"TNF-alpha-mediated inflammatory pathways have been strongly implicated in a number of diseases, including atherosclerosis, rheumatoid arthritis, psoriasis, type II diabetes, irritable bowel syndrome, Crohn’s disease, and septicemia (Reimold, 2002; Popa et al., 2007; Williams et al., 2007). It is noteworthy that TNF-alpha and other cytokine-induced inflammatory pathways have also been linked to psychiatric conditions such as depression and bipolar disorder (Dunn et al., 2005; Kim et al., 2007), as well as schizophrenia (Saetre et al., 2007), and neurodegenerative diseases like Alzheimer’s and Parkinson’s disease and stroke (Tweedie et al., 2007). As such, inhibitors of TNF-alpha-mediated proinflammatory pathways represent potential therapeutics for each of these conditions. Currently, the only available therapeutic inhibitors Fig. 7.
Activation and translocation of NF-alphaB p65 in RASM cells is blocked by 5-HT2A receptor stimulation with (R)-DOI. A, the top portion of the figure shows p65 localization as visualized with Alexa Fluor 488-conjugated secondary antibody (green). The lower portion of the figure shows the position of the nuclei as visualized with 4,6-diamidino-2-phenylindole (blue). The distribution of p65 in RASM cells under control conditions is shown in the top left, and it is mainly cytoplasmic. The nuclei are visible as dark areas within the cell (top left panel). Thirty minutes after TNF-alpha (10 ng/ml) is added, p65 has activated and translocated to the nuclei (top center panel), now visible as bright areas within the cells. Pretreatment with (R)-DOI (1nM) for 1 h before the addition of TNF-alpha blocks nuclear translocation of p65 (top right panel). B, quantitation of nuclear translocation shows that the number of cells with p65 in the nucleus is highly increased after addition of TNF-alpha and that pretreatment with (R)-DOI (1 nM) completely blocks this process (average of three fields for each treatment; p 0.01 versus control and #, p 0.01 versus TNF-alpha; ANOVA with Tukey’s post hoc test).
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of TNF-alpha pathways are monoclonal antibodies against TNF-alpha (infliximab and adalimumab) and soluble TNF-alpha receptor (enteracept), and the development of small molecules for this purpose is highly desirable (Tracey et al., 2007).
Our results indicate that activation of 5-HT2A receptors by (R)-DOI, as well as additional 5-HT2A receptor agonists, represents a novel and extremely potent therapeutic avenue to explore for the treatment of diseases and disorders involving TNF-alpha-mediated inflammation. It is noteworthy that 5-HT2A receptor expression has been detected in most, if not all, of the tissues mediating the inflammatory conditions mentioned above. Given the extremely high potency of (R)-DOI to suppress multiple proinflammatory markers rapidly, ranging from NOS activity, through NF-alpha B translocation, to gene expression of ICAM-1, VCAM-1, and IL-6, the predicted therapeutic dose would be at least two orders of magnitude below that necessary to produce undesirable hallucinogenic side effects. It is noteworthy that because (R)-DOI can significantly inhibit the effects of TNF-alpha many hours after the administration of TNF- alpha, potential therapies could be aimed at not only preventing inflammation, but also treating inflammation or injury that has already occurred or is ongoing."
references:
Serotonin 5-Hydroxytryptamine2A Receptor Activation Suppresses Tumor Necrosis Factor-alpha-Induced Inflammationwith Extraordinary Potency
Bangning Yu, Jaime Becnel, Mourad Zerfaoui, Rasika Rohatgi, A. Hamid Boulares,
and Charles D. Nichols
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center,
New Orleans, Louisiana
Received July 11, 2008; accepted August 14, 2
http://jpet.aspetjournals.org/content/327/2/316.full.pdf+html
I am going to look at it tomorrow, math classes in the morning...
