Attenuation of pain and inflammation in adjuvant-induced arthritis by the proteasome inhibitor MG132.
OBJECTIVE
In rheumatoid arthritis (RA), pain and joint destruction are initiated and propagated by the production of proinflammatory mediators. Synthesis of these mediators is regulated by the transcription factor NF-kappaB, which is controlled by the ubiquitin proteasome system (UPS). The present study explored the effects of the proteasome inhibitor MG132 on inflammation, pain, joint destruction, and expression of sensory neuropeptides as markers of neuronal response in a rat model of arthritis.


METHODS
Arthritis was induced in rats by injection of heat-killed Mycobacterium butyricum. Arthritis severity was scored, and nociception was evaluated by mechanical pressure applied to the hind paw. Joint destruction was assessed by radiologic and histologic analyses. NF-kappaB DNA-binding activity was analyzed by electromobility shift assay, and changes in the expression of the p50 NF-kappaB subunit and the proinflammatory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) were detected by immunohistochemistry.


RESULTS
Arthritic rats treated with MG132 demonstrated a marked reduction in inflammation, pain, and joint destruction. The elevated DNA-binding activity of the NF-kappaB/p50 homodimer and p50, as well as the neuronal expression of SP and CGRP, observed in the ankle joints of arthritic rats were normalized after treatment with MG132.


CONCLUSIONS
In arthritic rats, inhibition of proteasome reduced the severity of arthritis and reversed the pain behavior associated with joint inflammation. These effects may be mediated through the inhibition of NF-kappaB activation and may possibly involve the peripheral nervous system. New generations of nontoxic proteasome inhibitors may represent a novel pharmacotherapy for RA.
Ahmed
Aisha S
AS
Section of Orthopedics, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden. aisha.ahmed@ki.se
Li
Jian
J
Ahmed
Mahmood
M
Hua
Long
L
Yakovleva
Tatiana
T
Ossipov
Michael H
MH
Bakalkin
Georgy
G
Stark
André
A
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001170:Arthritis, Infectious / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D005260:Female; D007596:Joints / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007976:Leupeptins / Q000494:pharmacology*; D009161:Mycobacterium / Q000276:immunology; D009164:Mycobacterium Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D013373:Substance P / Q000378:metabolism
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D016328:NF-kappa B; D013373:Substance P; D004247:DNA; D015740:Calcitonin Gene-Related Peptide; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde