Gene expression and association analyses of the phosphodiesterase 4B (PDE4B) gene in major depressive disorder in the Japanese population.
ABSTRACT The phosphodiesterase 4B (PDE4B) interacts with disrupted-in-schizophrenia 1 (DISC1), which is a known genetic risk factor for schizophrenia, bipolar disorder and major depressive disorder (MDD). PDE4B is also important in the regulation of cAMP signaling, a second messenger implicated in learning, memory, and mood. In this study, we determined mRNA expression levels of the PDE4B gene in the peripheral blood leukocytes of patients with MDD and control subjects (n = 33, each). Next we performed two-stage case-controlled association analyses (first set; case = 174, controls = 348; second set; case = 481, controls = 812) in the Japanese population to determine if the PDE4B gene is implicated in MDD. In the leukocytes, a significantly higher expression of the PDE4B mRNA was observed in the drug-naïve MDD patients compared with control subjects (P < 0.0001) and the expression of the MDD patients significantly decreased after antidepressant treatment (P = 0.030). In the association analysis, we observed significant allelic associations of four SNPs (the most significant, rs472952; P = 0.002) and a significant haplotypic association (permutation P = 0.019) between the PDE4B gene and MDD in the first-set samples. However, we could not confirm these significant associations in the following independent second-set of samples. Our results suggest that the PDE4B gene itself does not link to MDD but the elevated mRNA levels of PDE4B might be implicated in the pathophysiology of MDD.
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ABSTRACT: Major depressive disorder is a common, but serious, psychiatric dysfunction that affects 21% of the population worldwide. Rolipram, a first-generation phosphodiesterase-4 (PDE4) inhibitor, has been shown to have significant antidepressant and cognitive enhancement effects; however, it was unsuccessful in clinic trials because of PDE4-dependent side effects such as nausea and emesis. In this study, we investigated the neuropharmacology of the novel PDE4 inhibitor chlorbipram and the classical PDE4 inhibitor rolipram. Using antidepressant-sensitive behavioral tests, we demonstrated that the acute single administration of chlorbipram (0.075-0.6mg/kg) produced antidepressant-like effects, as evidenced by decreases in the duration of immobility in Kunming mice in the forced swim and tail suspension tests, and no significant changes in locomotor activity. Scopolamine-induced cognitive dysfunction was also significantly attenuated in the Morris water maze test after the treatment of Sprague Dawley rats with different doses of chlorbipram (0.5-1.5mg/kg). Furthermore, we evaluated the emetic potential of chlorbipram in beagle dogs. After oral administration, 0.5mg/kg rolipram showed emetic profiles in all dogs within 20 minutes, whereas chlorbipram did not induce any emesis during the 120-min observation period, even at the 1.0mg/kg dose. Together, our data suggest that chlorbipram is a novel antidepressant and cognitive enhancer with little or no emetic potency.European journal of pharmacology 10/2013; · 2.59 Impact Factor
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ABSTRACT: This experimentally based study considers the scaling of the flame length, the cross-stream dimension of the plume of combustion products, and the overall combustion efficiency of wake-stabilized jet diffusion flames. The study focuses on scaling with respect to the burner tube diameter (ds), but relationships include scaling with the jet exit velocity (Vj) and the transverse air velocity (U∞). Phenomenological models are used to correlate the data presented. The flame length (Lf) is shown to correlate well by relating the time-scale for the flow to advect the length of the flame (Lf/U∞) to the time scale of the external flow with respect to the fuel jet dimension (ds/U∞). A consequence of this model is that Lf∞ds, and Lf either increases or decreases depending on whether the operating conditions are greater or less than a critical value of ds/U∞. The maximum flame length occurs at the critical value of ds/U∞. The proposed model for flame length predicts that Lf actually scales with (pjVj)1/2ds/U∞, but the (pjVj)1/2 term has yet to be validated. The characteristic cross-stream dimension of the plume (dp*), defined by the square root of its cross-sectional area, is shown to correlate with non-reacting plume models that use buoyancy forces and air stream momentum to give dp*∝g13Vj13U∞x23ds23 g x d s 1/3Proceedings of The Combustion Institute - PROC COMBUST INST. 01/2000; 28(1):553-559.