Multifaceted effects of rapamycin on functional recovery after spinal cord injury in rats through autophagy promotion, anti-inflammation, and neuroprotection

Chen, Hsien Chih; Fong, Tsorng Harn; Hsu, Peng Wei; Chiu, Wen Ta

doi:10.1016/j.jss.2012.02.023

Cited by 93 publications

(76 citation statements)

References 42 publications

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“…23 Although the role of autophagy in SCI is controversial, increasing numbers of investigations have demonstrated autophagy in rats and the feasibility of manipulating its expression to improve functional outcomes. 24 Over the past few years, calcitriol has been reported to upregulate the level of autophagy-that is, it can induce autophagy in the SH-SY5Y neuroblastoma cell line as a model of Parkinson's disease. 7 In addition, calcitriol shows biochemical protective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease through induction of autophagy.…”

Section: Effects Of Calcitriol On Sci K-l Zhou Et Almentioning

confidence: 99%

Effects of calcitriol on experimental spinal cord injury in rats

Jin

et al. 2016

Spinal Cord

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Study design: Experimental, controlled, animal study. Objectives: To evaluate the effects of calcitriol on oxidative stress, apoptosis, autophagy and locomotor recovery in rats after spinal cord injury (SCI). Setting: China. Methods: Ninety female rats were randomly divided into three groups. Laminectomy only was performed in the control group. The SCI group received laminectomy as well as spinal cord compression injury. In the calcitriol group, SCI rats received an intraperitoneal injection of calcitriol (2 μg kg − 1 day − 1 ). Oxidative stress was assessed by the tissue superoxide dismutase (SOD) activity and the contents of glutathione (GSH) and malondialdehyde (MDA). The extent of apoptosis was assessed by immunohistochemistry for C-caspase3, TUNEL staining and western blotting for C-caspase3, Bax and Bcl2. Transmission electron microscopy was used to examine autophagosomes in the injured spinal cord of calcitriol-treated rats. Autophagy was detected by western blotting for LC3-II, Beclin1 and p62. Histological changes were assessed by haematoxylin and eosin staining and Nissl staining. Functional recovery was reflected by the Basso, Beattie and Bresnahan locomotion rating scale and the inclined plane test. Results: With calcitriol treatment, oxidative stress was decreased, SOD activity and GSH content were increased and MDA content was decreased. Moreover, apoptosis was inhibited in the SCI plus calcitriol group. However, a higher level of autophagy was detected in the lesions of the calcitriol group compared with the SCI group. Histological damage and neuron loss after SCI were reduced in calcitrioltreated rats, and functional recovery was significantly promoted in the calcitriol group compared with controls. Conclusions: Calcitriol promotes locomotor recovery after SCI by reducing oxidative stress and inhibiting apoptosis, as well as promoting autophagy.

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Section: Effects Of Calcitriol On Sci K-l Zhou Et Almentioning

confidence: 99%

Effects of calcitriol on experimental spinal cord injury in rats

Jin

et al. 2016

Spinal Cord

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“…Rapamycin, an mToR-selective inhibitor, promotes autophagy and anti-inflammation, thereby playing a neuroprotective role [133] . Based on a screen of the active ingredients of Tripterygium wilfordii Hook.…”

Section: Pharmacological Strategiesmentioning

confidence: 99%

The glial scar in spinal cord injury and repair

2013

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Glial scarring following severe tissue damage and inflammation after spinal cord injury (SCi) is due to an extreme, uncontrolled form of reactive astrogliosis that typically occurs around the injury site. The scarring process includes the misalignment of activated astrocytes and the deposition of inhibitory chondroitin sulfate proteoglycans. Here, we first discuss recent developments in the molecular and cellular features of glial scar formation, with special focus on the potential cellular origin of scar-forming cells and the molecular mechanisms underlying glial scar formation after SCi. Second, we discuss the role of glial scar formation in the regulation of axonal regeneration and the cascades of neuro-inflammation. Last, we summarize the physical and pharmacological approaches targeting the modulation of glial scarring to better understand the role of glial scar formation in the repair of SCi.Keywords: glial scar; spinal cord injury; axonal regeneration; astrocyte activation; reactive astrogliosis; neuroinflammation IntroductionSpinal cord injury (SCi) is a common and devastating central nervous system (CNS) insult that results in disruption of cord microstructure and is followed by limited neuronal regeneration and insufficient functional recovery in adult mammals. After severe SCi, and in response to changes in the local microenvironment, astrocytes, the most abundant glial cells in the CNS, transform into reactive astrocytes and undergo dramatic morphological changes [1] as well as massive variations in gene expression [2] . Reactive astrocytes, the major component of glial scars, along with other cells in the spinal cord and blood-borne cells leaking from the damaged blood-spinal cord barrier, participate in the process of scar formation [3] .From the historical perspective, a glial scar is recognized as an impediment to the regeneration of axons in the cord because of the irregular rearrangement of hypertrophic astrocytic processes, as well as major components of the axonal inhibitory extracellular matrix (ECM), including chondroitin sulfate proteoglycans (CSPGs) that are secreted by the reactive astrocytes [4] . Currently, increasing evidence is advancing our knowledge of the mechanism of the formation of glial scars after a lesion and the roles of glial scars in the regulation of neuro-inflammation and repair processes [5,6] .This article reviews the following: (1) the molecular and cellular properties of glial scar formation following SCi;(2) the roles of glial scar formation in axonal regeneration and neuro-inflammation; and (3) the current status of scarmodulating therapeutic strategies for spinal cord repair after injury. Molecular and Cellular Properties of Glial Scars Characterization of Glial ScarsTraumatic damage of the spinal cord can result in seallike scar tissue in the lesion zone, which is filled with dense cellular components and a connective matrix. Generally, the scar tissue is classified into two parts, fibrotic and glial. 422The fibrotic scar, primarily composed of invading fibrobl...

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“…11 In our previous study, promotion of autophagy by rapamycin treatment contributed to the functional recovery of rat SCIs. 7 In this study, after 7 days of combined treatment with VCE, apoptosis after the SCI was suppressed, and autophagy after the SCI was enhanced. These results were congruous with improved functional recovery.…”

Section: Vce Treatment Inhibits Apoptosis and Enhances Autophagymentioning

confidence: 59%

“…The VCE treatment dose and frequency were modified from our previous studies 6,7 and reviewed literatures. 13,14 Western blot analysis…”

Section: Drug Administrationmentioning

confidence: 99%

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Effects of the combined administration of vitamins C and E on the oxidative stress status and programmed cell death pathways after experimental spinal cord injury

et al. 2013

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Study Design: Experimental, controlled, animal study. Objectives: To assess the effects of vitamins C and E (VCE) treatment on oxidative stress and programmed cell deaths after rat spinal cord injury (SCI), as well as functional recovery. Setting: Taiwan. Methods: Fifty-four Sprague-Dawley rats were used for the experimental procedure. In the sham group, laminectomy at T10 was performed, followed by impactor contusion of the spinal cord. In the control group, only a laminectomy was performed without contusion. Oxidative stress status was assessed by measuring the spinal cord tissue content of superoxide dismutase (SOD) and gluthatione peroxidase (GSH-Px) activities. We also evaluated the effects of combined VCE treatment using western blot to analyze expression of cleaved caspase-3 and microtubule-associated protein light chain 3 (LC3), and the Basso, Beattie and Bresnahan (BBB) scale to evaluate functional outcomes. Results: Combined treatment of VCE significantly counteracted the effects of spinal cord contusion on oxidative stress represented by activities of SOD and GSH-Px (Po0.05). The VCE treatment also significantly enhanced LC3-II expression and decreased cleaved caspase-3 compared with the sham (Po0.05). Furthermore, BBB scores significantly improved in the VCE-treated group compared with the sham group (on day 14 and 28 after SCI; Po0.05). Conclusions: The combined administration of VCE was clearly capable of modulating the antioxidant effects, and of reducing apoptosis and increasing autophagy at the lesion epicenter leading to an improved functional outcome. Use of such clinically ready drugs could help earlier clinical trials in selected cases of human SCIs.

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Multifaceted effects of rapamycin on functional recovery after spinal cord injury in rats through autophagy promotion, anti-inflammation, and neuroprotection

Cited by 93 publications

References 42 publications

Effects of calcitriol on experimental spinal cord injury in rats

Effects of calcitriol on experimental spinal cord injury in rats

The glial scar in spinal cord injury and repair

Effects of the combined administration of vitamins C and E on the oxidative stress status and programmed cell death pathways after experimental spinal cord injury

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