Blocking of BDNF-TrkB signaling inhibits the promotion effect of neurological function recovery after treadmill training in rats with spinal cord injury

Li, Xiangzhe; Xie, Chunyan; Wang, Can; Wang, Qinghua; Dong, Chuanming; Fang, Lü; Ding, Jie; Wang, Tong

doi:10.1038/s41393-018-0173-0

Cited by 48 publications

(41 citation statements)

References 34 publications

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“…PSD-95 is constituent of the postsynaptic membrane that plays a key role in the plasticity and structure of the excitatory chemical synapse (Wu et al, 2017 ), and multiple studies have associated physical exercise with its induction (Jung and Kim, 2017 ; Pan et al, 2017 ). A series of studies have shed light on the relationship between these factors by demonstrating that BDNF/NGF participate in promoting neuroplasticity for motor rehabilitation after focal cerebral infarction (Matsuda et al, 2011 ; Mizutani et al, 2011 ; Mang et al, 2013 ); BDNF was reported to be induced by exercise, and may regulate the expression of synaptic proteins including GAP-43 (Liu W. et al, 2018 ), SYN (Ferreira et al, 2011 ), PSD-95 (Li X. et al, 2019 ) and Tau (Kerling et al, 2017 ). This research indicates that synaptic plasticity after stroke is determined, at least in part, by the induction and upregulation of axonal or synaptic proteins that, in our study, were found to be increased in both exercise cohorts.…”

Section: Discussionmentioning

confidence: 99%

In Search of a Dose: The Functional and Molecular Effects of Exercise on Post-stroke Rehabilitation in Rats

Huber

et al. 2020

Front. Cell. Neurosci.

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Although physical exercise has been demonstrated to augment recovery of the post-stroke brain, the question of what level of exercise intensity optimizes neurological outcomes of post-stroke rehabilitation remains unsettled. In this study, we aim to clarify the mechanisms underlying the intensity-dependent effect of exercise on neurologic function, and thereby to help direct the clinical application of exercisebased neurorehabilitation. To do this, we used a well-established rat model of ischemic stroke consisting of cerebral ischemia induction through middle cerebral artery occlusion (MCAO). Ischemic rats were subsequently assigned either to a control group entailing post-stroke rest or to one of two exercise groups distinguished by the intensity of their accompanying treadmill regimens. After 24 h of reperfusion, exercise was initiated. Infarct volume, apoptotic cell death, and neurological defects were quantified in all groups at 3 days, and motor and cognitive functions were tracked up to day-28. Additionally, Western blotting was used to assess the influence of our interventions on several proteins related to synaptogenesis and neuroplasticity (growth-associated protein 43, a microtubule-associated protein, postsynaptic density-95, synapsin I, hypoxia-inducible factor-1α, brain-derived neurotrophic factor, nerve growth factor, tyrosine kinase B, and cAMP response element-binding protein). Our results were in equal parts encouraging and surprising. Both mild and intense exercise significantly decreased infarct volume, cell death, and neurological deficits. Motor and cognitive function, as determined using an array of tests such as beam balance, forelimb placing, and the Morris water maze, were also significantly improved by both exercise protocols. Interestingly, while an obvious enhancement of neuroplasticity proteins was shown in both exercise groups, mild exercise rats demonstrated a stronger effect on the expressions of Tau (p < 0.01), brain-derived neurotrophic factor (p < 0.01), and tyrosine kinase B (p < 0.05). These findings contribute to the growing body of literature regarding the positive effects of both mild and intense long-term treadmill exercise on brain injury, functional outcome, and

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Section: Discussionmentioning

confidence: 99%

In Search of a Dose: The Functional and Molecular Effects of Exercise on Post-stroke Rehabilitation in Rats

Huber

et al. 2020

Front. Cell. Neurosci.

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“…One week before SCI, the L3-4 intrathecal catheter operation was conducted to observe whether this operation injured the spinal cord or nerve. 28 Briefly, all rats were anesthetized by intraperitoneal injection of 10% chloral hydrate (0.3 ml/100g). The interspace between the L3-4 spinous process was located and exposed, and the dura mater and subarachnoid cavity were broken through with a 19G puncture needle.…”

Section: Intrathecal Catheter and Scimentioning

confidence: 99%

Exercise training modulates glutamic acid decarboxylase-65/67 expression through TrkB signaling to ameliorate neuropathic pain in rats with spinal cord injury

et al. 2020

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Neuropathic pain is one of the most frequently stated complications after spinal cord injury. In post-spinal cord injury, the decrease of gamma aminobutyric acid synthesis within the distal spinal cord is one of the main causes of neuropathic pain. The predominant research question of this study was whether exercise training may promote the expression of glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67, which are key enzymes of gamma aminobutyric acid synthesis, within the distal spinal cord through tropomyosin-related kinase B signaling, as its synthesis assists to relieve neuropathic pain after spinal cord injury. Animal experiment was conducted, and all rats were allocated into five groups: Sham group, SCI/PBS group, SCI-TT/PBS group, SCI/tropomyosin-related kinase B-IgG group, and SCI-TT/tropomyosin-related kinase B-IgG group, and then T10 contusion SCI model was performed as well as the tropomyosin-related kinase B-IgG was used to block the tropomyosin-related kinase B activation. Mechanical withdrawal thresholds and thermal withdrawal latencies were used for assessing pain-related behaviors. Western blot analysis was used to detect the expression of brain-derived neurotrophic factor, tropomyosin-related kinase B, CREB, p-REB, glutamic acid decarboxylase-65, and glutamic acid decarboxylase-67 within the distal spinal cord. Immunohistochemistry was used to analyze the distribution of CREB, p-CREB, glutamic acid decarboxylase-65, and glutamic acid decarboxylase-67 within the distal spinal cord dorsal horn. The results showed that exercise training could significantly mitigate the mechanical allodynia and thermal hyperalgesia in post-spinal cord injury and increase the synthesis of brain-derived neurotrophic factor, tropomyosin-related kinase B, CREB, p-CREB, glutamic acid decarboxylase-65, and glutamic acid decarboxylase-67 within the distal spinal cord. After the tropomyosin-related kinase B signaling was blocked, the analgesic effect of exercise training was inhibited, and in the SCI-TT/tropomyosin-related kinase B-IgG group, the synthesis of CREB, p-CREB, glutamic acid decarboxylase-65, and glutamic acid decarboxylase-67 within the distal spinal cord were also significantly reduced compared with the SCI-TT/PBS group. This study shows that exercise training may increase the glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67 expression within the spinal cord dorsal horn through the tropomyosin-related kinase B signaling, and this mechanism may play a vital role in relieving the neuropathic pain of rats caused by incomplete SCI.

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“…As changes in GAP-43 and SYN expression levels in the injured SC have signi cant effects on improving motor function, an increase in these factors in the cMSC group may have contributed to improved motor function. In previous studies, BDNF enhanced GAP-43 and SYN expression in neurons through the Trk receptor and subsequent ERK/CREB signaling [50,51]. The promotion of GAP-43 and SYN expression may be mediated by endogenous BDNF of SC tissue that is increased by cMSC transplantation.…”

Section: Discussionmentioning

confidence: 77%

Comparisons of neurotrophic effects of mesenchymal stem cells derived from adipose tissue, bone marrow, and cranial bone on chronic spinal cord injury

Otsuka¹,

Maeda²,

Kurose³

et al. 2021

Preprint

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Background Cell-based therapies with mesenchymal stem cells (MSCs) are considered as promising strategies for spinal cord injury (SCI). MSCs have unique characteristics due to difference in the derived tissues. However, relatively few studies have focused on differences in the therapeutic effects of MSCs derived from different tissues. Here, the therapeutic effects of adipose tissue-derived MSCs (aMSCs), bone marrow-derived MSCs (bMSCs), and cranial bone-derived MSCs (cMSCs) on chronic SCI model rats were compared. Methods MSCs were established from adipose tissue, bone marrow, and cranial bone collected. Neurotrophic factor expression of each MSC type was analyzed by real-time PCR. SCI rats were established with the weight-drop method and transplanted intravenously with MSCs at 4 weeks after SCI. Hind-limb motor function was evaluated from before injury to 4 weeks after transplantation. Endogenous neurotrophic factor and neural repair factor expression in spinal cord (SC) tissue were examined by real-time PCR and western blot analyses. Furthermore, the neurotrophic effects (i.e., neurite formation and elongation) of each MSC type were verified by co-culture with NG108-15 neural cells. Results Although there were no differences in the expression levels of cell surface markers and multipotency, expression of Bdnf, Ngf, and Sort1 (Nt-3) was relatively higher in cMSCs. Transplantation of cMSCs improved motor function of chronic SCI model rats. Although there was no difference in the degree of engraftment of transplanted cells in the injured SC tissue, transplantation of cMSCs enhanced Bdnf, TrkB, and Gap-43 mRNA expression and synaptophysin protein expression in injured SC tissue. In vitro, cMSCs co-cultured with NG108-15 cells promoted neurite formation and elongation. Conclusion As compared with MSCs derived other tissues, cMSCs highly express many neurotrophic factors which improved motor function in chronic SCI model rats by promoting endogenous neurotrophic and neural plasticity factors. These results suggest the efficacy of cMSCs in cell-based therapy for chronic SCI.

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Blocking of BDNF-TrkB signaling inhibits the promotion effect of neurological function recovery after treadmill training in rats with spinal cord injury

Abstract: The BDNF-TrkB signaling is a critical pathway in exercise training that promotes the recovery of neurological function in rats with incomplete SCI.

Cited by 48 publications

References 34 publications

In Search of a Dose: The Functional and Molecular Effects of Exercise on Post-stroke Rehabilitation in Rats

In Search of a Dose: The Functional and Molecular Effects of Exercise on Post-stroke Rehabilitation in Rats

Exercise training modulates glutamic acid decarboxylase-65/67 expression through TrkB signaling to ameliorate neuropathic pain in rats with spinal cord injury

Comparisons of neurotrophic effects of mesenchymal stem cells derived from adipose tissue, bone marrow, and cranial bone on chronic spinal cord injury

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