| Alzheimer's disease (AD) is a fatal neurodegenerative disorder characterized by a progressive and global deterioration of mental function, most notably in cognitive performance. Currently, there is no treatment or prevention available for Alzheimer's disease. Organic nitrates are a group of drugs that can activate the NO/cGMP cascade in the brain, which was found to have beneficial properties that can be applied for the treatment of Alzheimer's disease. We investigated the use of hybrid organic nitrates for the treatment of Alzheimer's disease. Hybrid organic nitrates consist of an organic nitrate attached to pharmacologically active organic molecules. The active organic molecules were chosen to either lower the level of amyloid beta (flurbiprofen), a protein believed to play a key role in the development of Alzheimer's disease, or to treat depression (fluoxetine), a disease which occurs in high frequency among Alzheimer's disease patients and is believed to complicate Alzheimer's disease therapy and worsen the patients' quality of life. The advantage of a hybrid organic nitrate compared to a normal organic nitrate is the incorporation of a second warhead which can treat the disease at a different target. The benefit of aiming at more than one target is beneficial especially in diseases of multifactorial etiologies, such as Alzheimer's disease, where Abeta and neuroinflammation are believed to trigger many events leading to neurodegeneration and cognitive impairment. We designed and tested hybrid organic nitrates in both in vitro and in vivo assays. While developing a cell based assay for the determination of drug activity on the production of amyloid beta we have found that some drugs believed previously to lower amyloid beta by lowering its production were able to increase the degradation of amyloid beta. This new finding can be used to determine the biological target of these drugs and to rationally optimize their structures. |
