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Past Project - CERC

Center of Excellent for Research in Complementary and Alternative Medicine on Arthritis and Traditional Chinese Medicine

9/2005 – 8/2010

PI: Brian Berman, MD; Co-PI: Lixing Lao, PhD

This Center of Excellence for Research on CAM (CERC) program project grant (P01), funded in 2005 by the National Center for Complementary and Alternative Medicine (NCCAM) in the amount of $6 million, built on our substantial track record in examining the safety, efficacy, and mechanism of action associated with common TCM treatments (acupuncture and herbs) for arthritis. The research projects include:

Project 1: A Phase II Dose-Finding, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of a Chinese Herbal Compound Huo-Luo-Xiao-Ling (HLXL) for Knee OA

PI: Brian Berman, MD

Objective: The first project in the CERC is a randomized, placebo-controlled, dose-finding study of a traditional Chinese medicine 11-herb mixture called Huo-Luo-Xiao-Ling Dan (HLXL) to improve symptoms of participants with osteoarthritis of the knee. This clinical trial, ‘Traditional Chinese Medicine for OA of the Knee (TCM-OAK)’, has as its co-primary outcomes change in function and pain scores of the Western Ontario McMaster Universities (WOMAC) Osteoarthritis index.  The study was launched in May of 2007.

Summary: A total of 92 patients were enrolled: 53 in the U.S. and 39 in Hong Kong. Overall, the mean age was 60 years, 65 (71%) were women and 64 (70%) were of Asian ethnicity. Mean (SD) baseline WOMAC pain and function score was 4.3 (1.5) and 4.2 (1.6), respectively, and PGA was 2.2 (0.8). There were no significant differences between HLXL- and placebo-treated groups in baseline variables. While both groups had significant improvement in all outcome measures after 8 weeks, there were no significant differences between the HLXL- and placebo-treated groups. At 8 weeks, about two-thirds of subjects noted that they were better based on PGART responses; there was no difference between treatment groups. In mixed models repeated measures analysis, there were no significant differences in WOMAC pain or function scores or PGA between groups; furthermore, there was no interaction between clinical site and degree of improvement. Average adherence exceeded 80 percent and was similar between clinical sites. Finally, there was a significantly greater rise in mean ALT levels in the HLXL-treated group compared with the placebo-treated group (3.8 [10.4] vs 0.1 [5.8] U/l) but no significant difference in either AST or γGT levels. In conclusion, these data fail to demonstrate that a proprietary form of the Chinese herbal compound HLXL Dan is efficacious for treating the symptoms of knee OA.

Project 2: Mechanisms of Acupuncture’s Effect on Inflammatory Pain

PI: Lixing Lao, PhD, LAc

Objective:  The second project in the CERC is an investigation of the mechanisms by which electro-acupuncture (EA) has anti-inflammatory effects on pain.  The study utilized a rat model.

Summary:  1) Studies demonstrated that EA activates corticotropin-releasing factor (CRF) neurons in the paraventricular nuclei (PVN) which is located in the hypothalamus to significantly increase plasma adrenocorticotropic hormone (ACTH) and corticosterone levels which suppress inflammation. 

2) We demonstrated that EA significantly inhibits hyperalgesia through activating supraspinal descending inhibitory system, serotonergic and catecholaminergic neurons in the brain that project to the spinal cord through the dorsolateral nerve pathway. Endogenous supraspinal opioids may inhibit GABA-containing neurons, disinhibiting serotonin-containing neurons that project to the spinal cord to block the transmission of noxious messages in the spinal cord. Our study showed that α2a-ARs and 5-HT1ARs are involved in EA inhibition of inflammatory pain.

3) Our study also demonstrated that spinal IL-17 is produced by astrocytes and enhances p-NR1 to facilitate inflammatory pain and EA inhibits hyperalgesia by suppressing IL-17.  This data has been published in 14 peer-reviewed journals and orally presented in 15 workshop sessions.

4) Additionally, using monosodium iodoacetate (MIA)-induced knee osteoarthritis (OA) pain rat model, we demonstrated that EA treatment improved hind limb body weight bearing on the injured limb, inhibited mechanically- and thermally-evoked pain and, alleviated OA-associated affective component of pain. The pilot study also demonstrated that increased anterior cingulate cortex/Mortex cortex1/Sensory cortex1 connectivity in OA rats that was not present in naive or EA-treated rats, indicating that EA modulate central nervous system activities to inhibit pain.

Project 3: Modulation of Autoimmune Arthritis by Chinese Herbs

PI: Kamal Moudgil, PhD

Objective:  The third project of the CERC is to determine the immunological basis of the anti-inflammatory activity of HLXL.

Summary:   We extended our earlier study showing the anti-arthritic activity of Huo-Luo-Xiao-Ling Dan (HLXL) to determine the mechanism by which this herbal mixture affords protection against inflammation and bone damage in arthritis. In addition, we undertook a global gene expression study using microarray analysis to get an insight into different pathways influenced by HLXL. These studies were performed in the rat adjuvant arthritis (AA) model of human rheumatoid arthritis (RA). The results of 3 studies are summarized below. Taken together, our results suggest that HLXL might offer a promising alternative/adjunct treatment for both inflammation and bone damage in RA.

  1. Nanjundaiah SM, Lee DY, Berman BM, Moudgil KD. Chinese Herbal Formula Huo-Luo-Xiao-Ling Dan Protects against Bone Damage in Adjuvant Arthritis by Modulating the Mediators of Bone Remodeling. Evid Based Complement Alternat Med. 2013;2013:429606.

This study was aimed at evaluating the efficacy of HLXL against bone damage in the rat adjuvant arthritis (AA) model of human rheumatoid arthritis (RA). We observed that treatment with HLXL (2.3 g/kg/day by gavage, beginning at the onset of AA and then continued throughout the study period) reduced bone and cartilage damage in the joints of arthritic Lewis rats compared to control, vehicle-treated rats. This protective effect of HLXL was mediated primarily via inhibition of mediators of osteoclastic bone remodeling (e.g., receptor activator of nuclear factor kappa-B ligand; RANKL), deviation of RANKL/osteoprotegerin (OPG) ratio in favor of antiosteoclastic activity, reduction in the number of osteoclasts in the bones forming the joint, and inhibition of cytokine production and matrix metalloproteinase (MMP) activity.

  1. Nanjundaiah SM, Lee DY, Ma Z, Fong HH, Lao L, Berman BM, Moudgil KD. Modified huo-luo-xiao-ling dan suppresses adjuvant arthritis by inhibiting chemokines and matrix-degrading enzymes. Evid Based Complement Alternat Med. 2012;2012:589256.

In another study based on the rat AA model, we tested the effect HLXL on chemokines and MMPs. Chemokines play a vital role in the migration of leukocytes from the blood into the joints, whereas MMPs are involved in damage to cartilage and bone. The treatment protocol for HLXL was the same as described above. Rats were euthanized at the peak phase of AA, and their draining lymph node cells (LNC) and spleen adherent cells (SAC) were tested. The HLXL-treated rats showed a significant reduction in the levels of chemokines (RANTES, MCP-1, MIP-1α, and GRO/KC) and MMPs (MMP 2 and 9) compared to the control rats.

  1. Yu H, Lee DY, Nanjundaiah SM, Venkatesha SH, Berman BM, Moudgil KD. Microarray analysis reveals the molecular basis of anti-arthritic activity of Huo-luo-xiao-ling dan. Evid Based Complement Alternat Med. vol. 2013, Article ID 524746, 8 pages, 2013. doi:10.1155/2013/524746

We performed analysis of gene expression using oligonucleotide microarrays in the lymph node cells (LNC) harvested from arthritic rats before and after 7 days of treatment with HLXL or vehicle (Water). LNC were restimulated in vitro with the disease-related antigen mycobacterial heat-shock protein 65. Cells cultured in medium alone served as controls. We identified 84 differentially-expressed genes (DEG) (64 upregulated and 20 downregulated) versus 120 DEG (94 upregulated and 26 downregulated) in HLXL-treated versus Water-treated groups, respectively. Further 62 DEG (45 upregulated and 17 downregulated) were shared between the two groups. The arthritis-related pathways influenced by HLXL included immune response, inflammation, cellular proliferation and apoptosis, and metabolic processes.