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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

Hindpaw hypersensitivity and clinical disease in our optimized RR-EAE mouse model of MS-induced neuropathic pain were progressively alleviated by once-daily administration of single s.c. bolus doses of ALA administered according to an intervention protocol at 15–35 d.p.i. (A, C) For vehicle-treated RR-EAE mice (Cohorts 1 and 2), mean (±SEM) hindpaw PWTs were significantly lower than those for vehicle-treated sham-mice (F(3,6,18/336 = 142.2, 73.43, 43.66; Cohort-1 and F(3,6,18/264 = 239.1, 25.11, 34.32; Cohort-2; P < 0.05). Chronic ALA treatment at 3 or 10 mg kg−1 day−1 (15–35 d.p.i.) evoked dose-dependent attenuation of hindpaw hypersensitivity in RR-EAE mice, whereas for vehicle-treated RR-EAE mice, mechanical allodynia was fully developed (PWTs ≤ 1 g) in the bilateral hindpaws from 26 d.p.i. onward (P < 0.05). After cessation of ALA-treatment (10 mg kg−1 day−1) at 35 d.p.i. in Cohort-2 RR-EAE mice, there was temporal development of mechanical allodynia in the bilateral hindpaws that was fully developed at study completion (55 d.p.i.). P < 0.05 (two way ANOVA, post hoc: Bonferroni). (B) and (D) For vehicle-treated RR-EAE mice (Cohorts 1 and 2), clinical disease onset was at 10–13 d.p.i. and it exhibited a relapsing-remitting profile (F(4,144 = 34.89; Cohort-1 and F(4,164 = 33.05; Cohort-2; P < 0.05). By contrast, vehicle-treated sham-mice did not exhibit EAE-clinical disease (mean ± SEM clinical score >1 a.u.). For both cohorts of RR-EAE mice, ALA at 10 mg kg−1 day−1 but not 3 mg kg−1 day−1 successfully prevented clinical disease relapse. After cessation of ALA-treatment (10 mg kg−1 day−1) at 35 d.p.i. in Cohort-2 RR-EAE mice, clinical disease recurred. The shaded areas on figure panels highlight the chronic ALA or vehicle treatment period (15–35 d.p.i.). *P < 0.05 (Kruskal–Wallis multiple comparison, post hoc: Dunn’s test). ALA, alpha lipoic acid; EAE, experimental autoimmune encephalomyelitis; PWT, Paw withdrawal threshold; p.i., postimmunization; Veh, vehicle. MS, multiple sclerosis.
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fig01: Hindpaw hypersensitivity and clinical disease in our optimized RR-EAE mouse model of MS-induced neuropathic pain were progressively alleviated by once-daily administration of single s.c. bolus doses of ALA administered according to an intervention protocol at 15–35 d.p.i. (A, C) For vehicle-treated RR-EAE mice (Cohorts 1 and 2), mean (±SEM) hindpaw PWTs were significantly lower than those for vehicle-treated sham-mice (F(3,6,18/336 = 142.2, 73.43, 43.66; Cohort-1 and F(3,6,18/264 = 239.1, 25.11, 34.32; Cohort-2; P < 0.05). Chronic ALA treatment at 3 or 10 mg kg−1 day−1 (15–35 d.p.i.) evoked dose-dependent attenuation of hindpaw hypersensitivity in RR-EAE mice, whereas for vehicle-treated RR-EAE mice, mechanical allodynia was fully developed (PWTs ≤ 1 g) in the bilateral hindpaws from 26 d.p.i. onward (P < 0.05). After cessation of ALA-treatment (10 mg kg−1 day−1) at 35 d.p.i. in Cohort-2 RR-EAE mice, there was temporal development of mechanical allodynia in the bilateral hindpaws that was fully developed at study completion (55 d.p.i.). P < 0.05 (two way ANOVA, post hoc: Bonferroni). (B) and (D) For vehicle-treated RR-EAE mice (Cohorts 1 and 2), clinical disease onset was at 10–13 d.p.i. and it exhibited a relapsing-remitting profile (F(4,144 = 34.89; Cohort-1 and F(4,164 = 33.05; Cohort-2; P < 0.05). By contrast, vehicle-treated sham-mice did not exhibit EAE-clinical disease (mean ± SEM clinical score >1 a.u.). For both cohorts of RR-EAE mice, ALA at 10 mg kg−1 day−1 but not 3 mg kg−1 day−1 successfully prevented clinical disease relapse. After cessation of ALA-treatment (10 mg kg−1 day−1) at 35 d.p.i. in Cohort-2 RR-EAE mice, clinical disease recurred. The shaded areas on figure panels highlight the chronic ALA or vehicle treatment period (15–35 d.p.i.). *P < 0.05 (Kruskal–Wallis multiple comparison, post hoc: Dunn’s test). ALA, alpha lipoic acid; EAE, experimental autoimmune encephalomyelitis; PWT, Paw withdrawal threshold; p.i., postimmunization; Veh, vehicle. MS, multiple sclerosis.

Mentions: RR-EAE mice received once-daily s.c. injections of ALA at 3 or 10 mg kg−1 day−1, or vehicle for 21 consecutive days commencing at 15 d.p.i., as the first episode of clinical disease had occurred in all EAE mice by day 15. Sham-control mice received once-daily s.c. vehicle injections for the same treatment period. Solutions of ALA or vehicle were prepared freshly each day and masked before administration to animals in a blinded manner. All drug treatments were administered between 09.00 am and 11.00 am. The total number of sham- and RR-EAE mice (in Cohorts 1 and 2) treated with vehicle or ALA is shown in Figure1. To maintain blinding, equal numbers of animals were included in each group. Animals were randomized in a blinded manner and received masked solutions of ALA or vehicle by the first person.


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)

Hindpaw hypersensitivity and clinical disease in our optimized RR-EAE mouse model of MS-induced neuropathic pain were progressively alleviated by once-daily administration of single s.c. bolus doses of ALA administered according to an intervention protocol at 15–35 d.p.i. (A, C) For vehicle-treated RR-EAE mice (Cohorts 1 and 2), mean (±SEM) hindpaw PWTs were significantly lower than those for vehicle-treated sham-mice (F(3,6,18/336 = 142.2, 73.43, 43.66; Cohort-1 and F(3,6,18/264 = 239.1, 25.11, 34.32; Cohort-2; P < 0.05). Chronic ALA treatment at 3 or 10 mg kg−1 day−1 (15–35 d.p.i.) evoked dose-dependent attenuation of hindpaw hypersensitivity in RR-EAE mice, whereas for vehicle-treated RR-EAE mice, mechanical allodynia was fully developed (PWTs ≤ 1 g) in the bilateral hindpaws from 26 d.p.i. onward (P < 0.05). After cessation of ALA-treatment (10 mg kg−1 day−1) at 35 d.p.i. in Cohort-2 RR-EAE mice, there was temporal development of mechanical allodynia in the bilateral hindpaws that was fully developed at study completion (55 d.p.i.). P < 0.05 (two way ANOVA, post hoc: Bonferroni). (B) and (D) For vehicle-treated RR-EAE mice (Cohorts 1 and 2), clinical disease onset was at 10–13 d.p.i. and it exhibited a relapsing-remitting profile (F(4,144 = 34.89; Cohort-1 and F(4,164 = 33.05; Cohort-2; P < 0.05). By contrast, vehicle-treated sham-mice did not exhibit EAE-clinical disease (mean ± SEM clinical score >1 a.u.). For both cohorts of RR-EAE mice, ALA at 10 mg kg−1 day−1 but not 3 mg kg−1 day−1 successfully prevented clinical disease relapse. After cessation of ALA-treatment (10 mg kg−1 day−1) at 35 d.p.i. in Cohort-2 RR-EAE mice, clinical disease recurred. The shaded areas on figure panels highlight the chronic ALA or vehicle treatment period (15–35 d.p.i.). *P < 0.05 (Kruskal–Wallis multiple comparison, post hoc: Dunn’s test). ALA, alpha lipoic acid; EAE, experimental autoimmune encephalomyelitis; PWT, Paw withdrawal threshold; p.i., postimmunization; Veh, vehicle. MS, multiple sclerosis.
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Related In: Results  -  Collection

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fig01: Hindpaw hypersensitivity and clinical disease in our optimized RR-EAE mouse model of MS-induced neuropathic pain were progressively alleviated by once-daily administration of single s.c. bolus doses of ALA administered according to an intervention protocol at 15–35 d.p.i. (A, C) For vehicle-treated RR-EAE mice (Cohorts 1 and 2), mean (±SEM) hindpaw PWTs were significantly lower than those for vehicle-treated sham-mice (F(3,6,18/336 = 142.2, 73.43, 43.66; Cohort-1 and F(3,6,18/264 = 239.1, 25.11, 34.32; Cohort-2; P < 0.05). Chronic ALA treatment at 3 or 10 mg kg−1 day−1 (15–35 d.p.i.) evoked dose-dependent attenuation of hindpaw hypersensitivity in RR-EAE mice, whereas for vehicle-treated RR-EAE mice, mechanical allodynia was fully developed (PWTs ≤ 1 g) in the bilateral hindpaws from 26 d.p.i. onward (P < 0.05). After cessation of ALA-treatment (10 mg kg−1 day−1) at 35 d.p.i. in Cohort-2 RR-EAE mice, there was temporal development of mechanical allodynia in the bilateral hindpaws that was fully developed at study completion (55 d.p.i.). P < 0.05 (two way ANOVA, post hoc: Bonferroni). (B) and (D) For vehicle-treated RR-EAE mice (Cohorts 1 and 2), clinical disease onset was at 10–13 d.p.i. and it exhibited a relapsing-remitting profile (F(4,144 = 34.89; Cohort-1 and F(4,164 = 33.05; Cohort-2; P < 0.05). By contrast, vehicle-treated sham-mice did not exhibit EAE-clinical disease (mean ± SEM clinical score >1 a.u.). For both cohorts of RR-EAE mice, ALA at 10 mg kg−1 day−1 but not 3 mg kg−1 day−1 successfully prevented clinical disease relapse. After cessation of ALA-treatment (10 mg kg−1 day−1) at 35 d.p.i. in Cohort-2 RR-EAE mice, clinical disease recurred. The shaded areas on figure panels highlight the chronic ALA or vehicle treatment period (15–35 d.p.i.). *P < 0.05 (Kruskal–Wallis multiple comparison, post hoc: Dunn’s test). ALA, alpha lipoic acid; EAE, experimental autoimmune encephalomyelitis; PWT, Paw withdrawal threshold; p.i., postimmunization; Veh, vehicle. MS, multiple sclerosis.
Mentions: RR-EAE mice received once-daily s.c. injections of ALA at 3 or 10 mg kg−1 day−1, or vehicle for 21 consecutive days commencing at 15 d.p.i., as the first episode of clinical disease had occurred in all EAE mice by day 15. Sham-control mice received once-daily s.c. vehicle injections for the same treatment period. Solutions of ALA or vehicle were prepared freshly each day and masked before administration to animals in a blinded manner. All drug treatments were administered between 09.00 am and 11.00 am. The total number of sham- and RR-EAE mice (in Cohorts 1 and 2) treated with vehicle or ALA is shown in Figure1. To maintain blinding, equal numbers of animals were included in each group. Animals were randomized in a blinded manner and received masked solutions of ALA or vehicle by the first person.

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