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1.
《Cell cycle (Georgetown, Tex.)》2013,12(9):1782-1795
Traumatic spinal cord injury (SCI) causes tissue loss and associated neurological dysfunction through mechanical damage and secondary biochemical and physiological responses. We have previously described the pathobiological role of cell cycle pathways following rat contusion SCI by examining the effects of early intrathecal cell cycle inhibitor treatment initiation or gene knockout on secondary injury. Here, we delineate changes in cell cycle pathway activation following SCI and examine the effects of delayed (24 h) systemic administration of flavopiridol, an inhibitor of major cyclin-dependent kinases (CDKs), on functional recovery and histopathology in a rat SCI contusion model. Immunoblot analysis demonstrated a marked upregulation of cell cycle-related proteins, including pRb, cyclin D1, CDK4, E2F1 and PCNA, at various time points following SCI, along with downregulation of the endogenous CDK inhibitor p27. Treatment with flavopiridol reduced induction of cell cycle proteins and increased p27 expression in the injured spinal cord. Functional recovery was significantly improved after SCI from day 7 through day 28. Treatment significantly reduced lesion volume and the number of Iba-1+ microglia in the preserved tissue and increased the myelinated area of spared white matter as well as the number of CC1+ oligodendrocytes. Furthermore, flavopiridol attenuated expression of Iba-1 and glactin-3, associated with microglial activation and astrocytic reactivity by reduction of GFAP, NG2, and CHL1 expression. Our current study supports the role of cell cycle activation in the pathophysiology of SCI and by using a clinically relevant treatment model, provides further support for the therapeutic potential of cell cycle inhibitors in the treatment of human SCI. 相似文献
2.
KPC1 (Kip1 ubiquitylation-promoting complex 1) is the catalytic subunit of the ubiquitin ligase KPC, which regulates the degradation
of the cyclin-dependent kinase inhibitor p27kip1 at the G1 phase of the cell cycle. To elucidate the expression and role of KPC1 in nervous system lesion and repair, we performed
an acute spinal cord contusion injury (SCI) model in adult rats. Western blot analysis showed a significant up-regulation
of KPC1 and a concomitant down-regulation of p27kip1 following spinal injury. Immunohistochemistry and immunofluorescence revealed wide expression of KPC1 in the spinal cord,
including expression in neurons and astrocytes. After injury, KPC1 expression was increased predominantly in astrocytes, which
highly expressed PCNA, a marker for proliferating cells. Co-immunoprecipitation demonstrated increased interactions between
p27kip1 and KPC1 4 days after injury. To understand whether KPC1 plays a role in astrocyte proliferation, we applied LPS to induce
astrocyte proliferation in vitro. Western blot analysis demonstrated that p27kip1 expression was negatively correlated with KPC1 expression following LPS stimulation. Immunofluorescence analysis showed subcellular
localizations of p27kip1 and KPC1 were also changed following the stimulation of astrocytes with LPS. These results suggest that KPC1 is related to
the down-regulation of p27kip1; this event may be involved in the proliferation of astrocytes after SCI. 相似文献
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4.
Ji Y Xiao F Sun L Qin J Shi S Yang J Liu Y Zhou D Zhao J Shen A 《Molecular and cellular biochemistry》2008,309(1-2):49-60
Protein kinases are critical signalling molecules for normal cell growth and development. CDK11p58 is a p34cdc2-related protein kinase, and plays an important role in normal cell cycle progression. However its distribution and function
in the central nervous system (CNS) lesion remain unclear. In this study, we mainly investigated the protein expression and
cellular localization of CDK11 during spinal cord injury (SCI). Western blot analysis revealed that CDK11p58 was not detected in normal spinal cord. It gradually increased, reached a peak at 3 day after SCI, and then decreased. The
protein expression of CDK11p58 was further analyzed by immunohistochemistry. The variable immunostaining patterns of CDK11p58 were visualized at different periods of injury. Double immunofluorescence staining showed that CDK11 was co-expressed with
NeuN, CNPase and GFAP. Co-localization of CDK11/active caspase-3 and CDK11/proliferating cell nuclear antigen (PCNA) were
detected in some cells. Cyclin D3, which was associated with CDK11p58 and could enhance kinase activity, was detected in the normal and injured spinal cord. The cyclin D3 protein underwent a
similar pattern with CDK11p58 during SCI. Double immunofluorescence staining indicated that CDK11 co-expressed with cyclin D3 in neurons and glial cells.
Coimmunoprecipitation further showed that CDK11p58 and cyclin D3 interacted with each other in the damaged spinal cord. Thus, it is likely CDK11p58 and cyclin D3 could interact with each other after acute SCI. Another partner of CDK11p58 was β-1,4-galactosyltransferase 1 (β-1,4-GT 1). The co-localization of CDK11/β-1,4-GT 1 in the damaged spinal cord was revealed
by immunofluorescence analysis. The cyclin D3-CDK4 complexes were also present by coimmunoprecipitation analysis. Taken together,
these data suggested that both CDK11 and cyclin D3 may play important roles in spinal cord pathophysiology.
The authors Yuhong Ji and Feng Xiao contributed equally to this work. 相似文献
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6.
Jieyuan Zhang Huijun Chen Zhaoxia Duan Kuijun Chen Zeng Liu Lu Zhang Dongdong Yao Bingcang Li 《Molecular neurobiology》2017,54(2):943-953
Inflammatory response following spinal cord injury (SCI) is important in regulation of the repair process. Olfactory ensheathing cells (OECs) and Schwann cells (SCs) are important donor cells for repairing SCI in different animal models. However, synergistic or complementary effects of co-transplantation of both cells for this purpose have not been extensively investigated. In the present study, we investigated the effects of co-transplantation of OECs and SCs on expression of pro- or anti-inflammatory factor and polarization of macrophages in the injured spinal cord of rats. Mixed cell suspensions containing OECs and SCs were transplanted into the injured site at 7 days after contusion at the vertebral T10 level. Compared with the DMEM, SC, or OEC group, the co-transplantation group had a more extensive distribution of the grafted cells and significantly reduced number of astrocytes, microglia/macrophage infiltration, and expression of chemokines (CCL2 and CCL3) at the injured site. The co-transplantation group also significantly increased arginase+/CD206+ macrophages (IL-4) and decreased iNOS+/CD16/32+ macrophages (IFN-γ), which was followed by higher IL-10 and IL-13 and lower IL-6 and TNF-α in their expression levels, a smaller cystic cavity area, and improved motor functions. These results indicate that OEC and SC co-transplantation could promote the shift of the macrophage phenotype from M(IFN-γ) to M(IL-4), reduce inflammatory cell infiltration in the injured site, and regulate inflammatory factors and chemokine expression, which provide a better immune environment for SCI repair. 相似文献
7.
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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9.
Junfang Wu Bogdan A Stoica Tao Luo Boris Sabirzhanov Zaorui Zhao Kelsey Guanciale 《Cell cycle (Georgetown, Tex.)》2014,13(15):2446-2458
Cognitive dysfunction has been reported in patients with spinal cord injury (SCI), but it has been questioned whether such changes may reflect concurrent head injury, and the issue has not been addressed mechanistically or in a well-controlled experimental model. Our recent rodent studies examining SCI-induced hyperesthesia revealed neuroinflammatory changes not only in supratentorial pain-regulatory sites, but also in other brain regions, suggesting that additional brain functions may be impacted following SCI. Here we examined effects of isolated thoracic SCI in rats on cognition, brain inflammation, and neurodegeneration. We show for the first time that SCI causes widespread microglial activation in the brain, with increased expression of markers for activated microglia/macrophages, including translocator protein and chemokine ligand 21 (C–C motif). Stereological analysis demonstrated significant neuronal loss in the cortex, thalamus, and hippocampus. SCI caused chronic impairment in spatial, retention, contextual, and fear-related emotional memory—evidenced by poor performance in the Morris water maze, novel objective recognition, and passive avoidance tests. Based on our prior work implicating cell cycle activation (CCA) in chronic neuroinflammation after SCI or traumatic brain injury, we evaluated whether CCA contributed to the observed changes. Increased expression of cell cycle-related genes and proteins was found in hippocampus and cortex after SCI. Posttraumatic brain inflammation, neuronal loss, and cognitive changes were attenuated by systemic post-injury administration of a selective cyclin-dependent kinase inhibitor. These studies demonstrate that chronic brain neurodegeneration occurs after isolated SCI, likely related to sustained microglial activation mediated by cell cycle activation. 相似文献
10.
Si Zhang Peijun Ju Editha Tjandra Yeeshan Yeap Hamed Owlanj Zhiwei Feng 《Cellular and molecular neurobiology》2016,36(7):1169-1178
Preventing demyelination and promoting remyelination of denuded axons are promising therapeutic strategies for spinal cord injury (SCI). Epidermal growth factor receptor (EGFR) inhibition was reported to benefit the neural functional recovery and the axon regeneration after SCI. However, its role in de- and remyelination of axons in injured spinal cord is unclear. In the present study, we evaluated the effects of EGFR inhibitor, PD168393 (PD), on the myelination in mouse contusive SCI model. We found that expression of myelin basic protein (MBP) in the injured spinal cords of PD treated mice was remarkably elevated. The density of glial precursor cells and oligodendrocytes (OLs) was increased and the cell apoptosis in lesions was attenuated after PD168393 treatment. Moreover, PD168393 treatment reduced both the numbers of OX42 + microglial cells and glial fibrillary acidic protein + astrocytes in damaged area of spinal cords. We thus conclude that the therapeutic effects of EGFR inhibition after SCI involves facilitating remyelination of the injured spinal cord, increasing of oligodendrocyte precursor cells and OLs, as well as suppressing the activation of astrocytes and microglia/macrophages. 相似文献
11.
《Cell cycle (Georgetown, Tex.)》2013,12(3):242-249
Glioblastoma (GBM) remains one of the most challenging solid cancers to treat due to its highly proliferative, angiogenic and invasive nature. Over 80% of adult high-grade astrocytomas show inactivation of the Rb tumor suppressor pathway. Therefore, one possible therapeutic strategy would be to directly modulate cyclin dependent kinase (CDK) activity resulting in inhibition of Rb phosphorylation and cell cycle progression. The small molecule CDK inhibitor, flavopiridol, has demonstrated antitumor activity in human xenograft models and is currently in clinical trials showing efficacy in patients with advanced disease. We have developed an experimental animal model using the murine glioma GL261 cells as a novel in vivo system to screen potential therapeutic agents for GBM. Results of in vitro testing demonstrate that flavopiridol has several relevant clinical characteristics such as its ability to: 1. inhibit cell growth; 2. inhibit cell migration;3. decrease expression of CDK inhibitor cyclin D1, CDK4 and p21; 4. induce apoptosis in cells with high levels of p27 expression; and5. decrease the expression of the anti-apoptotic protein Bcl-2. The mechanism by which flavopiridol induces apoptosis is mitochondrial-mediated. We demonstrate by electron microscopy and immunohistochemistry that drug treatment induces mitochondrial damage that was accompanied by the release of cytochrome c into the cytosol together with the translocation of apoptosis inducing factor (AIF) into the nucleus. This finding in murine glioma cells differs markedly from the mechanism of flavopiridol-induced apoptosis cell death reported by us for human glioma cells (Alonso et al., Mol Cancer Ther 2003; 2:139) where drug treatment induced a caspase- and cytochrome c-independent pathway in the absence of detectable damage to mitochondria. In apoptotic human glioma cells only translocation of AIF into the nucleus occurred. Thus, the same drug induces apoptosis inkills different types of glioma cells by different mitochondrial-dependent pathways. 相似文献
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Tae Y. Yune†‡ Jee Y. Lee†‡ Chun M. Cui† Ho C. Kim§ Tae H. Oh†‡ 《Journal of neurochemistry》2009,110(4):1276-1287
Inflammation has been known to play an important role in the pathogenesis after spinal cord injury (SCI). Microglia are activated after injury and produce a variety of proinflammatory factors such as tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, and reactive oxygen species leading to apoptosis of neurons and oligodendrocytes. In this study, we examined the neuroprotective effects of total ethanol extract of Scutellaria baicalensis (EESB) , after SCI. Using primary microglial cultures, EESB treatment significantly inhibited lipopolysaccharide-induced expression of such inflammatory mediators as tumor necrosis factor-α, IL-1β, IL-6, cyclooxygenase-2, and inducible nitric oxide synthase. Furthermore, reactive oxygen species and nitric oxide production were significantly attenuated by EESB treatment. For in vivo study, rats that had received a moderate spinal cord contusion injury at T9 received EESB orally at a dose of 100 mg/kg. EESB inhibited expression of proinflammatory factors and protein carbonylation and nitration after SCI. EESB also inhibited microglial activation at 4 h after injury. Furthermore, EESB significantly inhibited apoptotic cell death of neurons and oligodendrocytes and improved functional recovery after SCI. Lesion cavity and myelin loss were also reduced following EESB treatment. Thus, our data suggest that EESB significantly improve functional recovery by inhibiting inflammation and oxidative stress after injury. 相似文献
14.
Hongdou Jin Xin Ge Zhirong Huan Hao Yao Ce Xu Jimin Cai 《Journal of cellular and molecular medicine》2021,25(24):11075-11084
Spinal cord injury (SCI), a major cause of disability, causes high global disease and economic burdens. Stress-induced phosphoprotein 1 (STIP1) has been identified to be involved in spinal cord ischaemia-reperfusion injury (SCII); however, the effect of STIP1 on SCII remains unclear until now. This study aimed to examine the role of STIP1 in SCII and unravel the possible mechanisms. Western blotting and immunohistochemical staining showed that STIP1 expression rapidly increased and then decreased in rat spinal cord following SCII treatment. Neurological function scoring, HE staining, immunohistochemical staining and Western blotting revealed that STIP1 overexpression alleviated SCII-induced motor dysfunction of hind limbs, neuronal loss and inflammation in spinal cord, and inhibited activity of nuclear factor kappa B (NF-κB) signalling in rats. Immunoprecipitation identified that STIP1 was co-located with Iba-1. In addition, STIP1 was found to ameliorate oxygen and glucose deprivation (OGD)-induced inflammation and activation of NF-κB signalling in mouse microglia BV2 cells, and STIP1 resulted in decrease of heat shock protein family A member 8 (HSPA8), increase of IκBβ expression and reduced binding of IκBβ to HSPA8 in BV2 cells. The results of the present study demonstrate that STIP1 alleviates ischaemia/reperfusion-induced neuronal injury and inflammation in rat spinal cord and mouse microglial cells by deactivating NF-κB signalling. These findings may provide novel insights for the clinical diagnosis and treatment of SCI. 相似文献
15.
Yongxing Song Zhongyou Zeng Caiyi Jin Jianqiao Zhang Baoyue Ding Feng Zhang 《Neurochemical research》2013,38(3):610-619
This study aimed to investigate the correlation between ginkgolide B (GB) and the JAK/STAT signaling pathway and to explore its regulating effect on secondary cell apoptosis following spinal cord injury (SCI), to elucidate the protective mechanism GB against acute SCI. Sprague–Dawley rats were randomly divided into a sham-operated group, an SCI group, an SCI + GB group, an SCI + methylprednisolone (MP) group, and an SCI + specific JAK inhibitor AG490 group. A rat model of acute SCI was established using the modified Allen’s method. At 4 h, 12 h, 1 day, 3 days, 7 days and 14 days after injury, injured T10 spinal cord specimens were harvested. GB significantly increased inclined plane test scores and Basso, Beattie, and Bresnahan scale scores in SCI rats from postoperative day 3 to day 14. The effect was equal to that of the positive control drug, MP. Western blot analysis showed that JAK2 was significantly phosphorylated from 4 h after SCI, peaked at 12 h and gradually decreased thereafter, accompanied by phosphorylation of STAT3 with a similar time course. GB was shown to significantly inhibit the phosphorylation of JAK2 and STAT3 in rats with SCI. It significantly increased the ratio of B cell CLL/lymphoma-2 (Bcl-2)/Bcl-2-associated X protein (Bax) protein expression at 24 h, led to an obvious down-regulation of caspase-3 gene and protein expression at 3 days, and significantly decreased the cell apoptosis index at each time point after SCI. This effect was similar to that obtained with the JAK-specific inhibitor, AG490. Our experimental findings indicated that GB can protect rats against acute SCI, and that its underlying mechanism may be related to the inhibition of JAK/STAT signaling pathway activation, improvement of the Bcl-2/Bax ratio, decreased caspase-3 gene and protein expression and further inhibition of secondary cell apoptosis following SCI. 相似文献
16.
Desirée L. Salazar Nobuko Uchida Frank P. T. Hamers Brian J. Cummings Aileen J. Anderson 《PloS one》2010,5(8)
Background
Traumatic spinal cord injury (SCI) results in partial or complete paralysis and is characterized by a loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. Approximately 1,250,000 individuals have chronic SCI in the U.S.; therefore treatment in the chronic stages is highly clinically relevant. Human neural stem cells (hCNS-SCns) were prospectively isolated based on fluorescence-activated cell sorting for a CD133+ and CD24−/lo population from fetal brain, grown as neurospheres, and lineage restricted to generate neurons, oligodendrocytes and astrocytes. hCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30 days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery.Methods and Findings
hCNS-SCns were transplanted into immunodeficient NOD-scid mice 30 days post spinal cord contusion injury. hCNS-SCns transplanted mice demonstrated significantly improved locomotor recovery compared to vehicle controls using open field locomotor testing and CatWalk gait analysis. Transplanted hCNS-SCns exhibited long-term engraftment, migration, limited proliferation, and differentiation predominantly to oligodendrocytes and neurons. Astrocytic differentiation was rare and mice did not exhibit mechanical allodynia. Furthermore, differentiated hCNS-SCns integrated with the host as demonstrated by co-localization of human cytoplasm with discrete staining for the paranodal marker contactin-associated protein.Conclusions
The results suggest that hCNS-SCns are capable of surviving, differentiating, and promoting improved locomotor recovery when transplanted into an early chronic injury microenvironment. These data suggest that hCNS-SCns transplantation has efficacy in an early chronic SCI setting and thus expands the “window of opportunity” for intervention. 相似文献17.
Jinlong Zhang Guijuan Feng Guofeng Bao Guanhua Xu Yuyu Sun Weidong Li Lingling Wang Jiajia Chen Huricha Jin Zhiming Cui 《Cell cycle (Georgetown, Tex.)》2015,14(16):2609-2618
Aberrant functionality of the cell cycle has been implicated in the pathology of traumatic SCI. Although it has been reported that the expressions of various cell cycle related proteins were altered significantly following SCI, detailed information on the subject remains largely unclear. The embryonic pyruvate kinase M2 (PKM2) is an important metabolic kinase in aerobic glycolysis or the warburg effect, however, its functions in central nervous system (CNS) injury remains elusive. Here we demonstrate that PKM2 was not only significantly upregulated by western blot and immunohistochemistry but certain traumatic stimuli also induced translocation of PKM2 into the nucleus in astrocytes following spinal cord injury (SCI). Furthermore, the expression levels and localization of p-β-catenin, p27, cyclin D1 and PCNA were correlated with PKM2 after SCI. In vitro, we also found that PKM2 co-immunoprecipitation with p-β-catenin and p27 respectively. Knockdown of PKM2 apparently decreased the level of PCNA, cyclinD1, p27 in primary astrocyte cells. Taken together, our findings indicate that nuclear translocation of PKM2 promotes astrocytes proliferation after SCI through modulating cell cycle signaling. These discoveries firstly uncovered the role of PKM2 in spinal cord injury and provided a potential therapeutic target for CNS injury and repair. 相似文献
18.
Steve Lacroix Laura K. Hamilton Alexandre Vaugeois Stéfanny Beaudoin Christian Breault-Dugas Isabelle Pineau Sébastien A. Lévesque Catherine-Alexandra Grégoire Karl J. L. Fernandes 《PloS one》2014,9(1)
The adult mammalian spinal cord has limited regenerative capacity in settings such as spinal cord injury (SCI) and multiple sclerosis (MS). Recent studies have revealed that ependymal cells lining the central canal possess latent neural stem cell potential, undergoing proliferation and multi-lineage differentiation following experimental SCI. To determine whether reactive ependymal cells are a realistic endogenous cell population to target in order to promote spinal cord repair, we assessed the spatiotemporal dynamics of ependymal cell proliferation for up to 35 days in three models of spinal pathologies: contusion SCI using the Infinite Horizon impactor, focal demyelination by intraspinal injection of lysophosphatidylcholine (LPC), and autoimmune-mediated multi-focal demyelination using the active experimental autoimmune encephalomyelitis (EAE) model of MS. Contusion SCI at the T9–10 thoracic level stimulated a robust, long-lasting and long-distance wave of ependymal proliferation that peaked at 3 days in the lesion segment, 14 days in the rostral segment, and was still detectable at the cervical level, where it peaked at 21 days. This proliferative wave was suppressed distal to the contusion. Unlike SCI, neither chemical- nor autoimmune-mediated demyelination triggered ependymal cell proliferation at any time point, despite the occurrence of demyelination (LPC and EAE), remyelination (LPC) and significant locomotor defects (EAE). Thus, traumatic SCI induces widespread and enduring activation of reactive ependymal cells, identifying them as a robust cell population to target for therapeutic manipulation after contusion; conversely, neither demyelination, remyelination nor autoimmunity appears sufficient to trigger proliferation of quiescent ependymal cells in models of MS-like demyelinating diseases. 相似文献
19.
Chengwen Chen Qianbo Chen Yanfei Mao Shengming Xu Chunyan Xia Xueyin Shi John H. Zhang Hongbin Yuan Xuejun Sun 《Neurochemical research》2010,35(7):1111-1118
In the present study, we examined the mechanisms of hydrogen-rich saline, a reported therapeutic antioxidant, in the treatment
of acute spinal cord contusion injury. Male Sprague-Dawley rats were used to produce a standardized model of contuses spinal
cord injury (125 kdyn force). Hydrogen-rich saline was injected intraperitoneally (5 ml/kg) immediately, and at 24 and 48 h
after injury. All rats were sacrificed at 72 h after spinal cord injury (SCI). Apoptotic cell death, oxidative stress, inflammation,
level of Brain derived neurotrophic factor (BDNF) were evaluated. In addition, locomotor behavior was assessed using the Basso,
Beattice and Bresnahan (BBB) scale. We observed that administration of hydrogen-rich saline decreased the number of apoptotic
cells, suppressed oxidative stress, and improved locomotor functions. Hydrogen-rich saline increased the release of BDNF.
In conclusion, hydrogen-rich saline reduced acute spinal cord contusion injury, possibly by reduction of oxidative stress
and elevation of BDNF. 相似文献
20.
Epidermal growth factor attenuates blood‐spinal cord barrier disruption via PI3K/Akt/Rac1 pathway after acute spinal cord injury
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Yulong Zhou Sipin Zhu Qingqing Wang Hongxue Shi Daqing Chen Xiaojie Wei Zhouguang Wang Xiaokun Li Jian Xiao Huazi Xu Hongyu Zhang 《Journal of cellular and molecular medicine》2016,20(6):1062-1075
After spinal cord injury (SCI), disruption of blood–spinal cord barrier (BSCB) elicits blood cell infiltration such as neutrophils and macrophages, contributing to permanent neurological disability. Previous studies show that epidermal growth factor (EGF) produces potent neuroprotective effects in SCI models. However, little is known that whether EGF contributes to the integrity of BSCB. The present study is performed to explore the mechanism of BSCB permeability changes which are induced by EGF treatment after SCI in rats. In this study, we demonstrate that EGF administration inhibits the disruption of BSCB permeability and improves the locomotor activity in SCI model rats. Inhibition of the PI3K/Akt pathways by a specific inhibitor, LY294002, suppresses EGF‐induced Rac1 activation as well as tight junction (TJ) and adherens junction (AJ) expression. Furthermore, the protective effect of EGF on BSCB is related to the activation of Rac1 both in vivo and in vitro. Blockade of Rac1 activation with Rac1 siRNA downregulates EGF‐induced TJ and AJ proteins expression in endothelial cells. Taken together, our results indicate that EGF treatment preserves BSCB integrity and improves functional recovery after SCI via PI3K‐Akt‐Rac1 signalling pathway. 相似文献