Development of L-Dopa-containing diketopiperazines as blood-brain barrier shuttle
| العنوان: | Development of L-Dopa-containing diketopiperazines as blood-brain barrier shuttle |
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| المؤلفون: | Cornacchia, C., Marinelli, L., Di Rienzo, A., Dimmito, M. P., Serra, F., Di Biase, G., De Filippis, B., Turkez, H., Mardinoglu, Adil, Bellezza, I., Di Stefano, A., Cacciatore, I. |
| المصدر: | European Journal of Medicinal Chemistry. 243 |
| مصطلحات موضوعية: | Antioxidant, Blood brain shuttle, Brain delivery system, Diketopiperazine, Levodopa, Parkinson's disease, Animals, Antioxidants, Blood-Brain Barrier, Caco-2 Cells, Carcinoma, Renal Cell, Diketopiperazines, Humans, Kidney Neoplasms, Oxidative Stress, Parkinson Disease, Rats, 8 hydroxydeoxyguanosine, free radical, glutathione, neurotoxin, piperazinedione, reactive oxygen metabolite, transcription factor Nrf2, animal cell, animal experiment, animal model, animal tissue, Article, biomembrane, biosynthesis, blood brain barrier, brain cortex, cancer model, cell culture, cell death, comet assay, controlled study, cytotoxicity, DNA damage, genetic marker, genotoxicity, half life time, human, hydrolysis, in vitro study, intestine fluid, male, newborn, nonhuman, rat, simulation, stomach juice, total antioxidant capacity, animal, Caco-2 cell line, kidney tumor, metabolism, renal cell carcinoma |
| الوصف: | In our overall goal to develop anti-Parkinson drugs, we designed novel diketopiperazines (DKP1-6) aiming to both reach the blood-brain barrier and counteract the oxidative stress related to Parkinson's Disease (PD). The anti-Parkinson properties of DKP 1–6 were evaluated using neurotoxin-treated PC12 cells, as in vitro model of PD, while their cytotoxicity and genotoxicity potentials were investigated in newborn rat cerebral cortex (RCC) and primary human whole blood (PHWB) cell cultures. The response against free radicals was evaluated by the total antioxidant capacity (TAC) assay. Comet assay was used to detect DNA damage while the content of 8-hydroxyl-2′-deoxyguanosine (8-OH-dG) was determined as a marker of oxidative DNA damage. PAMPA-BBB and Caco-2 assays were employed to evaluate the capability of DKP1-6 to cross the membranes. Stability studies were conducted in simulated gastric and intestinal fluids and human plasma. Results showed that DKP5-6 attenuate the MPP + -induced cell death on a nanomolar scale, but a remarkable effect was observed for DKP6 on Nrf2 activation that leads to the expression of genes involved in oxidative stress response thus increasing glutathione biosynthesis and ROS buffering. DKP5-6 resulted in no toxicity for RCC neurons and PHWB cells exposed to 10–500 nM concentrations during 24 h as determined by MTT and LDH assays and TAC levels were not altered in both cultured cell types. No significant difference in the induction of DNA damage was observed for DKP5-6. Both DKPs resulted stable in simulated gastric fluids (t1/2 > 22h). In simulated intestinal fluids, DKP5 underwent immediate hydrolysis while DKP6 showed a half-life higher than 3 h. In human plasma, DKP6 resulted quite stable. DKP6 displayed both high BBB and Caco-2 permeability confirming that the DKP scaffold represents a useful tool to improve the crossing of drugs through the biological membranes. |
| وصف الملف: | |
| الوصول الحر: | https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-328828Test https://doi.org/10.1016/j.ejmech.2022.114746Test |
| قاعدة البيانات: | SwePub |
| تدمد: | 02235234 17683254 |
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| DOI: | 10.1016/j.ejmech.2022.114746 |