Corrigendum: Melatonin and Nitrones As Potential Therapeutic Agents for Stroke.

[This corrects the article on p. 281 in vol. 8, PMID: 27932976.].

Melatonin and Nitrones As Potential Therapeutic Agents for Stroke.

Stroke is a disease of aging affecting millions of people worldwide, and recombinant tissue-type plasminogen activator (r-tPA) is the only treatment approved. However, r-tPA has a low therapeutic window and secondary effects which limit its beneficial outcome, urging thus the search for new more efficient therapies. Among them, neuroprotection based on melatonin or nitrones, as free radical traps, have arisen as drug candidates due to their strong antioxidant power. In this Perspective article, an update on the specific results of the melatonin and several new nitrones are presented.

Novel tacrine-related drugs as potential candidates for the treatment of Alzheimer's disease.

A summary of the recently published efforts on tacrine derivatives as a renewed potential therapeutic approach for the treatment of Alzheimer's disease is presented.

Drugs for stroke: action of nitrone (Z)-N-(2-bromo-5-hydroxy-4-methoxybenzylidene)-2-methylpropan-2-amine oxide on rat cortical neurons in culture subjected to oxygen-glucose-deprivation.

The action of (Z)-N-(2-bromo-5-hydroxy-4-methoxybenzylidene)-2-methylpropan-2-amine oxide (RP6) on rat cortical neurons in culture, under oxygen-glucose-deprivation conditions, is reported. Cortical neurons in culture were treated during 1 h with OGD. After, they were placed under normal conditions during 24 h (reperfusion) in absence and presence of RP6. Different parameters were measured under each condition (control, 1 h OGD and 1 h OGD + reperfusion in absence and presence of RP6). RP6 protects neurons against ROS generation, lipid peroxidation levels, LDH release and mitochondrial membrane potential alteration, when administered during reperfusion after the OGD damage. Consequently, these results show that nitrone RP6 protects cells against ischemia injury produced during the reoxygenation, and could be a potential drug for the ictus therapy.

Synthesis, structure, theoretical and experimental in vitro antioxidant/pharmacological properties of α-aryl, N-alkyl nitrones, as potential agents for the treatment of cerebral ischemia.

The synthesis, structure, theoretical and experimental in vitro antioxidant properties using the DPPH, ORAC, and benzoic acid, as well as preliminary in vitro pharmacological activities of (Z)-α-aryl and heteroaryl N-alkyl-nitrones 6-15, 18, 19, 21, and 23, is reported. In the in vitro antioxidant activity, for the DPPH radical test, only nitrones bearing free phenol groups gave the best RSA (%) values, nitrones 13 and 14 showing the highest values in this assay. In the ORAC analysis, the most potent radical scavenger was nitrone indole 21, followed by the N-benzyl benzene-type nitrones 10 and 15. Interestingly enough, the archetypal nitrone 7 (PBN) gave a low RSA value (1.4%) in the DPPH test, or was inactive in the ORAC assay. Concerning the ability to scavenge the hydroxyl radical, all the nitrones studied proved active in this experiment, showing high values in the 94-97% range, the most potent being nitrone 14. The theoretical calculations for the prediction of the antioxidant power, and the potential of ionization confirm that nitrones 9 and 10 are among the best compounds in electron transfer processes, a result that is also in good agreement with the experimental values in the DPPH assay. The calculated energy values for the reaction of ROS (hydroxyl, peroxyl) with the nitrones predict that the most favourable adduct-spin will take place between nitrones 9, 10, and 21, a fact that would be in agreement with their experimentally observed scavenger ability. The in vitro pharmacological analysis showed that the neuroprotective profile of the target molecules was in general low, with values ranging from 0% to 18.7%, in human neuroblastoma cells stressed with a mixture of rotenone/oligomycin-A, being nitrones 18, and 6-8 the most potent, as they show values in the range 24-18.4%.

Mechanisms of nitric oxide-induced apoptosis in bovine chromaffin cells: Role of mitochondria and apoptotic proteins.

The aim of this work was to establish the possible involvement of mitochondria in the apoptotic event triggered by nitric oxide (NO) in chromaffin cells. Using bovine chromaffin cells in primary culture and several NO donors (SNP, SNAP, and GSNO) at apoptotic concentrations (50 microM-1 mM), we have shown that NO induces a time-dependent decrease in the mitochondrial transmembrane potential (DeltaPsi(m)), which correlates with the appearance of hypodiploid cells. Disruption in DeltaPsi(m) is followed by cytochrome c release to the cytosol, which in turn precedes caspase 3 activation. In this mechanism participates the Bcl-2 protein family, because NO donors downregulate the expression of anti-apoptotic members of the family such as Bcl-2 and Bcl-XL, and increase the expression of pro-apoptotic members, Bax and Bcl-Xs, inductors of cytochrome c release to cytosol. Different cell signaling pathways seem to regulate Bax induction and Bcl-2 inhibition because decreased Bcl-2 levels are detected later than enhanced Bax expression. The tumour suppressor protein p53 is also upregulated in a very early phase (30 min) of the NO-induced apoptosis and may be responsible for the further induction of Bax expression. Finally, the translocation of NF-kappaB to the nucleus seems to be another early event in NO-induced apoptosis and it may be involved in the regulation of p53 expression. These results support strongly the participation of mitochondrial mechanisms in NO-induced apoptosis in chromaffin cells and suggest that these cells may be good models for the investigation of molecular basis of neurodegeneration and neuroprotection.