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 signalling in the dorsal horn of the spinal cord

Khan, Nemat, Gordon, Richard, Woodruff, Trent M. and Smith, Maree T. (2015) 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 signalling in the dorsal horn of the spinal cord. Pharmacology Research and Perspectives, 3 3: 1-16. doi:10.1002/prp2.137


Author Khan, Nemat
Gordon, Richard
Woodruff, Trent M.
Smith, Maree T.
Title 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 signalling in the dorsal horn of the spinal cord
Journal name Pharmacology Research and Perspectives   Check publisher's open access policy
ISSN 2052-1707
Publication date 2015-06
Year available 2015
Sub-type Article (original research)
DOI 10.1002/prp2.137
Open Access Status DOI
Volume 3
Issue 3
Start page 1
End page 16
Total pages 16
Place of publication West Sussex United Kingdom
Publisher John Wiley & Sons
Collection year 2016
Language eng
Formatted 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.
Keyword Alpha lipoic acid
Analgesia
Brian-derived neurotrophic factor
Mechanical allodynia
Multiple sclerosis
Neuropathic pain
Relapsing-remitting experimental autoimmune encephalomyelitis
Tyrosine kinase B
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Thu, 21 May 2015, 18:55:54 EST by Professor Maree Smith on behalf of School of Pharmacy