Temperature sensitive anti-inflammatory Novel therapeuthic target against IBD
Ulcerative colitis (UC) together with Crohn’s disease (CD), are Inflammatory bowel diseases (mouse IBD). The chronic and relapsing inflammation of all or part of the digestive tract causes severe diarrhea, pain, fatigue and weight loss. Researchers currently believe that a dysregulated immune response to resident intestinal bacteria, influenced by genetic and environmental factors, is responsible for the disruption of the complex immune balance in the bowel environment and the intestinal tissue damage. The diseases are characterized by proinflammatory cytokine production, leukocyte infiltration, and consequent structural and functional damage to the gut.
Today, there is no cure for the diseases but treatments exist to limit the recurrence of the symptoms. Controlled tissue cooling or hypothermia is widely used to suppress tissue damage resulting from trauma, ischemia, and surgery and is known to result in a reduction in inflammation and severity of peripheral nerve injury and could be used to reduce the inflammatory response in colitis. Researchers looked into the mechanisms behind the cooling effect to find the key regulator responsible for the reduction of the inflammation.
Recently, Transient Receptor Potential Melastatin–8 (TRPM8) was identified as a temperature-sensitive ion channel activated by mild cooling and chemical stimuli such as menthol and icilin. Apart from its role in thermosensation, acute activation or inhibition of TRPM8 can have analgesic effects either to diminish neuropathic and visceral pain or to attenuate cold hypersensitivity in inflammatory and nerve-injury pain models. This suggests that neuronal TRPM8 may play a neurogenic anti-inflammatory role in certain settings and also attenuate systemic inflammation.
In two mouse IBD models – 2,4,6-trinitrobenzenesulfonic acid (TNBS) and Dextran Sodium Sulfate (DSS) – of colitis, researchers studied the involvement of TRPM8 in regulating colonic inflammation. Among various chemically induced colitis models, the dextran sulfate sodium (DSS)-induced colitis model is widely used because of its simplicity and many similarities with human ulcerative colitis. Mice are subjected several days to drinking water supplemented with DSS, which seems to be directly toxic to colonic epithelial cells of the basal crypts. Dextran Sodium Sulfate (DSS)-treated TRPM8 knockout mice showed elevated colonic levels of the inflammatory neuropeptide calcitonin-gene–related peptide.
The researchers also found that TRPM8 activation, very likely mediates some of the anti-inflammatory effects of mild cooling for trauma-induced peripheral inflammation, in addition to its neuronal sensory function. They showed that it was also responsible for the attenuation of tissue inflammation in the setting of experimental colitis as TRPM8 mRNA was up regulated in inflamed human and murine colon tissue.
TRPM8 activation had potent anti-inflammatory and disease-attenuating effects that occurred, at least in part, through the suppression of Transient Receptor Potential Vanilloid-1 (TRPV1)-dependent calcitonin-gene–related peptide (CGRP) release in the colon. The anti-inflammatory role for TRPM8 activation, is in part due to an inhibiton of neuropeptide release. In addition to its antinociceptive action, TRPM8 has thus an anti-inflammatory role, and this channel could become a promising therapeutic target for treating inflammatory diseases such as colitis/IBD.
Syncrosome is an Efficacy Characterization CRO that offers relevant disease models, cutting-edge techniques and a comprehensive background of physiopathology to assist drug discovery companies. Syncrosome uses DSS-rodent for drug screening and efficacy testing for Inflammatory Bowel disease (including Crohn’s disease et Ulcerative colitis).
Key words: preclinical CRO, preclinical study, animal model, disease model, animal research, DSS model, DSS – mouse model, Inflammatory Bowel disease, Crohn’s disease, Ulcerative colitis, gastrointestinal tract, inflammation, immune system, cytokine, interleukine, immunity, bowel, transgenic, cold, channel, analgesic, temperature-sensitive