L-3-n-Butylphthalide Improves Cognitive Impairment and Reduces Amyloid-  in a Transgenic Model of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is an age-related, progressive neurodegenerative disorder that occurs gradually and results in memory, behavior, and personality changes. L-3-n-butylphthalide (L-NBP), an extract from seeds of Apium graveolens Linn (Chinese celery), has been demonstrated to have neuroprotective effects on ischemic, vascular dementia, and amyloid-␤ (A␤)-infused animal models. In the current study, we examined the effects of L-NBP on learning and memory in a triple-transgenic AD mouse model (3xTg-AD) that develops both plaques and tangles with aging, as well as cognitive deficits. Ten-month-old 3xTg-AD mice were given 15 mg/kg L-NBP by oral gavage for 18 weeks. L-NBP treatment significantly improved learning deficits, as well as long-term spatial memory, compared with vehicle control treatment. L-NBP treatment significantly reduced total cerebral A␤ plaque deposition and lowered A␤ levels in brain homogenates but had no effect on fibrillar A␤ plaques, suggesting preferential removal of diffuse A␤ deposits. Furthermore, we found that L-NBP markedly enhanced soluble amyloid precursor protein secretion (␣APPs), ␣-secretase, and PKC␣ expression but had no effect on steady-state full-length APP. Thus, L-NBP may direct APP processing toward a non-amyloidogenic pathway and preclude A␤ formation in the 3xTg-AD mice. The effect of L-NBP on regulating APP processing was further confirmed in neuroblastoma SK-N-SH cells overexpressing wild-type human APP 695 (SK-N-SH APPwt). L-NBP treatment in 3xTg-AD mice also reduced glial activation and oxidative stress compared with control treatment. L-NBP shows promising preclinical potential as a multitarget drug for the prevention and/or treatment of Alzheimer's disease.

The endocannabinoid system in normal and pathological brain ageing

“…Generally, it was found that anti-oxidant treatment or activation of anti-oxidative pathways improve brain functions and partially restores age-dependent changes in gene expression both in normal ageing [87,88] and in models of accelerated ageing [89,90]. Clinical data suggest that dietary anti-oxidants have some protective effects against AD, Parkinson's disease and amyotrophic lateral sclerosis [91] and also in pharmacological and genetic models of neurodegenerative disorders [92][93][94]. We have to note that ROS have an important intracellular signalling function: oxidative stress responses may regulate autophagy and induce synaptic growth [95,96] suggesting that long-lasting diminished ROS production by pharmacological treatment could have a negative impact on brain functions.…”

Potassium 2-(1-Hydroxypentyl)-Benzoate Improves Memory Deficits and Attenuates Amyloid andτPathologies in a Mouse Model of Alzheimer's Disease

“…It is likely that aAPPs derived from dl-PHPB-mediated APP processing may serve as neuroprotective agents and contribute to the long-term benefit of dl-PHPB on memory in APP/PS1 mice. In addition, our previous study demonstrated that 3-nbutylphthalide (NBP) isoform could regulate APP processing and lowered Ab generation in AD mouse models (Peng et al, 2010. It has been demonstrated that Thr668-phosphorylated APP was significantly increased in AD brains.…”

“…Immunohistochemistry was performed using the ELITE ABC method (Vector Laboratories, Burlingame, CA) as previously described (Peng et al, 2010). Ten-micron sagittal cryosections of mouse brain were mounted on glass slides.…”

Pharmacokinetics, safety and tolerability of L-3-n-butylphthalide tablet after single and multiple oral administrations in healthy Chinese volunteers

“…(Chang, Wang, 2003). L-NBP has been shown to reduce β-amylase-induced neuronal apoptosis and to improve cognitive function in Alzheimer's disease animal models (Peng et al, 2009;Peng et al, 2012;Peng et al, 2010;Peng et al, 2008;Xiang et al, 2014). Additionally, L-NBP has been demonstrated to ameliorate cognitive deficits and neuronal loss in the hippocampus of mice exposed to repetitive cerebral ischemia and reperfusion (Huai et al, 2013).…”