Exercise, Neurotrophins, and Axon Regeneration in the PNS

English, Arthur W.; Wilhelm, Jennifer C.; Ward, Patricia J.

doi:10.1152/physiol.00028.2014

Cited by 56 publications

(62 citation statements)

References 83 publications

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“…An effective way to create an optimal microenvironment for nerve repair is supplying GFs and cytokines to the injured site [54]. NGF and bFGF, two extensively studied GFs of the neurotrophin family, have been shown to accelerate morphological and functional recovery in PNI and neurological disease [55]. Although both GFs can be endogenously synthesized and secreted by denervated neurons and SCs, their low expression levels are unable to induce survival and regrowth of damaged nerves [56,57].…”

Section: Discussionmentioning

confidence: 99%

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

et al. 2018

Biomaterials

185

121

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Peripheral nerve injury (PNI) is a major burden to society with limited therapeutic options, and novel biomaterials have great potential for shifting the current paradigm of treatment. With a rising prevalence of chronic illnesses such as diabetes mellitus (DM), treatment of PNI is further complicated, and only few studies have proposed therapies suitable for peripheral nerve regeneration in DM. To provide a supportive environment to restore structure and/or function of nerves in DM, we developed a novel thermo-sensitive heparin-poloxamer (HP) hydrogel co-delivered with basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) in diabetic rats with sciatic nerve crush injury. The delivery vehicle not only had a good affinity for large amounts of growth factors (GFs), but also controlled their release in a steady fashion, preventing degradation in vitro. In vivo, compared with HP hydrogel alone or direct GFs administration, GFs-HP hydrogel treatment is more effective at facilitating Schwann cell (SC) proliferation, leading to an increased expression of nerve associated structural proteins, enhanced axonal regeneration and remyelination, and improved recovery of motor function (all p<0.05). Our mechanistic investigation also revealed that these neuroprotective and neuroregenerative effects of the GFs-HP hydrogel may be associated with activations of phosphatidylinositol 3 kinase and protein kinase B (PI3K/Akt), janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways. Our work provides a promising therapy option for peripheral nerve regeneration in patients with DM.

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Section: Discussionmentioning

confidence: 99%

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

et al. 2018

Biomaterials

185

121

View full text Add to dashboard Cite

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“…It is also a potent neuromodulator that significantly impacts synaptic strength in the spinal cord. 242 It can be produced in an activity-dependent manner by a variety of nonneuronal cells in the nervous system including Schwann cells in the periphery and microglia in the dorsal horn of the spinal cord, which contribute to robust nerve regeneration 243 and nociception, respectively. 244 An important pathway for transducing the effect of locomotor training is de novo BDNF synthesis.…”

Section: From Step-training Dependent Plasticity To Functional Recovementioning

confidence: 99%

Rehabilitation Strategies after Spinal Cord Injury: Inquiry into the Mechanisms of Success and Failure

Côté

Murray

Lemay

2017

Journal of Neurotrauma

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Body-weight supported locomotor training (BWST) promotes recovery of load-bearing stepping in lower mammals, but its efficacy in individuals with a spinal cord injury (SCI) is limited and highly dependent on injury severity. While animal models with complete spinal transections recover stepping with step-training, motor complete SCI individuals do not, despite similarly intensive training. In this review, we examine the significant differences between humans and animal models that may explain this discrepancy in the results obtained with BWST. We also summarize the known effects of SCI and locomotor training on the muscular, motoneuronal, interneuronal, and supraspinal systems in human and non-human models of SCI and address the potential causes for failure to translate to the clinic. The evidence points to a deficiency in neuronal activation as the mechanism of failure, rather than muscular insufficiency. While motoneuronal and interneuronal systems cannot be directly probed in humans, the changes brought upon by step-training in SCI animal models suggest a beneficial re-organization of the systems' responsiveness to descending and afferent feedback that support locomotor recovery. The literature on partial lesions in humans and animal models clearly demonstrate a greater dependency on supraspinal input to the lumbar cord in humans than in non-human mammals for locomotion. Recent results with epidural stimulation that activates the lumbar interneuronal networks and/or increases the overall excitability of the locomotor centers suggest that these centers are much more dependent on the supraspinal tonic drive in humans. Sensory feedback shapes the locomotor output in animal models but does not appear to be sufficient to drive it in humans.

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“…Levels of neurotrophins, particularly BDNF, are significantly elevated in response to exercise, 23,50,51 with the increase being dependent on exercise intensity. 27,70 BDNF, unlike other neurotrophins, seems to be especially susceptible to regulation by activity, for both its expression and release, 9,34,38,41,48,64,71 whereas NGF secretion remains constitutive after activity.…”

Section: Possible Effects Of Exercise Intensity On Neurotrophins Exprmentioning

confidence: 99%

Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury

López-Alvarez

Mòdol²,

Navarro³

et al. 2015

Pain

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Activity treatments, such as treadmill exercise, are used to improve functional recovery after nerve injury, parallel to an increase in neurotrophin levels. However, despite their role in neuronal survival and regeneration, neurotrophins may cause neuronal hyperexcitability that triggers neuropathic pain. In this work, we demonstrate that an early increasing-intensity treadmill exercise (iTR), performed during the first week (iTR1) or during the first 2 weeks (iTR2) after section and suture repair of the rat sciatic nerve, significantly reduced the hyperalgesia developing rapidly in the saphenous nerve territory and later in the sciatic nerve territory after regeneration. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in sensory neurons and spinal cord was reduced in parallel. iTR prevented the extension of collateral sprouts of saphenous nociceptive calcitonin gene-related peptide fibers within the adjacent denervated skin and reduced NGF expression in the same skin and in the L3 dorsal root ganglia (DRG). Injury also induced Na⁺-K⁺-2Cl⁻ cotransporter 1 (NKCC1) upregulation in DRG, and K⁺-Cl⁻ cotransporter 2 (KCC2) downregulation in lumbar spinal cord dorsal horn. iTR normalized NKCC1 and boosted KCC2 expression, together with a significant reduction of microgliosis in L3-L5 dorsal horn, and a reduction of BDNF expression in microglia at 1 to 2 weeks postinjury. These data demonstrate that specific activity protocols, such as iTR, can modulate neurotrophins expression after peripheral nerve injury and prevent neuropathic pain by blocking early mechanisms of sensitization such as collateral sprouting and NKCC1/KCC2 disregulation.

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Exercise, Neurotrophins, and Axon Regeneration in the PNS

Cited by 56 publications

References 83 publications

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

Rehabilitation Strategies after Spinal Cord Injury: Inquiry into the Mechanisms of Success and Failure

Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury

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