2-Benzazepine nitrones protect dopaminergic neurons against 6-hydroxydopamine-induced oxidative toxicity

A number of C-3 spirocyclic 2-benzazepine analogs of α-phenyl-N-tert- butyl nitrone (PBN) were synthesized and tested for their activity in protecting rat brain mitochondria and dopaminergic (DA) neurons against 6-hydroxydopamine (6-OHDA), a toxin inducing destruction of the DA nigro-striatal pathway in rodent models of Parkinson's disease. The newly synthesized nitrone derivatives were firstly investigated for their activity in decreasing the level of hydroxyl radicals generated during 6-OHDA oxidation, and inhibit lipid peroxidation (TBARS assay) and protein carbonyl content (PCC) in rat brain mitochondria. Most of the studied 2-benzazepine nitrones showed inhibitory potencies in both TBARS and PCC assays at least two magnitude orders higher than that of PBN. The data obtained usefully complemented the known structure-activity relationships. In particular, 5 and 10, bearing C-3 spiro cyclopentyl and tetrahydropyranyl moieties, respectively, at 8μM concentration proved to be significantly more effective than PBN in protecting cultured DA neurons exposed to 6-OHDA, which alone causes about 45% cell loss in 24 h. In addition, we found that 5 inhibited butyrylcholinesterase with an IC50 value of 16.8μM, which would enhance its potential as neuroprotective agent in Alzheimer's neurodegeneration. These findings extend the utility of benzazepine-based PBN analogs in the treatment of age-related free radical-mediated disorders. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Authors
Soto-Otero R.1 , Méndez-Álvarez E.1 , Sánchez-Iglesias S.1 , Labandeira-García J.L.2 , Rodríguez-Pallares J.2 , Zubkov F.I. 3 , Zaytsev V.P. 3 , Voskressensky L.G. 3 , Varlamov A.V. 3 , De Candia M. , Fiorella F.4 , Altomare C.4
Number of issue
8
Language
English
Pages
598-609
Status
Published
Volume
345
Year
2012
Organizations
  • 1 Facultad de Medicina, Departamento de Bioquímica y Biología Molecular, Universidad de Santiago de Compostela, Santiago de Compostela, Spain
  • 2 Facultad de Medicina, Departamento de Ciencias Morfolõgicas, Universidad de Santiago de Compostela, Santiago de Compostela, Spain
  • 3 Organic Chemistry Department, Russian Peoples Friendship University, Moscow, Russian Federation
  • 4 Facoltá di Farmacia, Dipartimento Farmaco-Chimico, Universitá Degli Studi di Bari Aldo Moro, Via E.Orabona 4, I-70125 Bari, Italy
Keywords
2-Benzazepine nitrones; 6-Hydroxydopamine; Cholinesterase inhibition; Dopaminergic neurons; Neuroprotection
Date of creation
19.10.2018
Date of change
13.08.2021
Short link
https://repository.rudn.ru/en/records/article/record/2283/
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