Entwicklung zellulärer Testsysteme zur Suche nach neuen Wirkstoffen gegen die Alzheimer-Krankheit
Alzheimer's disease (AD) is a widespread, chronic and progressive neurodegenerative disorder of the central nervous system with multifactorial causes. AD treatment is currently based on three different types of drugs: extracts from the leaves of Ginkgo biloba, acetylcholinesterase inhibitors, and the N-methyl-D-aspartate receptor (NMDAR) antagonist memantine. Genetic polymorphisms of the APOE gene are well-known risk factors for the sporadic late-onset AD and can be related to a wide variety of neuropathological processes. There are structural differences between the apolipoprotein E (ApoE) isoforms. ApoE4 is the least stable isoform and much more susceptible to fragmentation compared to ApoE2 and ApoE3. Because of its unique conformation and reactivity, ApoE4 forms many neurotoxic fragments. A colorimetric bioassay was used to screen for protective effects against ApoE-induced toxicity. The N-methyl-D-aspartate receptor antagonist memantine is recommended for treatment of patients with moderate to severe AD. The therapeutic effect of memantine is thought to result from a reduction of glutamate-induced, Ca2+-mediated excitotoxicity in neurons. In the present study a bioassay was established to screen for new NMDAR antagonists using cell lines, which express the human NR1/NR2A and NR1/NR2B subunits of the NMDAR, respectively. Novel homobivalent ß-carboline derivatives, connecting two ß-carboline units by alkylene spacers in two different series, showed strong inhibitory activities with IC50 values comparable to memantine. The inhibitory activities of the homobivalent ß-carboline compounds seemed to depend on the presence of two quaternary nitrogens, the spacer length, and the ß-carboline structure. The pathogenesis of AD is currently not completely understood. Given that AD is caused by multiple factors, further extensive research is required to develop novel treatments that can slow down the progression of the disease or improve symptoms such as memory loss.