Arctigenin Effectively Ameliorates Memory Impairment in Alzheimer's Disease Model Mice Targeting Both  -Amyloid Production and Clearance

Abstract

Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery.

LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy

“…Primary cortical neuron culture Primary neuronal cultures from embryonic mouse brains (embryonic d 16 to 18) were created according to the approach described in the literature [12] . Briefly, cerebral cortices were separated from the brain, minced into small pieces, digested with D-Hanks buffer (5.4 mmol/L KCl, 0.41 mmol/L KH 2 PO 4 , 138 mmol/L NaCl, 4.5 mmol/L NaHCO 3 , 0.22 mmol/L Na 2 HPO 4 , pH 7.4) containing 0.125% trypsin and 200 U/mL DNase (Sigma-Aldrich, St Louis, MO, USA) and then incubated for 15 min at 37 °C, followed by mechanical dissociation by pipetting in DMEM with 10% FBS.…”

Amyloid beta: structure, biology and structure-based therapeutic development

“…Huperzine A [326,327] , 2,2',4'-trihydroxychalcone (TDC) [328] and bis(7)-cognitin [329] exhibit neuroprotective effects. Agenin [330] and clioquinol [331] can inhibit Aβ deposition. Other inhibitors, such as the RAGE inhibitor azeliragon, the α7-nAChR inhibitor encenicline and the calcium antagonist nilvaldipine, can improve memory and could be further candidates for Alzheimer's disease therapeutics [332][333][334] (Table 9).…”

Elucidation of Arctigenin Pharmacokinetics After Intravenous and Oral Administrations in Rats: Integration of In Vitro and In Vivo Findings via Semi-mechanistic Pharmacokinetic Modeling

“…It has been suggested that AR possesses anti-viral (1-3), anti-inflammation (4-6), and immunomodulation effects (7) in a variety of in vitro and in vivo models. It was also demonstrated, in a diseased mice model, that AR had potential as a drug candidate for the treatment of Alzheimer's disease through targeting β-amyloid formation and clearance, with the effect of ameliorating memory impairment (8). However, the most extensively studied therapeutic aspect of AR is its anti-cancer activity, resulting in the launch of its phase I and II clinical trials, in which AR was used as the second-line therapeutic agent for the treatment of pancreatic cancer (9).…”