The Potential Therapeutic Effects of THC on Alzheimer's Disease

Article · July 2014with4,279 Reads
DOI: 10.3233/JAD-140093 · Source: PubMed
The purpose of this study was to investigate the potential therapeutic qualities of Δ9-tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer's disease. N2a-variant amyloid-β protein precursor (AβPP) cells were incubated with THC and assayed for amyloid-β (Aβ) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Aβ level in N2a/AβPPswe cells. THC was also tested to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T assays and western blots were performed to test the direct anti-Aβ aggregation significance of THC. Lastly, THC was tested to determine its effects on glycogen synthase kinase-3β (GSK-3β) and related signaling pathways. From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin's enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer's disease through multiple functions and pathways.
    • The non-selective CBR agonist WIN-55,212-2 inhibited Ab-induced tau hyperphosphorylation via CB1R but not CB2R in PC12 neuronal cells (Esposito et al. 2006). In another study, D 9-THC reduced phosphorylated tau in N2a/APPswe cells (Cao et al. 2014). The CB2R agonist JWH-133 decreased tau phosphorylation at Thr181 and also decreased the expression of the active forms of GSK3b, p38 and SAPK/JNK in APP/PS1 mice (Aso et al. 2013).
    [Show abstract] [Hide abstract] ABSTRACT: Most neurodegenerative disorders (NDDs) are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well defined. Several mechanisms have been proposed to contribute to the development of NDDs. These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies. In this review, we discuss the functions of the endocannabinoid (EC) system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jun 2017
    • with neuroprotective properties. It directly affects Alzheimer's disease facilitating the decrease of the levels of the beta-amyloid protein, preventing its build-up and facilitating the mitochondrial function, according to Chuanhai Cao.[32]Cognitive rehabilitation is another alternative therapeutical method, aimed at re-training the abilities to think, to reason, to evaluate, to make decisions and to plan activities. It is focused on recovering the deficits of memory, attention, learning skills, etc., in patients with neurodegenerative nervous diseases.
    Full-text · Article · Apr 2017
    • The mechanisms by which CB 2 receptors mediate these anti-oxidant effects remain elusive. It has been reported that the CB 1 –CB 2 agonist ∆ 9 -THC improves mitochondrial function (Cao et al., 2014), thus presumably contributing to a reduction in the production of free radicals, but further study is needed to support this hypothesis. Additional benefits of the activation of CB 2 receptors in AD may derive from the ability of these receptors to mediate glucose uptake in brain (Moreno et al., 2012; Köfalvi et al., 2016), which may counteract the well-known glucose metabolism deficit in AD brains (Mosconi et al., 2008; Cohen and Klunk, 2014).
    [Show abstract] [Hide abstract] ABSTRACT: The CB2 receptor is one of the components of the endogenous cannabinoid system, a complex network of signaling molecules and receptors involved in the homeostatic control of several physiological functions. Accumulated evidence suggests a role for CB2 receptors in Alzheimer's disease (AD) and indicates their potential as a therapeutic target against this neurodegenerative disease. Levels of CB2 receptors are significantly increased in post-mortem AD brains, mainly in microglia surrounding senile plaques, and their expression levels correlate with the amounts of Aβ42 and β-amyloid plaque deposition. Moreover, several studies on animal models of AD have demonstrated that specific CB2 receptor agonists, which are devoid of psychoactive effects, reduce AD-like pathology, resulting in attenuation of the inflammation associated with the disease but also modulating Aβ and tau aberrant processing, among other effects. CB2 receptor activation also improves cognitive impairment in animal models of AD. This review discusses available data regarding the role of CB2 receptors in AD and the potential usefulness of specific agonists of these receptors against AD.
    Full-text · Article · May 2016
    • Since maternal cannabis consumption during pregnancy is associated with foetal growth restriction and lower birth weight (El Marroun et al., 2009), the THC enhancement of STs mitochondrial activity may be related to the mechanisms by which cannabis use leads to these complications. Supporting our evidence, Cao et al. (2014) recently reported that THC enhanced mitochondrial function in an Alzheimer's disease model. However, other studies demonstrated that THC disrupted mitochondrial function in other cell types, though this effect was observed with higher concentrations than those reported in our work (Badawy et al., 2009; Sarafian et al., 2003).
    [Show abstract] [Hide abstract] ABSTRACT: The noxious effects of cannabis consumption for fertility and pregnancy outcome are recognized for years. Its consumption during gestation is associated with alterations in foetal growth, low birth weight and preterm labor. The main psychoactive molecule of cannabis, Δ(9)-tetrahydrocannabinol (THC) impairs the production of reproductive hormones and is also able to cross the placenta barrier. However, its effect on the main placental cells, the trophoblasts, are unknown. Actually, the role of THC in cell survival/death of primary human cytotrophoblasts (CTs) and syncytiotrophoblasts (STs) and in the syncytialization process remains to be explored. Here, we show that THC has a dual effect, enhancing MTT metabolism at low concentrations, whereas higher doses decreased cell viability, on both trophoblast phenotypes, though the effects on STs were more evident. THC also diminished the generation of oxidative and nitrative stress and the oxidized form of glutathione, whereas the reduced form of this tripeptide was increased, suggesting that THC prevents ST cell death due to an antioxidant effect. Moreover, this compound enhances the mitochondrial function of STs, as observed by the increased MTT metabolism and intracellular ATP levels. These effects were independent of cannabinoid receptors activation. Besides, THC impaired CT differentiation into STs, since it decreased the expression of biochemical and morphological biomarkers of syncytialization, through a cannabinoid receptor-dependent mechanism. Together, these results suggest that THC interferes with trophoblast turnover, preventing trophoblast cell death and differentiation, and contribute to disclose the cellular mechanisms that lead to pregnancy complications in women that consume cannabis-derived drugs during gestation. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Full-text · Article · Jun 2015
    • Limiting the cytokines that produce the inflammatory response can help alleviate the pathologies of AD. The development of small peptides promoting anti-inflammatory response, through the suppression of inflammatory cytokines, have been seen to be beneficial in immunomodulation[74]. Compounds, such as melatonin[75,76], caffeine[77][78][79]and THC[80]over 1,000 clinical trials that are currently ongoing testing the effects of compounds on AD. As of now, there are a handful of known strategies to slow or stop the pathologies of AD through intervention with the amyloid cascade.
    Article · Jan 2015 · Toxicology
    • Wnt activation leads to inhibition of GSK-3, which is also known as tau protein kinase, responsible for a massive tau protein hyperphosphorylation and relative NFT formation observed in brains of AD patients [123]. A recent report also demonstrated that 9 -THC treatment inhibits activation of GSK-3 in N2a-variant APP cells [124].
    [Show abstract] [Hide abstract] ABSTRACT: Alzheimer's disease (AD) is the most common form of progressive neurodegenerative disease characterized by cognitive impairment and mental disorders. The actual cause and cascade of events in the progression of this pathology is not fully determined. AD is multifaceted in nature and is linked to different multiple mechanisms in the brain. This aspect is related to the lack of efficacious therapies that could slow down or hinder the disease onset/progression. The ideal treatment for AD should be able to modulate the disease through multiple mechanisms rather than targeting a single dysregulated pathway. Recently, the endocannabinoid system emerged as novel potential therapeutic target to treat AD. In fact, exogenous and endogenous cannabinoids seem to be able to modulate multiple processes in AD, although the mechanisms that are involved are not fully elucidated. This review provides an update of this area. In this review, we recapitulate the role of endocannabinoid signaling in AD and the probable mechanisms through which modulators of the endocannabinoid system provide their effects, thus highlighting how this target might provide more advantages over other therapeutic targets.
    Full-text · Article · Aug 2014
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