Sunday, February 28, 2010

Serotonin-Specific Reuptake Inhibitor (SSRIs) as antiinflammatory agents?

We know that Selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitor (SSRIs) are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. They are also typically effective and used in treating premature ejaculation problems as well as some cases of insomnia.  Now researchers from Brighton and Sussex Medical School (BSMS) in the UK, lead by Dr. Sandra Sacre have come up with an interesting findings, i.e., two SSRIs fluoxetine citalopram significantly inhibited disease progression of collagen-induced arthritis (CIA) in mice. As per the claim by the researchers both SSRIs exhibited antiinflammatory effects and may provide drug development opportunities for arthritic conditions such as rheumatoid arthritis (RA).

Prior studies (of SSRIs)  have shown that patients with depression,  who respond to treatment with SSRIs display a reduction in cytokine levels (signals that can induce inflammation), suggesting a connection between SSRIs and the immune system. 

In the current study, researchers used a CIA mouse model due to the similarities to human RA, including synovitis, bone erosion and pannus formation. At the onset of arthritis, mice were treated daily for 7 days with a dose of 10 or 25 mg/kg of fluoxetine and 25 mg/kg of citalopram. At the lower dose of fluoxetine the mice showed a small reduction in the clinical score (a combined measure of redness, swelling and joint mobility/deformity) and a slower increase in paw swelling. At a dose of 25 mg/kg, fluoxetine halted disease progression and no further elevation was noted in the clinical score or paw swelling.

Researchers observed reduced inflammation, reduced cartilage and bone erosion, and a preservation of the joint structure in the mice treated with a higher dose of fluoxetine.  Citalopram was not as effective as fluoxetine at inhibiting disease progression in this model. 

They  also observed a decrease in cytokine production from cultures of human RA synovial joint tissues that were treated with SSRIs.  Toll-like receptors (TLRs) are strong activators of immune cells leading to the production of cytokines that can induce inflammation. Fluoxetine was found to inhibit the activation of TLRs more effectively than citalopram. 

Researchers conclude that SSRIs effectively target TLRs contributing to inflammation and could provide therapeutic benefit in RA, they are not ideal candidates to progress into clinical trials (from the data, the  effective inhibition of RA requires levels of the drugs higher than the safe therapeutic dosages.) The authors suggest further study of the role of TLRs in chronic inflammation may uncover drugs that offer an effective treatment of RA in the future..... 

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