Establishment and characterization of an optimized mouse model of multiple sclerosis-induced neuropathic pain using behavioral, pharmacologic, histologic and immunohistochemical methods

Khan, Nemat; Woodruff, Trent M.; Smith, Maree T.

doi:10.1016/j.pbb.2014.09.003

Cited by 37 publications

(86 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our optimized RR‐EAE mouse model of MS‐associated neuropathic pain is novel and it is devoid of confounding motor deficits in the hindpaws (Khan et al. ). Briefly, mice were immunized with 200 μ g of MOG 35‐55 (Mimotopes, Clayton, Victoria, Australia) mixed with a solution of Quil A (45 μ g) in 100 μ L of phosphate‐buffered saline (PBS) (Sigma‐Aldrich, Sydney, New South Wales, Australia).…”

Section: Methodsmentioning

confidence: 99%

“…injection of pertussis toxin at 250 ng (Sigma‐Aldrich) in PBS (1 ng μ L −1 ) and this was repeated 48 h later (Khan et al. ). Sham‐mice (control group) received adjuvants only (Quil A and pertussis toxin).…”

Section: Methodsmentioning

confidence: 99%

“…). By contrast, neuropathic pain behaviors in rodent models of CNP are associated with pathobiologic mechanisms in sensory neurons in the dorsal horn (laminae I–II) of the spinal cord (Khan et al ; Watson et al ). Recommended drug treatments for the relief of peripheral neuropathic pain conditions (Dworkin et al.…”

Section: Introductionmentioning

confidence: 99%

“…Hence, the present work was designed to assess the potential pain‐relieving efficacy and mode of action of ALA administered chronically according to an intervention protocol, using an optimized relapsing‐remitting experimental autoimmune encephalomyelitis (RR‐EAE) mouse model of MS‐induced neuropathic pain developed by our group (Khan et al. ). Notably, our findings are novel showing that once‐daily subcutaneous (s.c.) administration of ALA at 3 or 10 mg kg −1 to RR‐EAE mice for 21 consecutive days, evoked dose‐dependent alleviation of mechanical hypersensitivity in the bilateral hindpaws.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Antiallodynic effects of alpha lipoic acid in an optimized RR‐EAE mouse model of MS‐neuropathic pain are accompanied by attenuation of upregulated BDNF‐TrkB‐ERK signaling in the dorsal horn of the spinal cord

Khan

Gordon

Woodruff

et al. 2015

Pharmacology Res & Perspec

Self Cite

View full text Add to dashboard Cite

Neuropathic pain may affect patients with multiple sclerosis (MS) even in early disease. In an experimental autoimmune encephalomyelitis (EAE)-mouse model of MS, chronic alpha lipoic acid (ALA) treatment reduced clinical disease severity, but MS-neuropathic pain was not assessed. Hence, we investigated the pain-relieving efficacy and mode of action of ALA using our optimized relapsing-remitting (RR)-EAE mouse model of MS-associated neuropathic pain. C57BL/6 mice were immunized with MOG35-55 and adjuvants (Quil A and pertussis toxin) to induce RR-EAE; sham-mice received adjuvants only. RR-EAE mice received subcutaneous ALA (3 or 10 mg kg−1 day−1) or vehicle for 21 days (15–35 d.p.i.; [days postimmunization]); sham-mice received vehicle. Hindpaw hypersensitivity was assessed blinded using von Frey filaments. Following euthanasia (day 35 d.p.i.), lumbar spinal cords were removed for immunohistochemical and molecular biological assessments. Fully developed mechanical allodynia in the bilateral hindpaws of vehicle-treated RR-EAE mice was accompanied by marked CD3+ T-cell infiltration, microglia activation, and increased brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling in the dorsal horn of the lumbar spinal cord. Consequently, phospho-ERK, a marker of central sensitization in neuropathic pain, was upregulated in the spinal dorsal horn. Importantly, hindpaw hypersensitivity was completely attenuated in RR-EAE mice administered ALA at 10 mg kg−1 day−1 but not 3 mg kg−1 day−1. The antiallodynic effect of ALA (10 mg kg−1 day−1) was associated with a marked reduction in the aforementioned spinal dorsal horn markers to match their respective levels in the vehicle-treated sham-mice. Our findings suggest that ALA at 10 mg kg−1 day−1 produced its antiallodynic effects in RR-EAE mice by reducing augmented CD3+ T-cell infiltration and BDNF-TrkB-ERK signaling in the spinal dorsal horn.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Antiallodynic effects of alpha lipoic acid in an optimized RR‐EAE mouse model of MS‐neuropathic pain are accompanied by attenuation of upregulated BDNF‐TrkB‐ERK signaling in the dorsal horn of the spinal cord

Khan

Gordon

Woodruff

et al. 2015

Pharmacology Res & Perspec

Self Cite

View full text Add to dashboard Cite

show abstract

“…We also found that other behaviors were associated with EAE, including mechanical allodynia (reflecting neuropathic pain), decreased voluntary wheel running (reflecting fatigue and motor impairments), and decreased social exploration (reflecting anxiety). These symptoms are rarely assessed in rodent models, despite their frequent association with MS. Assessment of nociceptive hypersensitivity in relapsing remitting models is limited, but several studies have demonstrated pharmacological reversal of allodynia (Khan et al, 2014; Lu et al, 2012; Lynch et al, 2008; Ramos et al, 2010; Schmitz et al, 2014; Sloane et al, 2009; Thibault et al, 2011; Tian et al, 2013). While anxiety behaviors are a known feature in EAE models (Acharjee et al, 2013; Peruga et al, 2011; Pollak et al, 2000), only two studies have evaluated therapeutic modulation (Di Prisco et al, 2014; Haji et al, 2012).…”

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

View full text Add to dashboard Cite

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.

show abstract

Multiparametric magnetic resonance imaging for detection of pathological changes in the central nervous system of a mouse model of multiple sclerosis in vivo

et al. 2023

Self Cite

View full text Add to dashboard Cite

Multiple sclerosis (MS) is an autoimmune disease involving demyelination and axonal damage in the central nervous system (CNS). In this study, we investigated pathological changes in the lumbar spinal cord of C57BL/6 mice induced with progressive experimental autoimmune encephalomyelitis (EAE) disease using 9.4‐T magnetic resonance imaging (MRI). Multiparametric MRI measurements including MR spectroscopy, diffusion tensor imaging (DTI) and volumetric analyses were applied to detect metabolic changes in the CNS of EAE mice. Compared with healthy mice, EAE mice showed a significant reduction in N‐acetyl aspartate and increases in choline, glycine, taurine and lactate. DTI revealed a significant reduction in fractional anisotropy and axial diffusivity and an increase in radial diffusivity in the lumbar spinal cord white matter (WM), while in the grey matter (GM), fractional anisotropy increased. High‐resolution structural imaging also revealed lumbar spinal cord WM hypertrophy and GM atrophy. Importantly, these MRI changes were strongly correlated with EAE disease scoring and pathological changes in the lumbar (L2–L6), particularly WM demyelination lesions and aggregation of immune cells (microglia/macrophages and astrocytes) in this region. This study identified changes in MRI biomarker signatures that can be useful for evaluating the efficacy of novel drugs using EAE models in vivo.

show abstract

Establishment and characterization of an optimized mouse model of multiple sclerosis-induced neuropathic pain using behavioral, pharmacologic, histologic and immunohistochemical methods

Cited by 37 publications

References 65 publications

Antiallodynic effects of alpha lipoic acid in an optimized RR‐EAE mouse model of MS‐neuropathic pain are accompanied by attenuation of upregulated BDNF‐TrkB‐ERK signaling in the dorsal horn of the spinal cord

Antiallodynic effects of alpha lipoic acid in an optimized RR‐EAE mouse model of MS‐neuropathic pain are accompanied by attenuation of upregulated BDNF‐TrkB‐ERK signaling in the dorsal horn of the spinal cord

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

Multiparametric magnetic resonance imaging for detection of pathological changes in the central nervous system of a mouse model of multiple sclerosis in vivo

Contact Info

Product

Resources

About