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1.
Nat Commun ; 9(1): 3025, 2018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-30072689

RESUMO

In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Substitution of phosphatidylcholine and phosphatidylethanolamine in the diet is sufficient to overcome the myelination deficit of affected Schwann cells in vivo. This treatment rescues the number of myelinated axons in the peripheral nerves of the CMT rats and leads to a marked amelioration of neuropathic symptoms. We propose that lipid supplementation is an easily translatable potential therapeutic approach in CMT1A and possibly other dysmyelinating neuropathies.


Assuntos
Doença de Charcot-Marie-Tooth/terapia , Metabolismo dos Lipídeos , Bainha de Mielina/metabolismo , Animais , Axônios/metabolismo , Axônios/ultraestrutura , Gorduras na Dieta/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/biossíntese , Bainha de Mielina/ultraestrutura , Fosfolipídeos/metabolismo , Ratos Transgênicos , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Células de Schwann/patologia
2.
Clin Pharmacol Ther ; 99(6): 633-41, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26659468

RESUMO

The low bioavailability of the anti-migraine drug sumatriptan is partially caused by first-pass hepatic metabolism. In this study, we analyzed the impact of the hepatic organic cation transporter OCT1 on sumatriptan cellular uptake, and of OCT1 polymorphisms on sumatriptan pharmacokinetics. OCT1 transported sumatriptan with high capacity and sumatriptan uptake into human hepatocytes was strongly inhibited by the OCT1 inhibitor MPP(+) . Sumatriptan uptake was not affected by the Met420del polymorphism, but was strongly reduced by Arg61Cys and Gly401Ser, and completely abolished by Gly465Arg and Cys88Arg. Plasma concentrations in humans with two deficient OCT1 alleles were 215% of those with fully active OCT1 (P = 0.0003). OCT1 also transported naratriptan, rizatriptan, and zolmitriptan, suggesting a possible impact of OCT1 polymorphisms on the pharmacokinetics of other triptans as well. In conclusion, OCT1 is a high-capacity transporter of sumatriptan and polymorphisms causing OCT1 deficiency have similar effects on sumatriptan pharmacokinetics as those observed in subjects with liver impairment.


Assuntos
Fígado/efeitos dos fármacos , Fígado/metabolismo , Fator 1 de Transcrição de Octâmero/genética , Fator 1 de Transcrição de Octâmero/metabolismo , Polimorfismo Genético , Agonistas do Receptor de Serotonina/farmacocinética , Sumatriptana/farmacocinética , Alelos , Disponibilidade Biológica , Permeabilidade da Membrana Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Genótipo , Células HEK293 , Hepatócitos/metabolismo , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Fator 1 de Transcrição de Octâmero/antagonistas & inibidores , Agonistas do Receptor de Serotonina/sangue , Sumatriptana/sangue , Triptaminas/farmacocinética
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