Our previous experimental studies showed that dauricine could protect the brain from ischemic damage, but the underlying mechanisms were unknown. In this study, we investigated the effect of dauricine on the changes of the inflammation process induced by ischemia/reperfusion (I/R). After I/R, the enzyme activity of MPO, the expression of ICAM-1 and the transcription of IL-1beta and TNF-alpha mRNA were all significantly increased (p < 0.01). And after treatment with dauricine, they were all significantly reduced compared to the vehicle-treated I/R group (p < 0.05 or p < 0.01). These results suggest that dauricin attenuates the inflammation process induced by I/R. The neuroprotective effect of dauricine may partly due to the inhibition acute inflammation induced by I/R.

Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive enlargement of multiple renal cysts, often leading to renal failure that cannot be prevented by a current treatment. Two proteins encoded by two genes are associated with ADPKD: PC1 (), primarily a signaling molecule, and PC2 (), a Ca channel. Dysregulation of cAMP signaling is central to ADPKD, but the molecular mechanism is unresolved. Here, we studied the role of histone deacetylase 6 (HDAC6) in regulating cyst growth to test the possibility that inhibiting HDAC6 might help manage ADPKD. Chemical inhibition of HDAC6 reduced cyst growth in PC1-knock-out mice. In proximal tubule-derived, PC1-knock-out cells, adenylyl cyclase 6 and 3 (AC6 and -3) are both expressed. AC6 protein expression was higher in cells lacking PC1, compared with control cells containing PC1. Intracellular Ca was higher in PC1-knock-out cells than in control cells. HDAC inhibition caused a drop in intracellular Ca and increased ATP-simulated Ca release. HDAC6 inhibition reduced the release of Ca from the endoplasmic reticulum induced by thapsigargin, an inhibitor of endoplasmic reticulum Ca-ATPase. HDAC6 inhibition and treatment of cells with the intracellular Ca chelator 1,2-bis(2-aminophenoxy)ethane-,,','-tetraacetic acid tetrakis(acetoxymethyl ester) reduced cAMP levels in PC1-knock-out cells. Finally, the calmodulin inhibitors W-7 and W-13 reduced cAMP levels, and W-7 reduced cyst growth, suggesting that AC3 is involved in cyst growth regulated by HDAC6. We conclude that HDAC6 inhibition reduces cell growth primarily by reducing intracellular cAMP and Ca levels. Our results provide potential therapeutic targets that may be useful as treatments for ADPKD.

Adult-onset autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in either the or gene, leading to malfunction of their gene products, polycystin 1 or 2. Histone deacetylase 6 (HDAC6) expression and activity are increased in mutant renal epithelial cells. Here we studied the effect of ACY-1215, a specific HDAC6 inhibitor, on cyst growth in ADPKD. Treatment with ACY-1215 slowed cyst growth in a mouse model of ADPKD that forms massive cysts within 3 wk after knockout of polycystin 1 function. It also prevented cyst formation in MDCK.2 cells, an in vitro model of cystogenesis, and in an ADPKD cell line derived from the proximal tubules from amouse (PN cells). In PN cells ACY-1215 also reduced the size of already established cysts. We found that ACY-1215 lowered cAMP levels and protein expression of adenylyl cyclase 6. Our results suggest that HDAC6 could potentially serve as a therapeutic target in ADPKD.