Role of neurotrophins in recovery of phrenic motor function following spinal cord injury

Sieck, Gary C.; Mantilla, Carlos B.

doi:10.1016/j.resp.2009.08.008

Cited by 42 publications

(49 citation statements)

References 95 publications

(150 reference statements)

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“…5,6 SH involves a unilateral transection of anterolateral funiculi at C2, which removes premotor drive to phrenic motoneurons, paralyzing the ipsilateral diaphragm muscle. [7][8][9][10][11][12][13][14] Following SH, there is gradual recovery of rhythmic diaphragm activity ipsilateral to injury, [15][16][17][18][19][20][21] suggesting neuroplasticity and strengthening of spared contralateral synaptic inputs to phrenic motoneurons. Importantly, recovery of ipsilateral diaphragm activity after SH can be enhanced by intrathecal delivery of BDNF at the level of the phrenic motor nucleus.…”

Section: Introductionmentioning

confidence: 99%

Localized Delivery of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Enhances Functional Recovery following Cervical Spinal Cord Injury

Gransee

Zhan

Sieck

et al. 2015

Journal of Neurotrauma

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116

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Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are important in modulating neuroplasticity and promoting recovery after spinal cord injury. Intrathecal delivery of BDNF enhances functional recovery following unilateral spinal cord hemisection (SH) at C2, a well-established model of incomplete cervical spinal cord injury. We hypothesized that localized delivery of BDNF-expressing mesenchymal stem cells (BDNF-MSCs) would promote functional recovery of rhythmic diaphragm activity after SH. In adult rats, bilateral diaphragm electromyographic (EMG) activity was chronically monitored to determine evidence of complete SH at 3 days post-injury, and recovery of rhythmic ipsilateral diaphragm EMG activity over time post-SH. Wild-type, bone marrow-derived MSCs (WT-MSCs) or BDNF-MSCs (2 · 10 5 cells) were injected intraspinally at C2 at the time of injury. At 14 days post-SH, green fluorescent protein (GFP) immunoreactivity confirmed MSCs presence in the cervical spinal cord. Functional recovery in SH animals injected with WT-MSCs was not different from untreated SH controls (n = 10; overall, 20% at 7 days and 30% at 14 days). In contrast, functional recovery was observed in 29% and 100% of SH animals injected with BDNF-MSCs at 7 days and 14 days post-SH, respectively (n = 7). In BDNF-MSCs treated SH animals at 14 days, root-mean-squared EMG amplitude was 63 -16% of the pre-SH value compared with 12 -9% in the control/WT-MSCs group. We conclude that localized delivery of BDNF-expressing MSCs enhances functional recovery of diaphragm muscle activity following cervical spinal cord injury. MSCs can be used to facilitate localized delivery of trophic factors such as BDNF in order to promote neuroplasticity following spinal cord injury.

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Section: Introductionmentioning

confidence: 99%

Localized Delivery of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Enhances Functional Recovery following Cervical Spinal Cord Injury

Gransee

Zhan

Sieck

et al. 2015

Journal of Neurotrauma

Self Cite

116

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“…mRNA may not necessarily translate to a similar difference at the protein level. However, it is shown that p75NTR appears not to have an undoubtedly distinct role following SCI but instead is a 'modifier' protein that is necessary for the maintenance of the balance between survival and death depending on the ratio of pro-natriuretic peptides (NTs) to mature NTs, 6 recruiting diverse intracellular-binding proteins and co-receptors, 18 the type of injury, 12 the cell type affected, 10,12,15,17 and the location from the site of the injury. 1 This may explain alteration of mRNA expression of p75 in our study.…”

Section: Resultsmentioning

confidence: 99%

“…16 Evidence from other studies suggests that p75NTR expression is enhanced post-injury. 6,8,17 Most of these studies investigated mRNA expression rather than protein expression with partial chronological resolution. The main function of p75NTR however, remains elusive.…”

Section: Discussionmentioning

confidence: 99%

“…5 In con-controversial, because this receptor can exert different effects depending on the cellular context, the type of ligand bound to it, and the presence or absence of Trk receptor. [6][7][8] P75NTR is initially expressed very early in embryogenesis in cells derived from all three germinal layers and becomes progressively restricted to specific cell populations such as CNS and peripheral nervous system. The p75NTR expression is induced after pathological conditions in a wide variety of cell types.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Messenger RNA expression patterns of p75 neurotrophin receptor and tropomyosin-receptor-kinase A following spinal cord injury

Montazeri

Esmaeili

Miroliaei

et al. 2013

The Journal of Spinal Cord Medicine

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Background: Induction of p75 neurotrophin receptor (p75NTR) could be one of the first steps that initiate apoptotic cascade after injury, or it may indicate regeneration responses undertaken by the injured system, possibly in collaboration with resident tropomyosin-receptor-kinase (Trk). Objective: To measure quantitative changes in messenger RNA (mRNA) expression levels of p75NTR, Trk A, and caspase-9 in rat's injured spinal cord (SCI). The reciprocal interaction between Trk and p75NTR signaling pathways can dictate cellular responses to neurotrophins. p75NTR can regulate Trk-dependent responses, but the role of Trk in regulating p75NTR-dependent signaling is not well documented. Design: Using real-time polymerase chain reaction, this study analyzed changes in the mRNA abundance of the mentioned genes at 6, 24, and 72 hours and 7 and 10 days after SCI in adult male rats. SCI was induced at T9 level by transsection. Results: Results show a complicated temporal and spatial pattern of alteration with different degrees and direction (up-or down-regulation) in p75NTR, Trk A, and caspase-9 mRNA expression levels after SCI. The greatest variation was seen in center regions following SCI. This study shows that alteration in p75NTR, Trk A, and caspase-9 expression starts as early as 6 hours after SCI. Alterations in p75NTR, Trk A, and caspase-9 expression within the spinal cord may play a key role in the apoptotic cell death. Conclusion: Results suggest that the role of p75NTR is to eliminate damaged cells by activating the apoptotic machinery, especially at the center of damage and during first week after injury.

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“…Neurotrophins have been known as a sort of promising agents that could be modulated functional neuroplasticity [6,7]. Among them, brain-derived neurotrophic factor (BD NF), binding with tropomyosin-related kinase receptor type B (TrkB), exhibited a positive effect to improve neuroplasticity following SCI [7].…”

Section: Reverse Transcription Pcrmentioning

confidence: 99%

BDNF Overexpression Exhibited Bilateral Effect on Neural Behavior in SCT Mice Associated with AKT Signal Pathway

et al. 2016

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Spinal cord injury (SCI), a severe health problem in worldwide, was commonly associated with functional disability and reduced quality of life. As the expression of brain-derived neurotrophic factor (BDNF) was substantial event in injured spinal cord, we hypothesized whether BDNF-overexpression could be in favor of the recovery of both sensory function and hindlimb function after SCI. By using BDNF-overexpression transgene mice [CMV-BDNF 26 (CB26) mice] we assessed the role of BDNF on the recovery of neurological behavior in spinal cord transection (SCT) model. BMS score and tail-flick test was performed to evaluate locomotor function and sensory function, respectively. Immunohistochemistry was employed to detect the location and the expression of BDNF, NeuN, 5-HT, GAP-43, GFAP as well as CGRP, and the level of p-AKT and AKT were examined through western blot analysis. BDNF overexpressing resulted in significant locomotor functional recovery from 21 to 28 days after SCT, compared with wild type (WT)+SCT group. Meanwhile, the NeuN, 5-HT and GAP-43 positive cells were markedly increased in ventral horn in BDNF overexpression animals, compared with WT mice with SCT. Moreover, the crucial molecular signal, p-AKT/AKT has been largely up-regulated, which is consistent with the improvement of locomotor function. However, in this study, thermal hyperpathia encountered in sham (CB26) group and WT+SCT mice and further aggravated in CB26 mice after SCT. Also, following SCT, the significant augment of positive-GFAP astrocytes and CGRP fibers were found in WT+SCT mice, and further increase was seen in BDNF over-expression transgene mice. BDNF-overexpression may not only facilitate the recovery of locomotor function via AKT pathway, but also contributed simultaneously to thermal hyperalgesia after SCT.

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Role of neurotrophins in recovery of phrenic motor function following spinal cord injury

Cited by 42 publications

References 95 publications

Localized Delivery of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Enhances Functional Recovery following Cervical Spinal Cord Injury

Localized Delivery of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Enhances Functional Recovery following Cervical Spinal Cord Injury

Messenger RNA expression patterns of p75 neurotrophin receptor and tropomyosin-receptor-kinase A following spinal cord injury

BDNF Overexpression Exhibited Bilateral Effect on Neural Behavior in SCT Mice Associated with AKT Signal Pathway

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