An overview of investigational antiapoptotic drugs with potential application for the treatment of neurodegenerative disorders.

IMPORTANCE OF THE FIELD: The increase in life expectancy in developed countries has given rise to several emerging social problems. Of particular note is the dramatic rise in the incidence of neurodegenerative diseases. Given this new social scenario, there is a need to identify therapeutic strategies to delay the advance of these pathologies, for which no effective treatment is currently available. AREAS COVERED IN THIS REVIEW: The present review discusses some of the drugs that are now under development with antiapoptotic activity or currently on the market that may have a potential application for the treatment of neurodegenerative diseases. Moreover, we also comment on potential compounds such as resveratrol and melatonin. Despite the lack of information from clinical trials on these two compounds, they are attracting considerable attention because of their natural origin and antioxidant and antiapoptotic action. Furthermore, they do not show toxicity in humans. In addition, we discuss the potential application of several compounds, such as NMDA antagonists, JNK inhibitors and GSK-3 inhibitors, for the treatment of neurodegenerative disorders. WHAT THE READER WILL GAIN: This article will review recent developments in the field of apoptosis inhibitors, which might provide future tools for the treatment of the neurodegenerative diseases. TAKE HOME MESSAGE: The treatment of neurodegenerative diseases is a major challenge in medicine. This is partly because the incidence of these disorders is expected to rise in the coming years. New developments in the field of apoptosis inhibitors may provide future tools for the treatment of the aforementioned neurodegenerative diseases.

Oxidative stress-related markers and langerhans cells in a hairless rat model exposed to UV radiation.

Biomarkers related to the oxidative stress in blood and epidermis and the number of Langerhans cells were determined in hairless rats after acute irradiation with 1.54, 1.93, or 2.41 J/cm2 of ultraviolet (UV) light and chronic exposure to 13 suberythemal UV doses of 1.1 J/cm2 for 2 mo. After acute UV irradiation, in epidermis, the thiobarbituric acid-reactive substances (TBARS) content increased at the highest UV dose, whereas the activities of glutathione S-transferase and catalase rose and the oxidized glutathione (GSSG) content diminished at all UV doses. In erythrocytes, glutathione S-transferase activity increased at the two lowest UV doses, glutathione peroxidase activity rose at all UV doses, and catalase activity increased after the highest UV dose. In plasma, the TBARS content and the reduced glutathione (GSH)/GSSG ratio increased at the highest UV dose; the number of Langerhans cells decreased at all UV doses. Linear Pearson correlation analysis revealed many relationships between different biomarkers, and multiple linear regression analysis indicated that the number of Langerhans cells was predicted by epidermal GSSG and catalase (R2 = .64) and by erythrocytic glutathione peroxidase and GSSG (R2 = .72). After suberythemal UV radiation, in epidermis, the GST activity and the content of GSH and GSSG increased; in erythrocytes, the GST activity decreased and the GSH/GSSG ratio increased. Thus, the hairless rat appears to be a useful model for studying the oxidative stress-related mechanisms after UV radiation, which are involved in the loss of the immune capacity mediated by Langerhans cells, even at suberythemal doses.

Cyclosporin A enhances colchicine-induced apoptosis in rat cerebellar granule neurons.

1. Cyclosporin A (CsA, 1-50 microM), an immunosuppressive drug with known neurotoxic effects, did not decrease the viability of primary cultures of rat cerebellar granule neurons (CGN) or induce apoptotic features. However, CsA specifically enhanced the cytotoxicity and apoptosis induced by colchicine (1 microM). 2. Flavopiridol, an inhibitor of cyclin-dependent kinases (CDKs), prevented the neurotoxic effects of colchicine plus CsA. At 0.1-5 microM, it also showed antiapoptotic effects, as revealed by propidium iodide staining, flow cytometry and counting of cell nuclei. 3. Roscovitine (25-50 microM), a selective cdk1, 2 and 5 inhibitor, showed an antiapoptotic effect against colchicine- and colchicine plus CsA-induced apoptosis. 4. CsA increased the expression of cdk5 and cdk5/p25 mediated by colchicine, a CDK involved in neuronal apoptosis. After treatment of CGN with colchicine plus CsA, the changes in the p25/p35 ratio pointed to cdk5 activation. 5. Immunohistochemical results showed a nuclear localization of cdk5 after neurotoxic treatment, which was prevented by cdk inhibitors. Thus, we propose a new mechanism of modulation of CsA neurotoxicity mediated by cdk5.