2-Benzazepine Nitrones Protect Dopaminergic Neurons against 6-Hydroxydopamine-Induced Oxidative Toxicity
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Abstract
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 8 µM 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 16.8 µM, 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.
Description
This is the peer reviewed version of the following article: Soto-Otero, R., Méndez-Álvarez, E., Sánchez-Iglesias, S., Labandeira-García, J.L., Rodríguez-Pallares, J., Zubkov, F.I., Zaytsev, V.P., Voskressensky, L.G., Varlamov, A.V., de Candia, M., Fiorella, F. and Altomare, C. (2012), 2-Benzazepine Nitrones Protect Dopaminergic Neurons against 6-Hydroxydopamine-Induced Oxidative Toxicity. Arch. Pharm. Pharm. Med. Chem., 345: 598-609, which has been published in final form at https://doi.org/10.1002/ardp.201200007. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.
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Soto-Otero, R., Méndez-Álvarez, E., Sánchez-Iglesias, S., Labandeira-García, J.L., Rodríguez-Pallares, J., Zubkov, F.I., Zaytsev, V.P., Voskressensky, L.G., Varlamov, A.V., de Candia, M., Fiorella, F. and Altomare, C. (2012), 2-Benzazepine Nitrones Protect Dopaminergic Neurons against 6-Hydroxydopamine-Induced Oxidative Toxicity. Arch. Pharm. Pharm. Med. Chem., 345: 598-609
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C. A. acknowledges the financial support by the Italian Ministry for Education Universities and Research (MIUR, Rome, Italy; PRIN 2007, Grant No. 2007T9HTFB_003). The Spanish authors (R. S.-O. and E. M.-A.) thank the Ministerio de Ciencia e Innovación and the European Regional Development Fund (Madrid, Spain, Grant SAF2007-66114) for financial support.