Unknown,Transcriptomics,Genomics,Proteomics

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Effects of MDMA and Venlafaxine treatment in Dark Agouti rats

ABSTRACT: The aim of this study was to examine the hippocampus, frontal cortex and dorsal raphe of Dark Agouti rats with gene expression arrays (Illumina RatRef bead arrays) looking for possible mechanisms and new candidates contributing to the effects of a single dose of MDMA (15 mg/kg) 3 weeks earlier or venlafaxine (40 mg/kg) administration for 3 weeks continously. We also examined the possible interaction between the single dose MDMA treatment and the continous venlafaxine treatment described above. With the present study we tried to evaluate the effects of a single, neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA) and/or 3 weeks long venlafaxine (VLX) treatment in the dorsal raphe, frontal cortical or hippocampal neurons in Dark Agouti rats. For the analysis of MDMA long-term effects rats were treated once with 15 mg/kg MDMA i.p. in a volume of 1 ml/kg 3 weeks prior to sacrificing the animals. In the case of VLX, the animals were administered 40 mg/kg of the drug for 3 weeks via Alzet 2001 minipumps inserted under the skin of the rats. In the third group rats received the mentioned treatment protocols simultaneously. Vehicle and sham-operated controls were used for comparison. For microarray analysis all groups consisted of 8 animals. Every two randomly selected samples from the same brain regions were pooled resulting in 4 pooled samples per region and treatment. From the total 48 pooled samples 2 were excluded because of quality control reasons. For RNA extraction Trizol reagent was used and microarray analysis was done by Service XS (Netherlands) according to Illumina protocols (San Diego, CA, USA). Results were validated with Fluidigm GEx (San Francisco, CA, USA) arrays using TaqMan Gene Expression (Carlsbad, CA, USA) assays. In this study no replicates were used.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Viola Tamasi

PROVIDER: E-GEOD-47541 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Gene-expression profiles of rat liver cirrhosis induced by diethylnitrosamine and the effect of erlotinib on liver fibrogenesis and liver cancer development Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. Given the lack of successful treatment options, chemoprevention in high-risk patients has been proposed as an alternative strategy. Mounting evidence supports a role for epidermal growth factor (EGF) during chronic liver disease and hepatocellular transformation. We address the hypothesis that blocking the EGF-EGF receptor (EGFR) pathway may be an effective strategy for inhibiting fibrogenesis and hepatocarcinogenesis. A rat model of diethylnitrosamine (DEN)-induced cirrhosis was used to examine the effects of erlotinib on underlying chronic liver disease and HCC formation. The DEN-induced rat model closely resembles disease progression in humans both pathologically and molecularly. Erlotinib significantly prevented the development of HCC tumor nodules in a dose-dependent fashion. Further, erlotinib inhibited the activation of hepatic stellate cells and prevented fibrogenesis. Erlotinib also reduced hepatotoxicity and improved liver function. Finally, a gene expression signature predictive of poor survival in human cirrhosis patients was reversed in response to erlotinib. Our data demonstrate for the first time that EGFR inhibition prevents liver fibrogenesis. Further, our results suggest that erlotinib is a potentially effective HCC chemoprevention strategy through inhibition of cirrhosis progression which can be monitored at the molecular level. Keywords: Cirrhotic liver, Expression array, Illumina, Signatures, Outcome prediction Animals received humane care according to the criteria outlined in the M-bM-^@M-^\Guide for the Care and Use of Laboratory AnimalsM-bM-^@M-^] of the National Academy of Sciences. All animals were maintained in accordance with the institutional guidelines of the Massachusetts General Hospital Subcommittee on Research Animal Care. Male Wistar rats received weekly IP injections of diethylnitrosamine (DEN) at 50 mg/kg, 100mg/kg, or vehicle control (PBS) for 18 weeks. A subset of rats received either daily (5X a week) IP injections of 2 mg/kg erlotinib or vehicle control during weeks 13 - 18. In a separate study, the erlotinib dose was lowered to 0.5 mg/kg. The vehicle groups from the two studies were not significantly different so they were combined together for analysis. Rats were weighed at the end of each week. Animals were sacrificed at 9, 13 and 19 weeks after a one-week washout period to eliminate acute effects of DEN. At the time of sacrifice, the non-tumor liver tissues were collected in RNase-free tubes and snap-frozen in liquid nitrogen. Frozen tissues were stored at -80M-BM-0C until RNA extraction.

Project description:Gene-expression profiles of rat hepatocellular carcinoma induced by diethylnitrosamine (DEN) and the effect of erlotinib Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. Given the lack of successful treatment options, chemoprevention in high-risk patients has been proposed as an alternative strategy. Mounting evidence supports a role for epidermal growth factor (EGF) during chronic liver disease and hepatocellular transformation. We address the hypothesis that blocking the EGF-EGF receptor (EGFR) pathway may be an effective strategy for inhibiting fibrogenesis and hepatocarcinogenesis. A rat model of diethylnitrosamine (DEN)-induced cirrhosis was used to examine the effects of erlotinib on underlying chronic liver disease and HCC formation. The DEN-induced rat model closely resembles disease progression in humans both pathologically and molecularly. Erlotinib significantly prevented the development of HCC tumor nodules in a dose-dependent fashion. Further, erlotinib inhibited the activation of hepatic stellate cells and prevented fibrogenesis. Erlotinib also reduced hepatotoxicity and improved liver function. Finally, a gene expression signature predictive of poor survival in human cirrhosis patients was reversed in response to erlotinib. Our data demonstrate for the first time that EGFR inhibition prevents liver fibrogenesis. Further, our results suggest that erlotinib is a potentially effective HCC chemoprevention strategy through inhibition of cirrhosis progression which can be monitored at the molecular level. Animals received humane care according to the criteria outlined in the M-bM-^@M-^\Guide for the Care and Use of Laboratory AnimalsM-bM-^@M-^] of the National Academy of Sciences. All animals were maintained in accordance with the institutional guidelines of the Massachusetts General Hospital Subcommittee on Research Animal Care. Male Wistar rats received weekly IP injections of diethylnitrosamine (DEN) at 50 mg/kg, 100mg/kg, or vehicle control (PBS) for 18 weeks. A subset of rats received either daily (5X a week) IP injections of 2 mg/kg erlotinib or vehicle control during weeks 13 - 18. In a separate study, the erlotinib dose was lowered to 0.5 mg/kg. The vehicle groups from the two studies were not significantly different so they were combined together for analysis. Rats were weighed at the end of each week. Animals were sacrificed at 9, 13 and 19 weeks after a one-week washout period to eliminate acute effects of DEN. At the time of sacrifice, the non-tumor liver tissues were collected in RNase-free tubes and snap-frozen in liquid nitrogen. Frozen tissues were stored at -80M-BM-0C until RNA extraction.

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Effects of MDMA and Venlafaxine treatment in Dark Agouti rats

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