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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 N, Gordon R, Woodruff TM, Smith MT - Pharmacol Res Perspect (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Integrated Preclinical Drug Development, University of Queensland St Lucia Campus, Brisbane, Queensland, 4072, Australia ; School of Pharmacy, University of Queensland, Pharmacy Australia Center of Excellence Woolloongabba, Brisbane, Queensland, 4102, Australia.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

In the dorsal horn of lumbar (L4-L6) spinal cord of vehicle-treated RR-EAE mice, BDNF is colocalized predominantly with (A) CD3+ T cells. It is also colocalized with a subset of (B) neurons (NeuN) and to a lesser extent with (C) microglia/macrophages (CD11b) and (D) minimally with astrocytes (GFAP). Scale bars represent 20 μm.
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fig06: In the dorsal horn of lumbar (L4-L6) spinal cord of vehicle-treated RR-EAE mice, BDNF is colocalized predominantly with (A) CD3+ T cells. It is also colocalized with a subset of (B) neurons (NeuN) and to a lesser extent with (C) microglia/macrophages (CD11b) and (D) minimally with astrocytes (GFAP). Scale bars represent 20 μm.

Mentions: Our data showing concurrent increases in pERK and pro-BDNF expression levels in vehicle-treated RR-EAE mice (Figs.4) are aligned with previous work by others showing that concentration-dependent activation of TrkB by pro-BDNF, albeit with lower affinity than mature-BDNF, elicits prototypical TrkB downstream signaling including ERK activation (Fayard et al. 2005; Boutilier et al. 2008; Sakuragi et al. 2013). As pERK is regarded as a marker of central sensitization in peripheral neuropathic pain conditions (Zhuang et al. 2005; Gao and Ji 2009), it may also have a pathobiologic role in CNP conditions such as MS-associated neuropathic pain. In vehicle-treated RR-EAE mice herein, upregulated expression levels of BDNF, TrkB, and pERK were colocalized primarily with infiltrated CD3+ T cells in the lumbar spinal dorsal horn. These markers were also colocalized with subsets of neurons and to a lesser extent with microglia/macrophages. However, there was minimal colocalization with astrocytes for BDNF and TrkB (Figs.6, 8). Hence, it is plausible that augmented levels of pro-BDNF signaling, at least in part, via full-length TrkB to increase pERK expression levels in the spinal dorsal horn of vehicle-treated RR-EAE mice, may contribute to the development of hindpaw hypersensitivity in these mice.


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 N, Gordon R, Woodruff TM, Smith MT - Pharmacol Res Perspect (2015)

In the dorsal horn of lumbar (L4-L6) spinal cord of vehicle-treated RR-EAE mice, BDNF is colocalized predominantly with (A) CD3+ T cells. It is also colocalized with a subset of (B) neurons (NeuN) and to a lesser extent with (C) microglia/macrophages (CD11b) and (D) minimally with astrocytes (GFAP). Scale bars represent 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492753&req=5

fig06: In the dorsal horn of lumbar (L4-L6) spinal cord of vehicle-treated RR-EAE mice, BDNF is colocalized predominantly with (A) CD3+ T cells. It is also colocalized with a subset of (B) neurons (NeuN) and to a lesser extent with (C) microglia/macrophages (CD11b) and (D) minimally with astrocytes (GFAP). Scale bars represent 20 μm.
Mentions: Our data showing concurrent increases in pERK and pro-BDNF expression levels in vehicle-treated RR-EAE mice (Figs.4) are aligned with previous work by others showing that concentration-dependent activation of TrkB by pro-BDNF, albeit with lower affinity than mature-BDNF, elicits prototypical TrkB downstream signaling including ERK activation (Fayard et al. 2005; Boutilier et al. 2008; Sakuragi et al. 2013). As pERK is regarded as a marker of central sensitization in peripheral neuropathic pain conditions (Zhuang et al. 2005; Gao and Ji 2009), it may also have a pathobiologic role in CNP conditions such as MS-associated neuropathic pain. In vehicle-treated RR-EAE mice herein, upregulated expression levels of BDNF, TrkB, and pERK were colocalized primarily with infiltrated CD3+ T cells in the lumbar spinal dorsal horn. These markers were also colocalized with subsets of neurons and to a lesser extent with microglia/macrophages. However, there was minimal colocalization with astrocytes for BDNF and TrkB (Figs.6, 8). Hence, it is plausible that augmented levels of pro-BDNF signaling, at least in part, via full-length TrkB to increase pERK expression levels in the spinal dorsal horn of vehicle-treated RR-EAE mice, may contribute to the development of hindpaw hypersensitivity in these mice.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Integrated Preclinical Drug Development, University of Queensland St Lucia Campus, Brisbane, Queensland, 4072, Australia ; School of Pharmacy, University of Queensland, Pharmacy Australia Center of Excellence Woolloongabba, Brisbane, Queensland, 4102, Australia.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus