ABSTRACT
Roflumilast, one of the second generation of phosphodiesterase-4 inhibitors, has been approved for the treatment of severe chronic obstructive pulmonary disease by the United States Food and Drug Administration since 2011. It has shown a variety of beneficial effects, including anti-inflammatory, anti-tumor, anti-alcoholic, and anti-diabetic profiles. Recent studies have demonstrated that roflumilast, like other PDE4 inhibitors, has neuroprotective and precognitive properties. It also has been shown to produce promising cognitive improvement in animals and humans. Therefore, roflumilast can be a potential drug for treatment of various degenerative diseases of the central nervous system, including Alzheimer disease and Parkinson disease. The major mechanism is the activation of cyclic AMP signaling and its downstream targeting molecules. All these are discussed and summarized in the current review.
ABSTRACT
Objective: To investigate the antidepressant mechanism of supercritical CO2 extract from Compound Chaigui Precription from the perspective of cAMP signaling pathway. Methods: The rats model were established by chronic unpredictable mild stress (CUMS). The rats were administrated with high, medium and low doses of supercritical CO2 extract from Compound Chaigui Precription and venlafaxine as intervention drugs. The protein expression levels of cAMP, PKA, p-CREB and BDNF in tissues and their corresponding mRNA levels were explored for their antidepressant mechanism. Results: Compared with the blank group, the expression levels of cAMP, PKA, p-CREB and BDNF in the hippocampus of the model group were significantly decreased (P < 0.05, P < 0.01). After the intervention of the Compound Chaigui Precription, compared with the model group, there was a significant difference in the callus of each dose group. At the same time, the mRNA levels of TrkB, PKA, p-CREB and BDNF in the hippocampus of the model group were significantly decreased (P < 0.05, P < 0.01). After the intervention, there was a callback in each dose group compared with the model group, with significant differences. Conclusion: Supercritical CO2 extract from Compound Chaigui Precription can exert antidepressant effect by regulating cAMP-PKA-CREB-BDNF signaling pathway.
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Objective@#To investigate the possible role of tag single nucleotide polymorphisms in cAMP signaling pathway in patients with recurrent major depressive disorder in Chinese Han population.@*Methods@#1 030 patients with recurrent major depressive disorder according to the DSM-Ⅳ criteria were recruited as case group and 851 age- and gender- matched healthy volunteers were recruited as control group.The sequenom mass spectrometry method was adopted to explore the genotype and allele frequency distributions of tag single nucleotide polymorphisms of cAMP signaling pathway in the two groups.@*Results@#The differences of genotype and allele frequencies of the ADCY7 gene loci rs1064448 and HTR2A gene loci rs17068986 were significant between case group and control group(P<0.05). The difference of the genotype frequencies(492∶423∶112, 356∶401∶91; 538∶392∶94, 414∶371∶61; 24∶165∶838, 3∶150∶694; 219∶468∶337, 139∶418∶237; 153∶481∶393, 115∶446∶286; 53∶286∶688, 25∶296∶524)of the ADCY9 gene loci rs2531995, BDNF gene loci rs10835210, rs7124442, CREB1 gene loci 4675690, rs2551645 and the HTR2A gene loci rs3125 were significant in case-control group(P<0.05); while the rest tagSNPs had no statistical difference in genotype and allele distribution frequencies in case-control group(P>0.05). In gender-specific analyses, the differences of the genotype and allele frequencies of the ADCY7 gene loci rs106448 and CREB1 gene loci rs2551645 were significant in male case-control group(P<0.05); the differences of the genotype(195∶177∶49, 193∶423∶41; 221∶158∶42, 237∶201∶28; 83∶188∶148, 85∶237∶122; 24∶113∶284, 10∶176∶281)of the ADCY9 gene loci rs2531995, BDNF gene loci rs10835210, CREB1 gene loci rs4675690, and HTR2A gene loci rs3125 were significant in male case-control group(P<0.05); while the rest tagSNPs had no statistical difference in genotype and allele distribution frequencies in male case-control group(P>0.05). The differences of the genotype and allele frequencies of the ADCY7 gene loci rs1064448 and HTR2A gene loci rs17068986 were significant in female case-control group(P<0.05). The differences of the genotype(16∶94∶497, 1∶73∶308; 136∶280∶189, 54∶181∶115)of the BDNF gene loci rs7124442 and CREB1 gene loci rs4675690 were significant in female case-control group(P<0.05). The differences of the allele frequencies(840: 372, 493: 267) of the ADCY9 gene loci rs2531995 were significant in female case-control group(P<0.05), while the rest tagSNPs had no statistical difference in genotype and allele distribution frequencies in female case-control group(P>0.05).@*Conclusion@#The ADCY7 gene loci rs1064448 and CREB1 gene loci rs4675690 are associated with recurrent major depressive disorder in Chinese Han population.