No abstract

There is a great interest in the relationship between Mild Cognitive Impairment (MCI) and the progression to Alzheimer's disease (AD). Several studies show the importance of oxidative stress in the pathogenesis of AD. The purpose of this study was the link between oxidative damage, MCI and AD. It analysed protein carbonyls and erythrocyte glutathione system plasma levels of 34 subjects with MCI, 45 subjects with AD and 28 age-matched control subjects. The results showed an increase in protein modification, a decrease in GSH levels and GSH/GSSG ratio in AD and MCI patients compared to age-matched control subjects (p<0.05). The present study shows that some peripheral markers of oxidative stress appear in MCI with a similar pattern to that observed in AD, which suggests that oxidative stress might represent a signal of the AD pathology. AD and MCI are biochemically equivalent. MCI does not necessarily need to progress to AD on a biochemical level.

Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. Because the current therapies only lead to temporary, limited improvement and have severe side effects, new approaches to treat PD need to be developed. To discover new targets for potential therapeutic intervention, a chemical genetic approach involving the use of small molecules as pharmacological tools has been implemented. First, a screening of an in-house chemical library on a wellestablished cellular model of PD was done followed by a detailed pharmacological analysis of the hits. Here, we report the results found for the small heterocyclic derivative called SC001, which after different enzymatic assays was revealed to be a new glycogen synthase kinase-3 (GSK-3) inhibitor with IC 50 = 3.38 ± 0.08 μM. To confirm that GSK-3 could be a good target for PD, the evaluation of a set of structurally diverse GSK-3 inhibitors as neuroprotective agents for PD was performed. Results show that inhibitors of GSK-3 have neuroprotective effects in vitro representing a new pharmacological option for the disease-modifying treatment of PD. Furthermore, we show that SC001 is able to cross the blood−brain barrier, protects dopaminergic neurons, and reduces microglia activation in in vivo models of Parkinson disease, being a good candidate for further drug development.