Voluntary wheel running delays disease onset and reduces pain hypersensitivity in early experimental autoimmune encephalomyelitis (EAE)

Benson, Curtis; Paylor, John W.; Tenorio, Gustavo; Winship, Ian R.; Baker, Glen B.; Kerr, Bradley J.

doi:10.1016/j.expneurol.2015.05.017

Cited by 59 publications

(61 citation statements)

References 52 publications

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“…1,6,14,15,42 Therefore, we investigated whether prior running normalized the expression of two neuroimmune signaling pathways in the dorsal spinal cord at 3 and 14 days after CCI.…”

Section: Resultsmentioning

confidence: 99%

“…1,6,7,12–15,18,31,34,42,54,60 Several studies have reported that neuroimmune signaling, processes that subserve neuropathic pain after nerve injury, 2,21 is suppressed in the neuraxis of rodents exercised after injury. For example, expression of activation markers for microglia (Iba1, CD11b) and astrocytes (GFAP) is decreased in the spinal dorsal horn, 1,6,15,31,42 while pro-inflammatory cytokines tumor necrosis factor and interleukin-1β (IL-1β) are downregulated in the brainstem and sciatic nerve. 7,12,13 Such pro-inflammatory cytokines are produced by reactive macrophages, microglia, and astrocytes, and increase neuroexcitability in nociceptive pathways (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Prior voluntary wheel running attenuates neuropathic pain

Grace

Fabisiak

Green‐Fulgham

et al. 2016

Pain

113

158

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Exercise is known to exert a systemic anti-inflammatory influence, but whether its effects are sufficient to protect against subsequent neuropathic pain is underinvestigated. We report that 6 weeks of voluntary wheel running terminating before chronic constriction injury (CCI) prevented the full development of allodynia for the ∼3-month duration of the injury. Neuroimmune signaling was assessed at 3 and 14 days after CCI. Prior exercise normalized ipsilateral dorsal spinal cord expression of neuroexcitatory interleukin (IL)-1β production and the attendant glutamate transporter GLT-1 decrease, as well as expression of the disinhibitory P2X4R-BDNF axis. The expression of the macrophage marker Iba1 and the chemokine CCL2 (MCP-1), and a neuronal injury marker (activating transcription factor 3), was attenuated by prior running in the ipsilateral lumbar dorsal root ganglia. Prior exercise suppressed macrophage infiltration and/or injury site proliferation, given decreased presence of macrophage markers Iba1, iNOS (M1), and Arg-1 (M2; expression was time dependent). Chronic constriction injury–driven increases in serum proinflammatory chemokines were suppressed by prior running, whereas IL-10 was increased. Peripheral blood mononuclear cells were also stimulated with lipopolysaccharide ex vivo, wherein CCI-induced increases in IL-1β, nitrite, and IL-10 were suppressed by prior exercise. Last, unrestricted voluntary wheel running, beginning either the day of, or 2 weeks after, CCI, progressively reversed neuropathic pain. This study is the first to investigate the behavioral and neuroimmune consequences of regular exercise terminating before nerve injury. This study suggests that chronic pain should be considered a component of “the diseasome of physical inactivity,” and that an active lifestyle may prevent neuropathic pain.

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“…1,6,14,15,42 Therefore, we investigated whether prior running normalized the expression of two neuroimmune signaling pathways in the dorsal spinal cord at 3 and 14 days after CCI.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prior voluntary wheel running attenuates neuropathic pain

Grace

Fabisiak

Green‐Fulgham

et al. 2016

Pain

113

158

View full text Add to dashboard Cite

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“…Furthermore, a transient vessel leak in the cortical gray matter has been described at the same time window [14]. Moreover, pain associated with microglia and astrocyte activation occurs in EAE prior to the onset of clinical signs [15, 16]. …”

Section: Introductionmentioning

confidence: 99%

Cytokine and chemokine alterations in tissue, CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis

Borjini

Fernández

Giardino

et al. 2016

J Neuroinflammation

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BackgroundExperimental allergic encephalomyelitis (EAE) is the most commonly used experimental animal model for human multiple sclerosis (MS) that has been used so far to study the acute and remission-relapsing phases of the disease. Despite the vast literature on neuroinflammation onset and progression in EAE, important questions are still open regarding in particular the early asymptomatic phase between immunization and clinical onset.MethodsIn this study, we performed a time-course investigation of neuroinflammation and demyelination biomarkers in the spinal cord (SC), cerebrospinal fluid (CSF), and blood in EAE induced in dark agouti (DA) female rats compared to the controls and adjuvant-injected rats, using high-throughput technologies for gene expression and protein assays and focusing on the time-course between immunization, clinical onset (1, 5, 8 days post-immunization (DPI)), and progression (11 and 18 DPI). The expression profile of 84 genes related to T cell activation/signaling, adaptive immunity, cytokine/chemokine inflammation, demyelination, and cellular stress were analyzed in the tissue; 24 cytokines were measured in the CSF and plasma.ResultsThe macrophage colony-stimulating factor (CSF1) was the first up-regulated protein as far as 1 DPI, not only in blood but also in CSF and SC. A treatment with GW2580, a selective CSF1R inhibitor, slowed the disease progression, significantly reduced the severity, and prevented the relapse phase. Moreover, both pro-inflammatory (IL-1β, TNF-α) and anti-inflammatory cytokines (IL-5, IL-10, VEGF) were up-regulated starting from 8 DPI. Myelin genes were down-regulated starting from 8 DPI, especially MAL, MBP, and PMP22 while an opposite expression profile was observed for inflammation-related genes, such as CXCL11 and CXCL10.ConclusionsThis early cytokine and chemokine regulation indicates that novel biomarkers and therapeutic options could be explored in the asymptomatic phase of EAE. Overall, our findings provide clear evidence that CSF1R signaling regulates inflammation in EAE, supporting therapeutic targeting of CSF1R in MS.

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“…We have previously shown that voluntary running serves as a measure of evoked pain (Grace et al, 2014b). Furthermore, voluntary wheel running may confound study of EAE, as movement has been shown to both attenuate (Benson et al, 2015) and exacerbate disease progression (Arima et al, 2012). Nonetheless, we propose that it may also serve as a measure of fatigue or lethargy in EAE (induced by the sickness response (Harden et al, 2011; Ray et al, 2011)), as voluntary running declined to nearly zero before the onset of motor symptoms or neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy

Grace

Loram

Christianson

et al. 2017

Brain, Behavior, and Immunity

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Relapsing-remitting multiple sclerosis is commonly associated with motor impairments, neuropathic pain, fatigue, mood disorders, and decreased life expectancy. However, preclinical pharmacological studies predominantly rely on clinical scoring of motor deficit as the sole behavioral endpoint. Thus, the translational potential of these studies is limited. Here, we have assessed the therapeutic potential of a novel anti-inflammatory interleukin-10 (IL-10) non-viral gene therapy formulation (XT-101-R) in a rat relapsing remitting experimental autoimmune encephalomyelitis (EAE) model. EAE induced motor deficits and neuropathic pain as reflected by induction of low-threshold mechanical allodynia, suppressed voluntary wheel running, decreased social exploration, and was associated with markedly enhanced mortality. We also noted that voluntary wheel running was depressed prior to the onset of motor deficit, and may therefore serve as a predictor of clinical symptoms onset. XT-101-R was intrathecally dosed only once at the onset of motor deficits, and attenuated each of the EAE-induced symptoms and improved survival, relative to vehicle control. This is the first pharmacological assessment of such a broad range of EAE symptoms, and provides support for IL-10 gene therapy as a clinical strategy for the treatment of multiple sclerosis.

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Voluntary wheel running delays disease onset and reduces pain hypersensitivity in early experimental autoimmune encephalomyelitis (EAE)

Cited by 59 publications

References 52 publications

Prior voluntary wheel running attenuates neuropathic pain

Prior voluntary wheel running attenuates neuropathic pain

Cytokine and chemokine alterations in tissue, CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis

Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy

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