Acute intermittent hypoxia enhances regeneration of surgically repaired peripheral nerves in a manner akin to electrical stimulation

Nadeau, J.R.; Arnold, Breanna M.; Johnston, Jayne M.; Muir, Gillian D.; Verge, Valerie M. K.

doi:10.1016/j.expneurol.2021.113671

Cited by 7 publications

(11 citation statements)

References 85 publications

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“…Mechanisms responsible for the AIH‐induced positive reparative outcomes are unknown, but likely involve AIH's ability to induce plasticity and increase neural activity (Lovett‐Barr et al, 2012; Navarrete‐Opazo et al, 2017) shown to benefit repair of focally demyelinated nervous tissue (Ayanwuyi et al, 2022; McLean et al, 2014; McLean & Verge, 2016). Elevated expression of early gene molecules induced by the increased neural activity associated with ES or AIH include brain‐derived neurotrophic factor (BDNF) and HIF1α, molecules which promote nervous system plasticity, repair and myelination (Baker‐Herman et al, 2004; Cho et al, 2015; Fletcher et al, 2018; Geremia et al, 2010; McLean et al, 2014; Miron et al, 2013; Nadeau et al, 2021; Yuen et al, 2014). Expression levels of BDNF and HIF1α in EAE mice 7d after the last AIH treatment were not discernibly different from the Normoxia group, as these inductive signals are transient and no longer at heightened levels (data not shown), a response seen in AIH SCI and nerve regeneration studies (Geremia et al, 2007; Hassan et al, 2018; Nadeau et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it is excellent that we find AIH effects significant repair in the absence of adjunct training, which also supports that it may exert positive outcomes in progressive forms of MS. Finally, the treatment paradigm employed parallels that employed in humans and falls within the optimal beneficial range of intermittent hypoxemia coupled with a low number of episodes/day shown to induce plasticity and repair (Nadeau et al, 2021; Navarrete‐Opazo et al, 2017; Navarrete‐Opazo & Mitchell, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…During treatment mice were placed in plexiglass chambers. AIH was performed under automated control as previously described (Nadeau et al, 2021). Briefly, chambers received continuous flow of medical air (21% O 2 ) for 5 min alternating with hypoxic air (11% O 2 ) for 5 min with a 1 min purge with O 2 levels for the next cycle condition in between.…”

Section: Acute Intermittent Hypoxia (Aih)mentioning

confidence: 99%

“…Acute intermittent hypoxia (AIH; intermittent periods of reduced oxygen) is an emerging non‐invasive therapy that improves outcomes in spinal cord and peripheral nerve injured subjects (Lovett‐Barr et al, 2012; Nadeau et al, 2021; Prosser‐Loose et al, 2015). We find AIH has a similar molecular signature to ES with respect to plasticity‐associated gene expression, peripheral nerve regeneration and remyelination (Nadeau et al, 2021). The impact on repair and remyelination are likely due to AIH's ability to also increase neural activity in both rodent models and humans (Christiansen et al, 2018; Dale‐Nagle et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Acute intermittent hypoxia alters disease course and promotes CNS repair including resolution of inflammation and remyelination in the experimental autoimmune encephalomyelitis model of MS

Tokarska

Naniong

Johnston

et al. 2023

Glia

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Remyelination and neurodegeneration prevention mitigate disability in Multiple Sclerosis (MS). We have shown acute intermittent hypoxia (AIH) is a novel, non‐invasive and effective therapy for peripheral nerve repair, including remyelination. Thus, we posited AIH would improve repair following CNS demyelination and address the paucity of MS repair treatments. AIH's capacity to enhance intrinsic repair, functional recovery and alter disease course in the experimental autoimmune encephalomyelitis (EAE) model of MS was assessed. EAE was induced by MOG35‐55 immunization in C57BL/6 female mice. EAE mice received either AIH (10 cycles—5 min 11% oxygen alternating with 5 min 21% oxygen) or Normoxia (control; 21% oxygen for same duration) once daily for 7d beginning at near peak EAE disease score of 2.5. Mice were followed post‐treatment for an additional 7d before assessing histopathology or 14d to examine maintenance of AIH effects. Alterations in histopathological correlates of multiple repair indices were analyzed quantitatively in focally demyelinated ventral lumbar spinal cord areas to assess AIH impacts. AIH begun at near peak disease significantly improved daily clinical scores/functional recovery and associated histopathology relative to Normoxia controls and the former were maintained for at least 14d post‐treatment. AIH enhanced correlates of myelination, axon protection and oligodendrocyte precursor cell recruitment to demyelinated areas. AIH also effected a dramatic reduction in inflammation, while polarizing remaining macrophages/microglia toward a pro‐repair state. Collectively, this supports a role for AIH as a novel non‐invasive therapy to enhance CNS repair and alter disease course following demyelination and holds promise as a neuroregenerative MS strategy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Acute Intermittent Hypoxia (Aih)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Acute intermittent hypoxia alters disease course and promotes CNS repair including resolution of inflammation and remyelination in the experimental autoimmune encephalomyelitis model of MS

Tokarska

Naniong

Johnston

et al. 2023

Glia

View full text Add to dashboard Cite

show abstract

“…The action potentials between neurons are conducted by axons, therefore, axonal regeneration and reconnection play a central role in poststroke recovery. In the central nervous system, the influence of RIC on axonal regeneration has not been tested yet, but encouraging results confirmed that hypoxic conditioning significantly increased the numbers of thinly myelinated regenerating axons in surgically repaired peripheral nerves 53 . Axon sprouting can be enhanced or limited by several transcription factors, cytokines, chemokines, growth factors, and other molecules.…”

Section: Evaluation Of the Hypothesismentioning

confidence: 99%

A review of remote ischemic conditioning as a potential strategy for neural repair poststroke

Ren

2022

CNS Neurosci Ther

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Ischemic stroke is one of the major disabling health‐care problem and multiple different approaches are needed to enhance rehabilitation, in which neural repair is the structural basement. Remote ischemic conditioning (RIC) is a strategy to trigger endogenous protect. RIC has been reported to play neuroprotective role in acute stage of stroke, but the effect of RIC on repair process remaining unclear. Several studies have discovered some overlapped mechanisms RIC and neural repair performs. This review provides a hypothesis that RIC is a potential therapeutic strategy on stroke rehabilitation by evaluating the existing evidence and puts forward some remaining questions to clarify and future researches to be performed in the field.

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The Hypoxia Response Pathway: A Potential Intervention Target in Parkinson's Disease?

Janssen Daalen,

Koopman,

Saris

et al. 2023

Movement Disorders

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Parkinson's disease (PD) is a progressive neurodegenerative disorder for which only symptomatic treatments are available. Both preclinical and clinical studies suggest that moderate hypoxia induces evolutionarily conserved adaptive mechanisms that enhance neuronal viability and survival. Therefore, targeting the hypoxia response pathway might provide neuroprotection by ameliorating the deleterious effects of mitochondrial dysfunction and oxidative stress, which underlie neurodegeneration in PD. Here, we review experimental studies regarding the link between PD pathophysiology and neurophysiological adaptations to hypoxia. We highlight the mechanistic differences between the rescuing effects of chronic hypoxia in neurodegeneration and short‐term moderate hypoxia to improve neuronal resilience, termed “hypoxic conditioning”. Moreover, we interpret these preclinical observations regarding the pharmacological targeting of the hypoxia response pathway. Finally, we discuss controversies with respect to the differential effects of hypoxia response pathway activation across the PD spectrum, as well as intervention dosing in hypoxic conditioning and potential harmful effects of such interventions. We recommend that initial clinical studies in PD should focus on the safety, physiological responses, and mechanisms of hypoxic conditioning, as well as on repurposing of existing pharmacological compounds. © 2023 International Parkinson and Movement Disorder Society.

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Acute intermittent hypoxia enhances regeneration of surgically repaired peripheral nerves in a manner akin to electrical stimulation

Cited by 7 publications

References 85 publications

Acute intermittent hypoxia alters disease course and promotes CNS repair including resolution of inflammation and remyelination in the experimental autoimmune encephalomyelitis model of MS

Acute intermittent hypoxia alters disease course and promotes CNS repair including resolution of inflammation and remyelination in the experimental autoimmune encephalomyelitis model of MS

A review of remote ischemic conditioning as a potential strategy for neural repair poststroke

The Hypoxia Response Pathway: A Potential Intervention Target in Parkinson's Disease?

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