici Robert Later Rudolf Beiermeister Falko Doberenz Michael Gelinsky Elke Leipnitz Gabriele Schackert Edmund Koch Valdas Sablinskas Gerald Steiner Matthias Kirsch 《PloS one》2015,10(11)
Spinal cord injury (SCI) induces complex biochemical changes, which result in inhibition of nervous tissue regeneration abilities. In this study, Fourier-transform infrared (FT-IR) spectroscopy was applied to assess the outcomes of implants made of a novel type of non-functionalized soft calcium alginate hydrogel in a rat model of spinal cord hemisection (n = 28). Using FT-IR spectroscopic imaging, we evaluated the stability of the implants and the effects on morphology and biochemistry of the injured tissue one and six months after injury. A semi-quantitative evaluation of the distribution of lipids and collagen showed that alginate significantly reduced injury-induced demyelination of the contralateral white matter and fibrotic scarring in the chronic state after SCI. The spectral information enabled to detect and localize the alginate hydrogel at the lesion site and proved its long-term persistence in vivo. These findings demonstrate a positive impact of alginate hydrogel on recovery after SCI and prove FT-IR spectroscopic imaging as alternative method to evaluate and optimize future SCI repair strategies. 相似文献
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Gail F. Forrest Karen Hutchinson Douglas J. Lorenz Jeffrey J. Buehner Leslie R. VanHiel Sue Ann Sisto D. Michele Basso 《PloS one》2014,9(5)
Objective
To evaluate the relationship and redundancy between gait speeds measured by the 10 Meter Walk Test (10MWT) and 6 Minute Walk Test (6MWT) after motor incomplete spinal cord injury (iSCI). To identify gait speed thresholds supporting functional ambulation as measured with the Spinal Cord Injury Functional Ambulation Inventory (SCI-FAI).Design
Prospective observational cohort.Setting
Seven outpatient rehabilitation centers from the Christopher and Dana Reeve Foundation NeuroRecovery Network (NRN).Participants
249 NRN patients with American Spinal Injury Association Impairment Scale (AIS) level C (n = 20), D (n = 179) and (n = 50) iSCI not AIS evaluated, from February 2008 through April 2011.Interventions
Locomotor training using body weight support and walking on a treadmill, overground and home/community practice.Main Outcome Measure(s)
10MWT and 6MWT collected at enrollment, approximately every 20 sessions, and upon discharge.Results
The 10MWT and 6MWT speeds were highly correlated and the 10MWT speeds were generally faster. However, the predicted 6MWT gait speed from the 10MWT, revealed increasing error with increased gait speed. Regression lines remained significantly different from lines of agreement, when the group was divided into fast (≥0.44 m/s) and slow walkers (<0.44 m/s). Significant differences between 6MWT and 10MWT gait speeds were observed across SCI-FAI walking mobility categories (Wilcoxon sign rank test p<.001), and mean speed thresholds for limited community ambulation differed for each measure. The smallest real difference for the 6MWT and 10MWT, as well as the minimally clinically important difference (MCID) values, were also distinct for the two tests.Conclusions
While the speeds were correlated between the 6MWT and 10MWT, redundancy in the tests using predictive modeling was not observed. Different speed thresholds and separate MCIDs were defined for community ambulation for each test. 相似文献10.
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Abrahamyan SS Meliksetyan IB Sulkhanyan RM Sarkissian JS Galoyan AA 《Neurochemical research》2001,26(11):1225-1230
Previously by immunohistochemical technique the distribution of immunophilin 1–15 fragment (IphF) isolated from bovine hypothalamus was examined in various tissues (heart, lung), including immune system organs (spleen and thymus) of intact rats. IphF-like immunoreactivity (IphF-LI) was revealed in several cell types: lymphocytes, monocytes, macrophages and mast cells. In the present study the immunohistochemical localization of IphF was examined in intact rat and frog brains. In rat brain several cell groups concentrated particularly in the supraoptic nucleus (SON) of hypothalamus, medulla oblongata (reticular formation, olives, hypoglossal and facial motor nuclei) and cerebellum (lateral cerebellar nucleus) demonstrated IphF-LI. In frog hypothalamus (SON) the same working dilution (1:5000) of IphF-antiserum revealed very strong immunoreactivity. In the paraventricular nucleus (PVN) IphF-LI varicosities were scattered around the immunonegative cells. The second cell groups showing IphF-LI in the frog brain were gliocytes (mainly the astrocytes). Besides, IphF distribution was investigated in rats subjected to hemisection of spinal cord (SC) with and without administration of proline-rich polypeptide (PRP). PRP was isolated from bovine neurohypophysis neurosecretory granules, produced by magnocellular nuclei of hypothalamus. Hemisection of SC led to changes of IphF distribution in the hypothalamus. In PRP treated animals IphF showed no immunoreactivity. PRP is suggested to act as a neurotransmitter and neuroregulator. 相似文献
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Transient Spinal Cord Ischemia in Rat: The Time Course of Spinal FOS Protein Expression and the Effect of Intraischemic Hypothermia (27°C) 总被引:1,自引:0,他引:1
Yang LC Orendacova J Wang V Ishikawa T Yaksh TL Marsala M 《Cellular and molecular neurobiology》2000,20(3):351-365
1. In the present study, we characterize the time course of spinal FOS protein expression after transient noninjurious (6-min) or injurious (12-min) spinal ischemia induced by inflation of a balloon catheter placed into the descending thoracic aorta. In addition, this work examined the effects of spinal hypothermia on FOS expression induced either by ischemia or by potassium-evoked depolarization (intrathecal KCl).2. Short-lasting (6-min) spinal ischemia evoked a transient FOS protein expression. The peak expression was seen 2 hr after reperfusion in all laminar levels in lumbosacral segments. At 4 hr of reperfusion, more selective FOS expression in spinal interneurons localized in the central part of laminae V–VII was seen. At 24 hr no significant increase in FOS protein was detected.3. After 12 min of ischemia and 2 hr of reflow, nonspecific FOS expression was seen in both white and gray matter, predominantly in nonneuronal elements. Intrathecal KCl-induced FOS expression in spinal neurons in the dorsal horn and in the intermediate zone. Spinal hypothermia (27°C) significantly suppressed FOS expression after 6 or 12 min of ischemia but not after KCl-evoked depolarization.4. Data from the present study show that an injurious (but not noninjurious) interval of spinal ischemia evokes spinal FOS protein expression in glial cells 2 hr after reflow. The lack of neuronal FOS expression corresponds with extensive neuronal degeneration seen in this region 24 hr after reflow. Noninjurious (6-min) ischemia induced a transient, but typically neuronal FOS expression. The significant blocking effect of hypothermia (27°C) on the FOS induction after ischemia but not after potassium-evoked depolarization also suggests that simple neuronal depolarization is a key trigger in FOS induction. 相似文献
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Taekyun Shin Meejung Ahn Changjong Moon Seungjoon Kim Ki-Bum Sim 《Molecular neurobiology》2013,47(3):1011-1019
Tissues within the central nervous system (CNS) have generally been regarded as immunologically privileged. However, in recent decades, it has been shown that immune reactions in the CNS continuously occur via various types of inflammation following autoimmune diseases and mechanical insults such as spinal cord injury (SCI). Among the various inflammatory cells associated with CNS disease, activated macrophages are classically known to induce detrimental consequences that are mediated by the secretion of pro-inflammatory molecules. Alternatively activated macrophages have recently been shown to modulate various types of CNS inflammation, including SCI. This review summarizes the potential roles of alternatively activated macrophages in the course of CNS inflammation in rodent SCI models. 相似文献
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Kong Ganggang Liu Junhao Li Rong Lin Junyu Huang Zucheng Yang Zhou Wu Xiuhua Huang Zhiping Zhu Qingan Wu Xiaoliang 《Neurochemical research》2021,46(2):213-229
Neurochemical Research - Ketogenic diet (KD) has been shown to be beneficial in a range of neurological disorders, with ketone metabolite β-hydroxybutyrate (βOHB) reported to block the... 相似文献
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Zhida Su Yimin Yuan Jingjing Chen Li Cao Yanling Zhu Liang Gao Yang Qiu Cheng He 《PloS one》2009,4(12)
Background
After spinal cord injury (SCI), the formation of glial scar contributes to the failure of injured adult axons to regenerate past the lesion. Increasing evidence indicates that olfactory ensheathing cells (OECs) implanted into spinal cord are found to migrate into the lesion site and induce axons regeneration beyond glial scar and resumption of functions. However, little is known about the mechanisms of OECs migrating from injection site to glial scar/lesion site.Methods and Findings
In the present study, we identified a link between OECs migration and reactive astrocytes in glial scar that was mediated by the tumor necrosis factor-α (TNF-α). Initially, the Boyden chamber migration assay showed that both glial scar tissue and reactive astrocyte-conditioned medium promoted OECs migration in vitro. Reactive astrocyte-derived TNF-α and its type 1 receptor TNFR1 expressed on OECs were identified to be responsible for the promoting effect on OECs migration. TNF-α-induced OECs migration was demonstrated depending on activation of the extracellular signal-regulated kinase (ERK) signaling cascades. Furthermore, TNF-α secreted by reactive astrocytes in glial scar was also showed to attract OECs migration in a spinal cord hemisection injury model of rat.Conclusions
These findings showed that TNF-α was released by reactive astrocytes in glial scar and attracted OECs migration by interacting with TNFR1 expressed on OECs via regulation of ERK signaling. This migration-attracting effect of reactive astrocytes on OECs may suggest a mechanism for guiding OECs migration into glial scar, which is crucial for OECs-mediated axons regrowth beyond the spinal cord lesion site. 相似文献18.
Yuwu Zhao Xueyuan Liu Aiyong Yu Yajun Zhou Bangjian Liu 《Cell biochemistry and biophysics》2010,58(3):141-145
Occludin is an essential component of tight junctions, which are involved in controlling the integrity of the blood–brain
barrier and blood–spinal cord barrier (BSCB). Diabetes-induced alteration of occludin in rat BSCB and the relationship between
occludin level and disease course was examined. Diabetes was induced using streptozotocin. Occludin rat spinal cord mRNA levels
were assessed by real-time quantitative RT-PCR. Protein levels were examined by western blot. Occludin expression in 1-month
diabetic rats was significantly reduced compared to the controls (0.20 ± 0.01 vs 1.00 ± 0.01, respectively; P < 0.05). Expression was also significantly lower in the 3-month diabetic group (0.06 ± 0.02; P < 0.01). Occludin protein levels of 1-month (0.53 ± 0.01) and 3-month (0.31 ± 0.01) diabetic rats were also significantly
reduced compared to controls (0.91 ± 0.06; P < 0.01 for both). Diabetes decreased BSCB occludin expression at the mRNA and protein level. This down-regulation appears
to correlate with the course of the disease, and may be a causal factor of diabetes-induced increase of BSCB permeability. 相似文献
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The Neuroprotective Potential of Phase II Enzyme Inducer on Motor Neuron Survival in Traumatic Spinal Cord Injury In vitro 总被引:1,自引:0,他引:1
Liu XY Li CY Bu H Li Z Li B Sun MM Guo YS Zhang L Ren WB Fan ZL Wu DX Wu SY 《Cellular and molecular neurobiology》2008,28(5):769-779
(1) Phase II enzyme inducer is a kind of compound which can promote the expression of antioxidative enzymes through nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Recently, it has been reported that these compounds show neuroprotective effect via combating oxidative stress. The purpose of this study is to determine whether phase II enzyme inducers have neuroprotective effects on traumatic spinal cord injury. (2) An organotypic spinal cord culture system was used, Phase II enzyme inducers were added to culture medium for 1 week, motor neurons were counted by SMI-32 staining, glutamate, Nrf2, and Heme oxygenase-1(HO-1) mRNA were tested. (3) This study showed motor neuron loss within 1 week in culture. After 1 week in culture, the system was stable. Moreover, Glutamate was increased when in culture 48 h and decreased after 1 week in culture. There was no significant change between 1 and 4 weeks in culture. Necrotic motor neuron and damaged mitochondrial were observed in culture 48 h. Furthermore, phase II enzyme inducers: tert-butyhydroquinone (t-BHQ), 3H-1,2-dithiole-3-thione (D3T), and 5,6-dihydrocyclopenta-1,2-dithiole-3-thione (CPDT) were shown to promote motor neuron survival after dissection, it was due to increasing Nrf2 and HO-1 mRNA expression and protecting mitochondrial not due to decreasing glutamate level. (4) The loss of motor neuron due to dissection can mimic severe traumatic spinal cord injury. These results demonstrate that glutamate excitotoxicity and the damage of mitochondrial is possibly involve in motor neuron death after traumatic spinal cord injury and phase II enzyme inducers show neuroprotective potential on motor neuron survival in traumatic spinal cord injury in vitro. 相似文献