resumo
The new palladium agent Pd(2)Spermine (Spm) has been reported to exhibit promising cytotoxic properties, while potentially circumventing the known disadvantages associated to cisplatin therapeutics, namely acquired resistance and high toxicity. This work presents a nuclear magnetic resonance (NMR) metabolomics study of brain extracts obtained from healthy mice, to assess the metabolic impacts of the new Pd(2)Spm complex in comparison to that of cisplatin. The proton NMR spectra of both polar and nonpolar brain extracts were analyzed by multivariate and univariate statistics, unveiling several metabolite variations during the time course of exposition to each drug (1-48 h). The distinct time-course dependence of such changes revealed useful information on the drug-induced dynamics of metabolic disturbances and recovery periods, namely regarding amino acids, nucleotides, fatty acids, and membrane precursors and phospholipids. Putative biochemical explanations were proposed, based on existing pharmacokinetics data and previously reported metabolic responses elicited by the same metal complexes in the liver of the same animals. Generally, results suggest a more effective response of brain metabolism towards the possible detrimental effects of Pd(2)Spm, with more rapid recovery back to metabolites' control levels and, thus, indicating that the palladium drug may exert a more beneficial role than cDDP in relation to brain toxicity.
palavras-chave
PLATINUM-INDUCED NEUROTOXICITY; IN-VITRO; N-ACETYLASPARTATE; TISSUE; NMR; SPERMINE; CELL; TOXICITY; PALLADIUM(II); SPECTROSCOPY
categoria
Pharmacology & Pharmacy
autores
Carneiro, TJ; Vojtek, M; Goncalves-Monteiro, S; Neves, JR; de Carvalho, ALMB; Marques, MPM; Diniz, C; Gil, AM
nossos autores
Ana Maria Pissarra Coelho Gil
Professor Associado com Agregação
Tatiana João Ribeiro Gonçalves Carneiro
Estudante de doutoramentoProjectos
CICECO - Aveiro Institute of Materials (UIDB/50011/2020)
agradecimentos
This research was developed within the scope of the CICECO-Aveiro Institute of Materials, with references UIDB/50011/2020 and UIDP/50011/2020, financed by national funds through the Portuguese Foundation for Science and Technology (FCT/MEC) and when appropriate co-financed by the European Regional Development Fund (FEDER) under the PT2020 Partnership Agreement. This work was also funded by the FCT through LAQV/REQUIMTE FCT UIDB/50006/2020 (C.D.), UIDB/00070/2020 (A.L.M.B.d.C. and M.P.M.M.), POCI-01-0145-FEDER-0016786, and Centro-01-0145FEDER-029956 (co-financed by COMPETE 2020, Portugal 2020 and European Community through FEDER). We also acknowledge the Portuguese National NMR Network (PTNMR), supported by FCT funds as the NMR spectrometer used is part of PTNMR and partially supported by Infrastructure Project No. 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL, and the FCT through PIDDAC). M.V. thanks the FCT and the Ph.D. Program in Medicines and Pharmaceutical Innovation (i3DU) for his Ph.D. grant PD/BD/135460/2017 and T.J.C. thanks FCT for her Ph.D. grant SFRH/BD/145920/2019; both grants were funded by the European Social Fund of the European Union and national funds FCT/MCTES.