Aisha Siddiqah Ahmed1, Mahmood Ahmed2, Jian Li3, Harvest F Gu3, Georgy Bakalkin4, André Stark5, Helena Erlandsson Harris6. 1. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. 2. Department of Neurobiology, Care Sciences and Society, Center for Family and Community Medicine, Karolinska Institutet, Huddinge, Sweden. 3. Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. 4. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. 5. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden. 6. Department of Medicine, Center for molecular medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Abstract
AIMS: In rheumatoid arthritis (RA), pain and inflammation are initial symptoms followed by various degrees of bone and cartilage destruction. Previously, we have shown that reversible proteasome inhibitor MG132 attenuates pain and joint inflammation in a rat model of adjuvant-arthritis. Our present study aims to study the effects of MG132 on molecular changes in the dorsal root ganglia (DRG) and in the spinal cord (SC) using the same animal model. METHODS: Arthritis was induced by heat-killed Mycobacterium butyricum in rats. The expression of substance P (SP) was analyzed by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in DRG and in the SC. The nuclear factor-κB (NF-κB) DNA-binding activity in the SC was analyzed by electromobility shift assay. RESULTS: Arthritic rats treated daily with MG132 demonstrated a marked reduction of SP gene expression in the DRG and number of SP-positive cells was reduced. In the spinal cord of arthritic rats elevated SP messenger RNA levels were normalized and NF-κB-DNA-binding activity was down-regulated in arthritic rats treated with MG132. CONCLUSION: Our results indicate that proteasome inhibitor MG132 attenuates pain in adjuvant arthritis by targeting the sensory neuropeptide substance P in the peripheral and central nervous systems. These effects may be mediated through the inhibition of NF-κB activation.
AIMS: In rheumatoid arthritis (RA), pain and inflammation are initial symptoms followed by various degrees of bone and cartilage destruction. Previously, we have shown that reversible proteasome inhibitor MG132 attenuates pain and joint inflammation in a rat model of adjuvant-arthritis. Our present study aims to study the effects of MG132 on molecular changes in the dorsal root ganglia (DRG) and in the spinal cord (SC) using the same animal model. METHODS:Arthritis was induced by heat-killed Mycobacterium butyricum in rats. The expression of substance P (SP) was analyzed by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in DRG and in the SC. The nuclear factor-κB (NF-κB) DNA-binding activity in the SC was analyzed by electromobility shift assay. RESULTS: Arthritic rats treated daily with MG132 demonstrated a marked reduction of SP gene expression in the DRG and number of SP-positive cells was reduced. In the spinal cord of arthritic rats elevated SP messenger RNA levels were normalized and NF-κB-DNA-binding activity was down-regulated in arthritic rats treated with MG132. CONCLUSION: Our results indicate that proteasome inhibitor MG132 attenuates pain in adjuvant arthritis by targeting the sensory neuropeptide substance P in the peripheral and central nervous systems. These effects may be mediated through the inhibition of NF-κB activation.
Authors: Jane E Hartung; Olivia Eskew; Terrence Wong; Inna E Tchivileva; Folabomi A Oladosu; Sandra C O'Buckley; Andrea G Nackley Journal: Brain Behav Immun Date: 2015-07-15 Impact factor: 7.217
Authors: Aisha S Ahmed; Svante Berg; Kanar Alkass; Henrik Druid; David A Hart; Camilla I Svensson; Eva Kosek Journal: Int J Mol Sci Date: 2019-02-03 Impact factor: 5.923