Inhibiting epidermal growth factor receptor attenuates reactive astrogliosis and improves functional outcome after spinal cord injury in rats

Li, Zaiwang; Tang, Ronghua; Zhang, Jianping; Tang, Zhouping; Qu, Wensheng; Zhu, Wenhao; Li, Jijun; Xie, Mingxing; Tian, Dai-Shi; Wang, Wei

doi:10.1016/j.neuint.2011.03.007

Cited by 39 publications

(50 citation statements)

References 40 publications

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“…Moreover, in this study, evidently increased expression of GAP-43, a commonly used indicator of neuronal growth propensity [24], was observed in the spinal cord after SCI. Similar findings were reported by Cizkova's and Wang's groups [25,26]. The upregulated GAP-43 and decreased number of neurons indicated the auto-compensation could not restore the neuron injury.…”

Section: Discussionsupporting

confidence: 88%

The Neuroprotective Effect of Puerarin in Acute Spinal Cord Injury Rats

Zhang

Hou

et al. 2016

Cell Physiol Biochem

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Background: Acute spinal cord injury (SCI) leads to permanent disabilities. This study evaluated the neuroprotective effect of puerarin, a natural extract, in a rat model of SCI. Methods: Acute SCI models were established in rats using a modified Allen's method. Locomotor function was evaluated using the BBB test. The histological changes in the spinal cord were observed by H&E staining. Neuron survival and glial cells activation were evaluated by immunostaining. ELISA and realtime PCR were used to measure secretion and gene expression of cytokines. TUNEL staining was used to examine cell apoptosis and western blot analysis was used to detect protein expression. Results: Puerarin significantly increased BBB score in SCI rats, attenuated histological injury of spinal cord, decreased neuron loss, inhibited glial cells activation, alleviated inflammation, and inhibited cell apoptosis in the injured spinal cords. In addition, the downregulated PI3K and phospho-Akt protein expression were restored by puerarin. Conclusion: Puerarin accelerated locomotor function recovery and tissue repair of SCI rats, which is associated with its neuroprotection, glial cell activation suppression, anti-inflammatory and anti-apoptosis effects. These effects may be associated with the activation of PI3K/Akt signaling pathway.

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Section: Discussionsupporting

confidence: 88%

The Neuroprotective Effect of Puerarin in Acute Spinal Cord Injury Rats

Zhang

Hou

et al. 2016

Cell Physiol Biochem

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“…Their death and degeneration in and around the lesion site disrupt neural circuitry and contribute to neurological dysfunction [55]. Remyelination and protection of neuronal death are crucial to support the axonal refining after SCI [56,57]. EETs in the brain have been shown to exert anti-apoptotic effects in several components of the neurovascular unit [6][7][8].…”

Section: Discussionmentioning

confidence: 99%

Soluble epoxide hydrolase inhibition provides multi-target therapeutic effects in rats after spinal cord injury

Chen

Huang

et al. 2015

Mol Neurobiol

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Multiple players are involved in motor and sensory dysfunctions after spinal cord injury (SCI). Therefore, therapeutic approaches targeting these various players in the damage cascade hold considerable promise for the treatment of traumatic spinal cord injury. Soluble epoxide hydrolase (sEH) is an endogenous key enzyme in the metabolic conversion and degradation of P450 eicosanoids called epoxyeicosatrienoic acids (EETs). sEH inhibition has been shown to provide neuroprotective effects upon multiple elements of neurovascular unit under cerebral ischemia. However, its role in the pathological process after SCI remains unclear. In this study, we tested the hypothesis that sEH inhibition may have therapeutic effects in preventing secondary damage in rats after traumatic SCI. sEH was widely expressed in spinal cord tissue, mainly confined to astrocytes, and neurons. Administration of sEH inhibitor AUDA significantly suppressed local inflammatory responses as indicated by the reduced microglia activation and IL-1 β expression, as well as the decreased infiltration of neutrophils and T lymphocytes. Meanwhile, reactive astrogliosis was remarkably attenuated. Furthermore, treatment of AUDA improved angiogenesis, inhibited neuron cells apoptosis, alleviated demyelination and formation of cavity and improved motor recovery. Together, these results provide the first in vivo evidence that sEH inhibition could exert multiple targets protective effects after SCI in rats. sEH may thereby serve as a promising multi-mechanism therapeutic target for the treatment of SCI.

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“…Adult female Sprague-Dawley rats (n = 96; weight 220 to 250 g) were randomly classified into SCI and sham-operated groups. A T10 contusion injury was produced as previously described [8,16]. Briefly, rats were anesthetized by intraperitoneal (ip) injection of ketamine (80 mg/kg) and xylazine (10 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

“…Specifically, epidermal growth factor (EGF) and transforming growth factor-a (TGF-a) have been shown to play crucial roles in the transformation of quiescent astrocytes toward a reactive state [6]. Enhanced expression of the membrane-localized target of these growth factors, the receptor tyrosine kinase epidermal growth factor receptor (EGFR), has been observed in astrocytes following trauma to the CNS [7,8]. Therefore, the EGFR pathway is commonly perceived as a key signaling cascade by which to regulate and control reactive astrogliosis and proliferation following SCI [8].…”

Section: Introductionmentioning

confidence: 99%

“…Enhanced expression of the membrane-localized target of these growth factors, the receptor tyrosine kinase epidermal growth factor receptor (EGFR), has been observed in astrocytes following trauma to the CNS [7,8]. Therefore, the EGFR pathway is commonly perceived as a key signaling cascade by which to regulate and control reactive astrogliosis and proliferation following SCI [8]. If so, inhibition of EGFR signaling may benefit axonal regeneration and improve functional outcome in SCI.…”

Section: Introductionmentioning

confidence: 99%

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Epidermal growth factor receptor inhibitor ameliorates excessive astrogliosis and improves the regeneration microenvironment and functional recovery in adult rats following spinal cord injury

Wang³

et al. 2014

Journal of Neuroinflammation

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BackgroundAstrogliosis is a common phenomenon after spinal cord injury (SCI). Although this process exerts positive effects on axonal regeneration, excessive astrogliosis imparts negative effects on neuronal repair and recovery. Epidermal growth factor receptor (EGFR) pathway is critical to the regulation of reactive astrogliosis, and therefore is a potential target of therapeutics to better control the response. In this report, we aim to investigate whether blocking EGFR signaling using an EGFR tyrosine kinase specific inhibitor can attenuate reactive astrogliosis and promote functional recovery after a traumatic SCI.MethodThe astrocyte scratch injury model in vitro and the weight-drop SCI model in vivo were used as model systems. PD168393 was used to inhibit EGFR signaling activation. Astrocytic activation and phosphorylated EGFR (pEGFR) were observed after immunofluorescence staining and Western blot analysis. The rate of proliferation was determined by immunofluorescence detection of BrdU-incorporating cells located next to the wound. The levels of TNF-α, iNOS, COX-2 and IL-1β in the culture medium under different conditions were assayed by ELISA. Western blot was performed to semi-quantify the expression of EGFR/pEGFR, glial fibrillary acid protein (GFAP) and chondroitin sulfate proteoglycans (CSPGs). Myelin was stained by Luxol Fast Blue Staining. Cresyl violet eosin staining was performed to analyze the lesion cavity volume and neuronal survival following injury. Finally, functional scoring and residual urine recording were performed to show the rats’ recovery.ResultsEGFR phosphorylation was found to parallel astrocyte activation, and EGFR inhibitor PD168393 potently inhibited scratch-induced reactive astrogliosis and proinflammatory cytokine/mediator secretion of reactive astrocytes in vitro. Moreover, local administration of PD168393 in the injured area suppressed CSPGs production and glial scar formation, and resulted in reduced demyelination and neuronal loss, which correlated with remarkable hindlimb motor function and bladder improvement in SCI rats.ConclusionsThe specific EGFR inhibitor PD168393 can ameliorate excessive reactive astrogliosis and facilitate a more favorable environment for axonal regeneration after SCI. As such, EGFR inhibitor may be a promising therapeutic intervention in CNS injury.

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Inhibiting epidermal growth factor receptor attenuates reactive astrogliosis and improves functional outcome after spinal cord injury in rats

Cited by 39 publications

References 40 publications

The Neuroprotective Effect of Puerarin in Acute Spinal Cord Injury Rats

The Neuroprotective Effect of Puerarin in Acute Spinal Cord Injury Rats

Soluble epoxide hydrolase inhibition provides multi-target therapeutic effects in rats after spinal cord injury

Epidermal growth factor receptor inhibitor ameliorates excessive astrogliosis and improves the regeneration microenvironment and functional recovery in adult rats following spinal cord injury

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