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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

Expression levels of mRNA for BDNF and TrkB in lumbar (L4-L6) spinal cord of RR-EAE mice administered either ALA at 10 mg kg−1 day−1 or vehicle for 3 weeks did not differ significantly (F(2,8) = 3.8; BDNF and F(2,7) = 3.59; P > 0.05) from the respective data for the lumbar spinal cord of vehicle-treated sham-mice (one-way ANOVA followed by Tukey’s multiple comparison test). EAE, experimental autoimmune encephalomyelitis, Veh, vehicle; ALA, alpha lipoic acid; BDNF, brain-derived neurotrophic factor; TrkB, tyrosine kinase B; ANOVA, analysis of variance.
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fig05: Expression levels of mRNA for BDNF and TrkB in lumbar (L4-L6) spinal cord of RR-EAE mice administered either ALA at 10 mg kg−1 day−1 or vehicle for 3 weeks did not differ significantly (F(2,8) = 3.8; BDNF and F(2,7) = 3.59; P > 0.05) from the respective data for the lumbar spinal cord of vehicle-treated sham-mice (one-way ANOVA followed by Tukey’s multiple comparison test). EAE, experimental autoimmune encephalomyelitis, Veh, vehicle; ALA, alpha lipoic acid; BDNF, brain-derived neurotrophic factor; TrkB, tyrosine kinase B; ANOVA, analysis of variance.

Mentions: Herein, we showed that for vehicle-treated RR-EAE mice with fully developed mechanical allodynia in the bilateral hindpaws, lumbar spinal dorsal horn expression levels of BDNF and TrkB were markedly increased compared with the corresponding expression levels in vehicle-treated sham-mice (Figs.4). However, lumbar spinal cord expression levels of mRNA for BDNF and TrkB in our RR-EAE-mouse model of MS-neuropathic pain did not differ significantly (P > 0.05) from the respective levels for vehicle-treated sham-mice (Fig.5). Our findings are aligned with reports by others of unchanged mRNA levels for BDNF and TrkB in the CNS of EAE mice exhibiting clinical disease (Zhu et al. 2012, 2014).


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)

Expression levels of mRNA for BDNF and TrkB in lumbar (L4-L6) spinal cord of RR-EAE mice administered either ALA at 10 mg kg−1 day−1 or vehicle for 3 weeks did not differ significantly (F(2,8) = 3.8; BDNF and F(2,7) = 3.59; P > 0.05) from the respective data for the lumbar spinal cord of vehicle-treated sham-mice (one-way ANOVA followed by Tukey’s multiple comparison test). EAE, experimental autoimmune encephalomyelitis, Veh, vehicle; ALA, alpha lipoic acid; BDNF, brain-derived neurotrophic factor; TrkB, tyrosine kinase B; ANOVA, analysis of variance.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig05: Expression levels of mRNA for BDNF and TrkB in lumbar (L4-L6) spinal cord of RR-EAE mice administered either ALA at 10 mg kg−1 day−1 or vehicle for 3 weeks did not differ significantly (F(2,8) = 3.8; BDNF and F(2,7) = 3.59; P > 0.05) from the respective data for the lumbar spinal cord of vehicle-treated sham-mice (one-way ANOVA followed by Tukey’s multiple comparison test). EAE, experimental autoimmune encephalomyelitis, Veh, vehicle; ALA, alpha lipoic acid; BDNF, brain-derived neurotrophic factor; TrkB, tyrosine kinase B; ANOVA, analysis of variance.
Mentions: Herein, we showed that for vehicle-treated RR-EAE mice with fully developed mechanical allodynia in the bilateral hindpaws, lumbar spinal dorsal horn expression levels of BDNF and TrkB were markedly increased compared with the corresponding expression levels in vehicle-treated sham-mice (Figs.4). However, lumbar spinal cord expression levels of mRNA for BDNF and TrkB in our RR-EAE-mouse model of MS-neuropathic pain did not differ significantly (P > 0.05) from the respective levels for vehicle-treated sham-mice (Fig.5). Our findings are aligned with reports by others of unchanged mRNA levels for BDNF and TrkB in the CNS of EAE mice exhibiting clinical disease (Zhu et al. 2012, 2014).

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