A novel glycogen synthase kinase‐3 inhibitor 2‐methyl‐5‐(3‐{4‐[(S )‐methylsulfinyl]phenyl}‐1‐benzofuran‐5‐yl)‐1,3,4‐oxadiazole decreases tau phosphorylation and ameliorates cognitive deficits in a transgenic model of Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration in cognitive function and memory and has two pathological hallmark lesions: senile plaques and neurofibrillary tangles (NFTs). These pathological features are comprised of the small AbstractAlzheimer's disease (AD) is a neurodegenerative disorder leading to a progressive loss of cognitive function and is pathologically characterized by senile plaques and neurofibrillary tangles. Glycogen synthase kinase-3 (GSK-3) is involved in AD pathogenesis. GSK-3 is reported not only to phosphorylate tau, a major component of neurofibrillary tangles, but also to regulate the production of amyloid b, which is deposited in senile plaques. Therefore, pharmacological inhibition of GSK-3 is considered an attractive therapeutic approach. In this study, we report the pharmacological effects of a novel GSK-3 inhibitor, 2-methyl-5-(3-{4-[(S)-methylsulfinyl] phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole (MMBO), which displays high selectivity for GSK-3 and brain penetration following oral administration. MMBO inhibited tau phosphorylation in primary neural cell culture and also in normal mouse brain. When administered to a transgenic mouse model of AD, MMBO significantly decreased hippocampal tau phosphorylation at GSK-3 sites. Additionally, chronic MMBO administration suppressed tau pathology as assessed by AT8-immunoreactivity without affecting amyloid b pathology. Finally, in behavioral assessments, MMBO significantly improved memory and cognitive deficits in the Y-maze and in novel object recognition tests in the transgenic AD mouse model. These results indicate that pharmacological GSK-3 inhibition ameliorates behavioral dysfunction with suppression of tau phosphorylation in an AD mouse model, and that MMBO might be beneficial for AD treatment.

Blockade of Tau Hyperphosphorylation and Aβ1–42 Generation by the Aminotetrahydrofuran Derivative ANAVEX2-73, a Mixed Muscarinic and σ1 Receptor Agonist, in a Nontransgenic Mouse Model of Alzheimer’s Disease

“…Indeed, an orally administrable-related oxidiazole, 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole (MMBO), was recently shown to decrease hippocampal Tau phosphorylation at GSK-3 sites, but without affecting Ab pathology, in the 3xTg transgenic AD mouse model. In behavioral assessments, MMBO significantly improved memory deficits in the Y-maze and novel object recognition tests (Onishi et al, 2011). Therefore, these molecules appeared effective in preclinical tests.…”

Therapeutic strategies for tau mediated neurodegeneration

“…By contrast, the trial in amnestic mild cognitive impairment suggested that lithium treatment was associated with a decrease in p-tau in the CSF and better cognitive performance. Another GSK inhibitor, 2-methyl-5-(3-{4-[(S)-methylsulfinyl] phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole, reduces hippocampal tau phosphorylation at GSK-3 sites and ameliorates behavioural dysfunction in 3×Tg-AD mice 70. The non-specific tau kinase inhibitor K252a (for CDK5, GSK3 and ERK1) also reduced levels of hyperphosphorylated tau and ameliorated the motor phenotype in P301L mutant tau Tg mice (JNPL3) 71.…”

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…However, the mice did not live longer. 2-Methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole, another novel GSK-3 inhibitor, has recently been reported to produce a similar positive outcome in vitro and in a mouse model (Onishi et al, 2011). Successfully targeting GSK-3, now a goal in many disease fields, is evidently a complex undertaking.…”

“…Surprisingly, A␤ plaque removal was the only mechanism considered by these authors, despite the doubt cast on the utility of this endpoint by the AD patient trial of AN1792 (A␤42; Elan Pharmaceuticals, South San Francisco, CA) several years ago (Holmes et al, 2008). It is useful to recall, when interpreting Onishi et al, 2011 this bexarotene data, that anti-TNF treatment produces a very similar outcome in the same mouse model (Shi et al, 2011), and an apoE mimetic has since done so in a related mouse strain (Vitek et al, 2012). Literature exists on the side effects of bexarotene, but whether these arise from high apoE or other consequences of retinoid X receptor activation has yet to be determined.…”