Current medicinal chemistry
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Recent evidence suggests that the development of Alzheimer's disease (AD) and related cognitive loss is due to mutations in the Amyloid Precursor Protein (APP) gene on chromosome 21 and increased activation of eukaryotic translation initiation factor-2α (eIF2α) phosphorylation. The high level of misfolded and unfolded proteins loading in Endoplasmic Reticulum (ER) lumen triggers ER stress and as a result Unfolded Protein Response (UPR) pathways are activated. Stress-dependent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) leads to the significant elevation of phospho-eIF2α. ⋯ Thus, blocking PERK-dependent eIF2α phosphorylation through specific, small-molecule PERK branch inhibitors seems to be a potential treatment strategy for AD individuals. That may contribute to the restoration of global translation rates and reduction of expression of ATF4 and BACE1. Hence, the treatment strategy can block accelerated β -amyloidogenesis by reduction in APP cleaving via the BACE1-dependent amyloidogenic pathway.
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Alcoholism is an increasing problem all over the world, and nowadays especially amongst teenagers. Although several drug treatments have been proposed for this condition, only a few have demonstrated a significant efficacy. ⋯ This drug can be very helpful in reducing the alcohol intake, and, as such, it can be considered one of the first and fundamental steps towards alcohol abstinence. The aim of this review is to discuss and comment on the available literature on nalmefene, as well as on novel treatment strategies of this condition (and perhaps of other addictions) opened by this latest pharmacological approach.