The Disease-modifying Drug Candidate, SAK3 Improves Cognitive Impairment and Inhibits Amyloid beta Deposition in App Knock-in Mice. (1st May 2018)

• Record Type: Journal Article
• Authors: Izumi, Hisanao; Shinoda, Yasuharu; Saito, Takashi; Saido, Takaomi C.; Sato, Keita; Yabuki, Yasushi; Matsumoto, Yotaro; Kanemitsu, Yoshitomi; Tomioka, Yoshihisa; Abolhassani, Nona; Nakabeppu, Yusaku; Fukunaga, Kohji
• Is Part Of: Neuroscience. Volume 377(2018)
• Page Start: 87
• Page End: 97
• Publication Date: 2018-05-01
• Subjects: APP amyloid precursor protein -- Aβ amyloid beta -- CaMKII Ca2+/calmodulin-dependent protein kinase II -- LTP long-term potentiation -- OBX olfactory-bulbectomized -- SAK3 ethyl-8′-methyl-2′, 4-dioxo-2-(piperidin-1-yl)-2′H-spiro[cyclopentane-1, 3′-imidazo[1, 2-a]pyridin]-2-ene-3-carboxylate -- SGK1 serum- and glucocorticoid-induced protein kinase 1 -- ST101 piro[imidazo[1, 2-a]pyridine-3, 2-indan]-2(3H)-one -- T-VGCCs T-type voltage-gated Ca2+ channels -- UPLC ultra performance liquid chromatography; T-type voltage-gated Ca2+ channel -- SAK3 -- cognitive function -- AppNL-F knock-in mouse -- pharmacokinetics; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2018.02.031
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: SAK3 treatment improves cognitive function in App NL-F knock-in mice. SAK3 decreases Aβ deposition in the brain of App NL-F knock-in mice. SAK3 is quickly absorbed and distributed in the brain after oral administration. Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of elderly dementia in the world. At present, acetylcholine inhibitors, such as donepezil, galantamine and rivastigmine, are used for AD therapy, but the therapeutic efficacy is limited. We recently proposed T-type voltage-gated Ca 2+ channels' (T-VGCCs) enhancer as a new therapeutic candidate for AD. In the current study, we confirmed the pharmacokinetics of SAK3 in the plasma and brain of mice using ultra performance liquid chromatography-tandem mass spectrometry. We also investigated the effects of SAK3 on the major symptoms of AD, such as cognitive dysfunction and amyloid beta (Aβ) accumulation, in App NL-F knock-in (NL-F) mice, which have been established as an AD model. Chronic SAK3 (0.5 mg/kg/day) oral administration for 3 months from 9 months of age improved cognitive function and inhibited Aβ deposition in 12-month-old NL-F mice. Using microarray and real-time PCR analysis, we discovered serum- and glucocorticoid-induced protein kinase 1 (SGK1) as one of possible genes involved in the inhibition of Aβ deposition and improvement of cognitive function by SAK3. These results support the idea that T-VGCC enhancer, SAK3 could be a novel candidate for disease-modifying therapeutics for AD.