Mesopram

The type IV phosphodiesterase specific inhibitor mesopram inhibits experimental autoimmune encephalomyelitis in rodents.[Pubmed:10900347]

J Neuroimmunol. 2000 Aug 1;108(1-2):136-46.

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease with pathological features reminiscent of those seen in multiple sclerosis and thus serves as an animal model for this disease. Inhibition of type IV phosphodiesterase (PDE IV) in animals with this disease has been shown to result in amelioration of disease symptoms. Here we describe the immunomodulatory activity of the novel potent and selective PDE IV inhibitor Mesopram. In vitro, Mesopram selectively inhibits the activity of type 1 helper T (Th1) cells without affecting cytokine production or proliferation of type 2 helper T (Th2) cells. Administration of Mesopram to rodents inhibits EAE in various models. Clinically, EAE is completely suppressed by Mesopram in Lewis rats. This is accompanied by a reduction of inflammatory lesions in spinal cord and brain. RT-PCR analysis revealed a marked reduction in the expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the brains of these animals. Furthermore, the ex vivo production of Th1 cytokines by activated spleen cells derived from Mesopram-treated animals is significantly reduced compared to vehicle-treated controls. Amelioration of the clinical symptoms is also observed during chronic EAE in Mesopram-treated SJL mice as well as in relapsing-remitting EAE in SWXJ mice using a therapeutic treatment regimen. These data demonstrate the anti-inflammatory activity of Mesopram and provide a rationale for its clinical development.

The specific type-4 phosphodiesterase inhibitor mesopram alleviates experimental colitis in mice.[Pubmed:12606674]

J Pharmacol Exp Ther. 2003 May;305(2):549-56.

Mesopram, a specific inhibitor of type-4 phosphodiesterase, decreases the synthesis of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). In the present study, we investigated the effect of Mesopram in dextran sulfate sodium (DSS)-induced murine colitis. In the preventive model, colitis was induced by DSS simultaneously with the application of Mesopram in BALB/c mice. In the therapeutic model, colitis was induced in BALB/c mice by DSS over 7 days. At day 8, DSS was discontinued, and treatment was started. Mesopram was applied intraperitoneally or orally. The clinical score was calculated daily during the course of each study. Post mortem, colon length, histologic score, and expression of TNF-alpha and IFN-gamma in colons were determined. In the preventive model, Mesopram significantly reduced the maximal clinical score, decreased colon shortening, and the histologic score. A dose finding study, using the preventive model, showed that most clinical and post mortem benefit was achieved with 50 mg/kg Mesopram compared with 2 and 10 mg/kg. In the therapeutic model, i.p. Mesopram treatment led to a significant reduction of clinical score. Both, i.p. and p.o. Mesopram significantly reversed DSS-induced colon shortening and reduced the ex vivo colonic production of IFN-gamma. We conclude that the specific type-4 phosphodiesterase inhibitor Mesopram ameliorates murine colitis both in a preventive and a therapeutic setting.

Pharmacological inhibition of phosphodiesterase 4 triggers ovulation in follicle-stimulating hormone-primed rats.[Pubmed:15448112]

Endocrinology. 2005 Jan;146(1):208-14.

Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze cyclic nucleotides to render them biologically inactive. As such, these enzymes are critical regulators of signal transduction pathways that use cyclic nucleotides as second messengers. PDE4 is one such member that has been identified in ovarian tissue and purported to have a role in the regulation of gonadotropin action. In the present study, selective PDE4 inhibitors enhanced intracellular signaling in a human LH receptor-expressing granulosa cell line. In vivo, PDE4 inhibition in FSH-primed rats resulted in ovulation, indicating that the PDE4 inhibitors can substitute for LH and human chorionic gonadotropin (hCG) in this process. Moreover, when coadministered with a subeffective dose of hCG, PDE4 inhibitors acted synergistically to enhance the ovulation response. Inhibitors of PDE3 or PDE5 had no ovulatory effect under similar conditions. Oocytes that were ovulated after PDE4 inhibition could be fertilized in vitro at a rate similar to that of oocytes from hCG-induced ovulation. Moreover, such oocytes were fully capable of being fertilized in vivo and developing into normal live pups. These results indicate that small molecule PDE4 inhibitors may be orally active alternatives to hCG as part of a fertility treatment regimen.