Pharmacogenomic Study to Predict Neurotoxicity of Oxaliplatin
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ABSTRACT:
DISEASE(S): Curatively Resected Stage Iii Colon Cancer,Colonic Neoplasms
PROVIDER: 2078065 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:In this study, we used the adult zebrafish model of ACR acute neurotoxicity for determining the suitability of NAC to protect the brain against ACR toxicity. First, the potential protective effects of NAC on the ACR neurotoxicity were evaluated at the behavioral and molecular (transcriptome and proteome) levels. Then, in order to understand the mild to negligible protective effect of NAC, the ability of this drug to cross BBB by passive diffusion was evaluated by different approaches. Whereas the BBB parallel artificial membrane permeability assay (BBB-PAMPA) was used to determine the ability of NAC to cross BBB-like phospholipid membranes by passive diffusion, the determination of the NAC content in the brain provides direct evidences of the BBB permeability in vivo. Finally, we evaluated the ability of drug to recover the depleted GSx stores and to scavenge ACR in the brain of ACR-exposed fish.
2020-05-26 | PXD014228 | Pride
Project description:Chemotherapy neurotoxicity is codependent on cancer
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Project description:Treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) can cause neurotoxicity in patients. The role of microglia in CAR19-induced neurotoxicity was unclear. We observed morphological microglia alterations, increased production of GM-CSF, MCP-1 and TNF by microglia and neurocognitive deficits in B-cell lymphoma-bearing mice upon CAR19 transfer. Gene expression analysis was performed to determine the microglial activation and downstream signalling in response to CAR19 transfer.
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Project description:Background: Acrylamide (ACR) is a broadly spread neurotoxic chemical of public health concern, as occupational or environmental exposure of humans to ACR may lead to a synaptopathy characterized by ataxia, skeletal muscles weakness and numbness of the extremities. Currently, only the mildly affected patients undergo complete recovery, and identification of new molecules with therapeutic bioactivity against ACR acute neurotoxicity is urgently needed. Objectives: We aimed to develop a zebrafish model for human ACR neurotoxicity. Methods: Adverse effects have been assessed at different levels, including analysis of the motor function (basal locomotor activity, visual motor response, kinematic of the touch-evoked escape response), histopathological evaluation (toluidine blue and whole-mount immunofluorescence), analysis of neural transcriptional markers (qPCR), proteomic analysis (μLC-MS-MS) and neurotransmitters profile (LC-MS/MS). Results: Our results show that zebrafish mimics most of the pathophysiological processes described in humans and mammalian models. Motor function was altered, including the response to sudden changes in light intensity. Specific effects were found on the presynaptic nerve terminals at the neuromuscular junction level, but not on the axonal tracts or myelin sheath integrity. Transcriptional markers of proteins involved in synaptic vesicle cycle were selectively altered, and the proteomic analysis showed that ACR-adducts were formed on cysteine residues of some synaptic proteins. Finally, analysis of neurotransmitters profile showed a significant effect found on cholinergic and dopaminergic systems. Conclusions: Thus, the zebrafish model for ACR acute neurotoxicity is suitable to be used larvae for in vivo high-throughput screening of small molecule libraries for identifying new drugs against this synaptopathy.
2018-10-24 | PXD007169 | Pride
Project description:Defective mitochondrial dynamics underlie manganese-induced neurotoxicity
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