Amelioration of Cognitive Dysfunction in APP/PS1 Double Transgenic Mice by Long-Term Treatment of 4-O-Methylhonokiol

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease without known ways to cure. A key neuropathologic manifestation of the disease is extracellular deposition of beta-amyloid peptide (Aβ). Specific mechanisms underlying the development of the disease have not yet been fully understood. In this study, we investigated effects of 4-O-methylhonokiol on memory dysfunction in APP/PS1 double transgenic mice. 4-O-methylhonokiol (1 mg/kg for 3 month) significantly reduced deficit in learning and memory of the transgenic mice, as determined by the Morris water maze test and step-through passive avoidance test. Our biochemical analysis suggested that 4-O-methylhonokiol ameliorated Aβ accumulation in the cortex and hippocampus via reduction in beta-site APP-cleaving enzyme 1 expression. In addition, 4-O-methylhonokiol attenuated lipid peroxidation and elevated glutathione peroxidase activity in the double transgenic mice brains. Thus, suppressive effects of 4-O-methylhonokiol on Aβ generation and oxidative stress in the brains of transgenic mice may be responsible for the enhancement in cognitive function. These results suggest that the natural compound has potential to intervene memory deficit and progressive neurodegeneration in AD patients.

4′-O-methylhonokiol increases levels of 2-arachidonoyl glycerol in mouse brain via selective inhibition of its COX-2-mediated oxygenation

“…These findings suggest that MH maintained the ability to specifically inhibit COX-2-mediated EC oxygenation in vivo without affecting the oxygenation of AA. Several publications have recently demonstrated in vitro and in vivo beneficial effects of MH in neurodegenerative disease models [ 2 , 4 , 36 ]. Nonetheless, the penetration of the compound across the blood-brain barrier has never been investigated.…”

“…Despite the reported poor bioavailability after single oral administration [ 57 ], upon repeated doses, MH might accumulate and exert pharmacological effects in the brain. This could also explain the beneficial effects reported for long-term treatment with low doses of MH administered per os (0.1 to 1 mg kg −1 ) in neurodegenerative animal models [ 2 , 4 , 36 ]. CB 2 receptors are almost absent in the CNS under normal conditions, but upon inflammation, they are significantly upregulated in microglial cells.…”

“…4′- O -methylhokiol (MH) is the major bioactive constituent of Magnolia grandiflora L. seed oil and shows pronounced anti-inflammatory, anti-osteoclastogenic, and neuroprotective effects [ 1 - 4 ]. In mouse models, MH prevents LPS-induced memory loss and β -amyloid (1 to42) accumulation [ 2 ].…”

The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice

“…These oxidative damage associated changes can be partially modeled in APP/PS1 transgenic mice expressing human mutations for the amyloid precursor protein (APP) and human presenilin-1 (PS-1). These mice also have increased Aβ content in the brain and exhibit changes associated with enhanced oxidative stress (Jung, et al, 2014,Kanninen, et al, 2009,Liu, et al, 2014,Lv, et al, 2014)…”

Synthetic Cannabinoid Receptor Agonists and Antagonists: Implication in CNS Disorders

“…8) is a relatively simple biphenyl scaffold which is the major bioactive constituent of Magnolia grandiflora L. seed oil. MH showed to potently and selectively activate CB2 receptors [110] and to exert pronounced anti-inflammatory, anti-osteoclastogenic, and neuroprotective effects in vivo [111][112][113]. MH was patented as a potential treatment for inflammatory diseases [114], dementia [115] and preventing amyloid-related diseases [116].…”