ABSTRACT
The previous study indicated that aquaporin 4 (AQP4) deficiency attenuated opioid physical dependence. However, the underlying mechanism remains unknown. In the present study, the effects of AQP4 deficiency on the expression of three factors, protein kinase C (PKC) α, PKCγ and c-Fos in the spinal cord, which are known to be concerned with spinal neuronal sensitization and opiate dependence, were investigated in AQP4 knockout mice using Western blotting analysis. It was observed that AQP4 deficiency reduced the score of naloxone-precipitated abstinent jumping after repeated morphine administration compared with wild-type (P < 0.001). Meanwhile, the protein levels of PKCα and c-Fos in the spinal cord of AQP4 knockout mice were significantly higher than those in the wild-type mice; while the expression of PKCγ was decreased remarkably by AQP4 knockout during the withdrawal (P < 0.01). These data suggest that AQP4 deficiency-attenuated morphine withdrawal responses may be partially attributed to the changes in the spinal expression of PKCα, PKCγ or c-Fos.
Subject(s)
Animals , Mice , Analgesics, Opioid , Pharmacology , Aquaporin 4 , Genetics , Mice, Knockout , Morphine , Pharmacology , Naloxone , Pharmacology , Protein Kinase C , Metabolism , Protein Kinase C-alpha , Metabolism , Spinal Cord , Metabolism , Substance Withdrawal Syndrome , MetabolismABSTRACT
Because c-Src and iNOS are key regulatory enzymes in tumorigenesis, a new series of 4-heterocycle amine-3-quinolinecarbonitriles as potent dual inhibitors of both enzymes were designed, synthesized and evaluated as multiple targets agents in cancer therapy. All compounds were evaluated by two related enzyme inhibition assays and an anti-proliferation assay in vitro. The results showed that most compounds inhibited c-Src and iNOS well. The best compound 33 inhibited both enzymes with the IC50 values of 0.0484 micromol x L(-1) and 34.5 micromol x (-1), respectively. Some of the compounds also showed moderate anti-proliferation activities at 10 micromol x L(-1) against colon cancer HT-29 and liver cancer HepG2 cell lines.