HDAC Inhibition by Valproic Acid Induces Neuroprotection and Improvement of PD-like Behaviors in LRRK2 R1441G Transgenic Mice

Parkinson’s disease (PD) is one of the late-onset neurodegenerative movement disorder. Major pathological markers of PD include progressive loss of dopaminergic neurons, Lewy body formation, genetic mutations, and environmental factors. Epigenetic regulation of specific gene expression via impaired histone acetylation is associated with neuronal dysfunction in various neurodegenerative diseases. In this study, we hypothesized that histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can improve motor function by enhancing cell survival in PD genetic model mice with LRRK2 R1441G mutation. To address this question, we administered VPA in LRRK2 R1441G transgenic mice to determine whether VPA affects 1) histone acetylation and HDAC expression, 2) dopaminergic neuron survival, 3) inflammatory responses, 4) motor or non-motor symptoms. As results, VPA administration increased histone acetylation level and the number of tyrosine hydroxylase (TH) positive neurons in substantia nigra of LRRK2 R1441G mice. VPA reduced iba-1 positive activated microglia and the mRNA levels of pro-inflammatory marker genes in LRRK2 R1441G mice. In addition, VPA induced the improvement of PD-like motor and non-motor behavior in LRRK2 R1441G mice. These data suggest that the inhibition of HDAC can be further studied as potential future therapeutics for PD.

VPApromotesEMTincoloncarcinomacellsvianucleartranslocationofE-cadherin / 中国肿瘤生物治疗杂志

@# Objective: To explore the effect of histone deacetylase (HDAC) inhibitor valproic acid (VPA) on the epithelial-mesenchymal transition (EMT) of colon cancer. Methods: With four colon carcinoma cell lines (DLD-1, HCT116, SW480 and HT29) as study subjects, the effect of different concentrations of VPA(0.5，5 mmol/L) on cell proliferation was detected by MTT assay. The expression level of EMT-related proteins (E-cadherin and vimentin) was detected by Western blotting; Phenotypic changes of E-cadherin and vimentin were detected by immunofluorescence staining; Cell migration and invasion ability was detected by wound healing and Transwell invasion assay, respectively. Results:After treated with different concentrations of VPAfor 48 h, low concentration of VPAmerely exerted any effect on the cell proliferation rate of four colon cancer cell lines, and thus was chosen as the experiment concentration; The results of Western blotting showed that the expression of E-cadherin was reduced (P<0.05) and vimentin was increased (P<0.05) in colon carcinoma cells by VPAtreatment (0.5 mmol/L); Immunofluorescence staining revealed membranous attenuation or nuclear translocation of E-cadherin and enhanced expression of vimentin after VPA treatment (0.5 mmol/L), and these responses occurred after 6 h and sustained until 24 h; Wound healing and Transwell invasion assay showed increased migration and invasion ability following VPA treatment (0.5 mmol/L). Conclusion: Low concentration VPA could induce the development of EMT in colon cancer cells by nuclear translocation of E-cadherin, and obviously enhance the migration and invasion ability of colon cancer cells; Thus, HDAC inhibitors, as a new type anti-cancer option, shall be carefully considered before their application in colon cancer.

Protective function of L-carnitine against valproate-associated hepatotoxicity in infant rats and its mechanism / 重庆医科大学学报

Objective:To explore the protective function of L-carnitine against valproate-associated hepatotoxicity in infant rats and its mechanism.Methods:Rat models with VPA liver lesion were established by oral administration of VPA and PB.L-carnitine was adopted as intervention measure:to observe its protection of experiment rat livers,especially the function of liver mitochondrion.Levels of plasma ammonia,L-carnitine and coagulation factors in sera as well as the changes of respiratory enzymes in hepatic mitochondria were measured by chemical colorimetry. Mitochondrial membrane potential(MMP),and VPA and PB blood drug levels in liver were determined by flow cytometer and HPLC,respectively.and morphological changes of hepatocytes were observed under microscope with Oil-Red-O staining.Results(1)In the groups affected by VPA or VPA added with PB,the activities of SDH and CCO significantly decreased compared with control group(P

Modulation of Caspase expression by up-regulating histone acetylizad level with VPA / 中国免疫学杂志

Objective:To investigate modulation of a specific HDAC inhibitor,Valproate acid sodium(VPA),on expression of Caspase3,Caspase8,Caspase9 by inhiting HDAC,as well as apoptosis rate of cancer cells treated with VPA and the specific inhibitors of Caspase3,Caspase8,Caspase9.Methods:Heptocellular carcinoma cells-HepG2,gastric carcinoma cells-BGC-823 and breast cancer cells-MCF-7 were cultured with 0.75-4.0 mmol/L of VPA for 48 hrs in vivo,apoptosis was analyzed by flow cytometry with Annexin V/PI assay.The activities and protein expressions of Caspase3,Caspase8,Caspase9 were detected by spectrophotometry and indirect immunofluorescence technique.Results:Contrary to control groups,VPA at concentrations between 0.75 and 4.0 mmol/L induced a significant apoptosis in HepG2,BGC-823,MCF-7 cells(P0.05).The apoptosis rates of cancer cells treated with VPA and specific inhibitors of Caspase3,Caspase9 together was lower than in the groups with VPA treatment singlely(P