5 research outputs found
2-Benzazepine Nitrones Protect Dopaminergic Neurons against 6-Hydroxydopamine-Induced Oxidative Toxicity
A number of C-3 spirocyclic 2-benzazepine analogs of a-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 nigrostriatal
pathway in rodent models of Parkinsonâs 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 structureâactivity relationships. In particular, 5 and 10, bearing
C-3 spiro cyclopentyl and tetrahydropyranyl moieties, respectively, at 8 mM 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 mM, which would enhance its potential as neuroprotective agent in
Alzheimerâs neurodegeneration. These findings extend the utility of benzazepine-based PBN
analogs in the treatment of age-related free radical-mediated disorders