Cannabidiol improves memory and decreases IL-1β serum levels in rats with lipopolysaccharide-induced inflammation

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“Memory improving and anti-inflammatory properties of cannabidiol (CBD) were investigated in an experimental model of lipopolysaccharide (LPS)-induced inflammation.”

“Cannabis sativa is a plant that has been cultivated by humans and utilized in medicine since ancient times.”

“Cannabidiol (CBD) is one of the most important Cannabis-derived molecules,”

“CBD improved spatial working and recognition memory in rats with LPS-induced inflammation. Suppression of IL-1β production could be attributed to the observed effect.”

Alzheimer’s disease, aging, and cannabidiol treatment: a promising path to promote brain health and delay aging

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“Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by progressive memory loss, neurodegeneration, and cognitive decline. Aging is one of the risk factors for AD. Although the mechanisms underlying aging and the incidence rate of AD are unclear, aging and AD share some hallmarks, such as oxidative stress and chronic inflammation.

Cannabidiol (CBD), the major non-psychoactive phytocannabinoid extracted from Cannabis sativa, has recently emerged as a potential candidate for delaying aging and a valuable therapeutic tool for the treatment of aging-related neurodegenerative diseases due to its antioxidant and anti-inflammation properties.

This article reviews the relevant literature on AD, CBD treatment for AD, cellular senescence, aging, and CBD treatment for aging in recent years. By analyzing these published data, we attempt to explore the complex correlation between cellular senescence, aging, and Alzheimer’s disease, clarify the positive feedback effect between the senescence of neurocytes and Alzheimer’s disease, and summarize the role and possible molecular mechanisms of CBD in preventing aging and treating AD.

These data may provide new ideas on how to effectively prevent and delay aging, and develop effective treatment strategies for age-related diseases such as Alzheimer’s disease.”

Identification of Anti-Neuroinflammatory Bioactive Compounds in Essential Oils and Aqueous Distillation Residues Obtained from Commercial Varieties of Cannabis sativa L

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“Neuroinflammation, which is mainly triggered by microglia, is a key contributor to multiple neurodegenerative diseases.

Natural products, and in particular Cannabis sativa L., due to its richness in phytochemical components, represent ideal candidates to counteract neuroinflammation.

We previously characterized different C. sativa commercial varieties which showed significantly different chemical profiles. On these bases, the aim of this study was to evaluate essential oils and aqueous distillation residues from the inflorescences of three different hemp varieties for their anti-neuroinflammatory activity in BV-2 microglial cells. Cells were pretreated with aqueous residues or essential oils and then activated with LPS. Unlike essential oils, aqueous residues showed negligible effects in terms of anti-inflammatory activity. Among the essential oils, the one obtained from ‘Gorilla Glue’ was the most effective in inhibiting pro-inflammatory mediators and in upregulating anti-inflammatory ones through the modulation of the p38 MAPK/NF-κB pathway. Moreover, the sesquiterpenes (E)-caryophyllene, α-humulene, and caryophyllene oxide were identified as the main contributors to the essential oils’ anti-inflammatory activity. To our knowledge, the anti-neuroinflammatory activity of α-humulene has not been previously described.

In conclusion, our work shows that C. sativa essential oils characterized by high levels of sesquiterpenes can be promising candidates in the prevention/counteraction of neuroinflammation.”

Characterizing cannabis-prevalent terpenes for neuroprotection reveal a role for α and β-pinenes in mitigating amyloid β-evoked neurotoxicity and aggregation in vitro

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Background: Cannabis Sativa L. (C. sativa) can efficiently synthesize of over 200 terpenes, including monoterpenes, sesquiterpenes and triterpenes that may contribute to the known biological activities of phytocannabinoids of relevance for the burgeoning access to medicinal cannabis formulations globally; however, to date have been uncharacterized. We assessed twelve predominant terpenes in C. sativa for neuroprotective and anti-aggregative properties in semi-differentiated PC12 neuronal cell line that is robust and validated as a cell model responsive to amyloid β (Aβ1-42) protein exposure and oxidative stress.

Methods: Cell viability was assessed biochemically using the MTT assay in the presence of myrcene, β-caryophyllene, terpinolene, limonene, linalool, humulene, α-pinene, nerolidol, β-pinene, terpineol, citronellol and friedelin (1-200μM) for 24hr. Sub-toxic threshold test concentrations of each terpene were then applied to cells, alone or with concomitant incubation with the lipid peroxidant tert-butyl hyrdroperoxide (t-BHP; 0-250μM) or amyloid β (Aβ1-42; 0-1μM) to assess neuroprotective effects. Direct effects of each terpene on Aβ fibril formation and aggregation were also evaluated using the Thioflavin T (ThT) fluorometric kinetic assay and transmission electron microscopy (TEM) to visualize fibril and aggregate morphology

Results: Terpenes were intrinsically benign to PC12 cells up to 50μM, with higher concentrations of β-caryophyllene, humulene and nerolidol inducing some loss of PC12 cell viability. No significant protective effects of terpenes were observed following t-BHP (0-200µM) administration, with some enhanced toxicity instead demonstrated from both β-caryophyllene and humulene treatment (each at 50µM). α-pinene and β-pinene demonstrated a significant neuroprotective effect against amyloid β exposure. α-pinene, β-pinene, terpineol, terpinolene and friedelin were associated with a variable inhibition of Aβ1-42 fibril and aggregate density.

Conclusions: The outcomes of this study underline a neuroprotective role of α-pinene and β-pinene against Aβ-mediated neurotoxicity associated with an inhibition of Aβ1-42 fibrilization and density. This demonstrates the bioactive potential of selected terpenes for consideration in the development of medicinal cannabis formulations targeting neurodegenerative diseases.”

“In summary, the outcomes from this study reveal a novel and efficacious neuroprotective and anti-aggregatory effect of α-pinene and β-pinene against β amyloid-mediated toxicity. The modest inhibition of lipid peroxidation from α-pinene, β-pinene, and terpinolene may also contribute to the multifaceted neuroprotection of C. sativa-prevalent terpenes. In addition, limited anti-aggregatory effects were observed from terpineol, terpinolene, α-pinene, β-pinene and friedelin. The outcomes of this study contribute to an emerging body of knowledge towards the potential synergistic bioactivities of selected terpenes for consideration in the development of medicinal cannabis formulations targeting neurodegenerative diseases.”

Assessing Cannabidiol as a Therapeutic Agent for Preventing and Alleviating Alzheimer’s Disease Neurodegeneration

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“Alzheimer’s disease (AD) is a leading neurodegenerative condition causing cognitive and memory decline. With small-molecule drugs targeting Aβ proving ineffective, alternative targets are urgently needed. Neuroinflammation, which is central to AD’s pathology, results in synaptic and neuronal damage, highlighting the importance of addressing inflammation and conserving neuronal integrity. Cannabidiol (CBD), derived from cannabis, is noted for its neuroprotective and anti-inflammatory properties, having shown efficacy in neuropathic pain management for epilepsy. To investigate the therapeutic efficacy of CBD in AD and to elucidate its underlying mechanisms, we aimed to contribute valuable insights for incorporating AD prevention recommendations into future CBD nutritional guidelines. Aβ1-42 was employed for in vivo or in vitro model establishment, CBD treatment was utilized to assess the therapeutic efficacy of CBD, and RNA-seq analysis was conducted to elucidate the underlying therapeutic mechanism. CBD mitigates Aβ-induced cognitive deficits by modulating microglial activity, promoting neurotrophic factor release, and regulating inflammatory genes. The administration of CBD demonstrated a protective effect against Aβ toxicity both in vitro and in vivo, along with an amelioration of cognitive impairment in mice. These findings support the potential inclusion of CBD in future nutritional guidelines for Alzheimer’s disease prevention.”

The Interplay between Cannabinoid Receptors and Microglia in the Pathophysiology of Alzheimer’s Disease

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“Alzheimer’s disease (AD) is characterized by massive neuronal death, brain atrophy, and loss of neurons and synapses, which all lead to a progressive cognitive decline. Neuroinflammation has been recently identified as one of the main causes of AD progression, and microglia cells are considered to have a central role in this process.

Growing evidence suggests that cannabinoids may be used as preventive treatment for AD.

An altered expression of the endocannabinoids (eCBs) and their receptors (CBRs) is reported in several neurodegenerative disorders, including AD. Moreover, the modulation of CBRs demonstrated neuroprotective effects in reducing aggregated protein deposition, suggesting the therapeutic potential of natural and synthetic CBR ligands in the treatment of neurodegenerative proteinopathies. Here, we review the current knowledge regarding the involvement of CBRs in the modulation of microglia activation phenotypes, highlighting the role of neuroinflammation in the pathogenesis of neurodegenerative diseases, like AD. We also provide an overview of recently developed candidate drugs targeting CBRs that may afford a new innovative strategy for the treatment and management of AD.”

An In Silico Study for Expanding the Utility of Cannabidiol in Alzheimer’s Disease Therapeutic Development

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“Cannabidiol (CBD), a major non-psychoactive component of the cannabis plant, has shown therapeutic potential in Alzheimer’s disease (AD). In this study, we identified potential CBD targets associated with AD using a drug-target binding affinity prediction model and generated CBD analogs using a genetic algorithm combined with a molecular docking system. As a result, we identified six targets associated with AD: Endothelial NOS (ENOS), Myeloperoxidase (MPO), Apolipoprotein E (APOE), Amyloid-beta precursor protein (APP), Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), and Presenilin-1 (PSEN1). Furthermore, we generated CBD analogs for each target that optimize for all desired drug-likeness properties and physicochemical property filters, resulting in improved pIC50 values and docking scores compared to CBD. Molecular dynamics (MD) simulations were applied to analyze each target’s CBD and highest-scoring CBD analogs. The MD simulations revealed that the complexes of ENOS, MPO, and ADAM10 with CBD exhibited high conformational stability, and the APP and PSEN1 complexes with CBD analogs demonstrated even higher conformational stability and lower interaction energy compared to APP and PSEN1 complexes with CBD. These findings demonstrated the capable binding of the six identified targets with CBD and the enhanced binding stability achieved with the developed CBD analogs for each target.”

Synergistic inhibition of glioblastoma multiforme through an in-silico analysis of luteolin and ferulic acid derived from Angelica sinensis and Cannabis sativa: Advancements in computational therapeutics

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“The primary objective of this study is to uncover novel therapeutic agents for the treatment of Glioblastoma Multiforme (GBM), a highly aggressive form of brain cancer, and Alzheimer’s Disease (AD). Given the complexity and resistance associated with both conditions, the study underscores the imperative need for therapeutic alternatives that can traverse the biological intricacies inherent in both neuro-oncological and neurodegenerative disorders. To achieve this, a meticulous, target-based virtual screening was employed on an ensemble of 50 flavonoids and polyphenol derivatives primarily derived from plant sources. The screening focused predominantly on molecular targets pertinent to GBM but also evaluated the potential overlap with neural pathways involved in AD. The study utilized molecular docking and Molecular Dynamic (MD) simulation techniques to analyze the interaction of these compounds with a key biological target, protein tyrosine phosphatase receptor-type Z (PTPRZ). Out of the 50 compounds examined, 10 met our stringent criteria for binding affinity and specificity. Subsequently, the highest value of binding energy was observed for the synergistic binding of luteolin and ferulic acid with the value of -10.5 kcal/mol. Both compounds exhibited inherent neuroprotective properties and demonstrated significant potential as pathway inhibitors in GBM as well as molecular modulators in AD. Drawing upon advanced in-silico cytotoxicity predictions and sophisticated molecular modeling techniques, this study casts a spotlight on the therapeutic capabilities of polyphenols against GBM. Furthermore, our findings suggest that leveraging these compounds could catalyze a much-needed paradigm shift towards more integrative therapeutic approaches that span the breadth of both neuro-oncology and neurodegenerative diseases. The identification of cross-therapeutic potential in flavonoids and polyphenols could drastically broaden the scope of treatment modalities against both fatal diseases.”

The Main Therapeutic Applications of Cannabidiol (CBD) and Its Potential Effects on Aging with Respect to Alzheimer’s Disease

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“The use of cannabinoids (substances contained specifically in hemp plants) for therapeutic purposes has received increased attention in recent years. Presently, attention is paid to two main cannabinoids: delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). With respect to the psychotropic effects and dependence potential of THC (though it is very mild), its use is associated with certain restrictions, and thus the therapeutic properties of CBD are frequently emphasized because there are no limitations associated with the risk of dependence. Therefore, this review covers the main pharmacodynamic and pharmacokinetic features of CBD (including characteristics of endocannabinoidome) with respect to its possible beneficial effects on selected diseases in clinical practice. A substantial part of the text deals with the main effects of CBD on aging, including Alzheimer’s disease and related underlying mechanisms.”

“According to all the results of the available clinical studies, CBD has shown clear therapeutic efficacy in the elderly human population. The frequency of side effects is comparable to other classes of drugs, and the risks of using CBD in elderly patients are rated as moderate.”

The Antioxidant and Neuroprotective Potential of Leaves and Inflorescences Extracts of Selected Hemp Varieties Obtained with scCO2

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“Cannabis sativa, a versatile plant with numerous varieties, holds promising potential for a wide range of biological activity. As raw materials for research, we chose leaves and inflorescences of hemp varieties such as Białobrzeskie, Henola, and Tygra, which are cultivated mainly for their fibers or seeds. The choice of extraction is a key step in obtaining the selected compositions of active compounds from plant material. Bearing in mind the lipophilic nature of cannabinoids, we performed supercritical carbon dioxide (scCO2) extraction at 50 °C under 2000 (a) and 6000 PSI (b). The cannabinoid contents were determined with the use of the HPLC-DAD method. The antioxidant capabilities were assessed through a series of procedures, including the DPPH, ABTS, CUPRAC, and FRAP methods. The capacity to inhibit enzymes that play a role in the progression of neurodegenerative diseases, such as acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tyrosinase was also studied. The dominant cannabinoids in the extracts were cannabidiol (CBD) and cannabidiolic acid (CBDA). The highest concentration of eight cannabinoids was detected in the Tygra inflorescences extract (b). The most notable antioxidant properties were provided by the Tygra inflorescences extract (b). Nonetheless, it was the Henola inflorescences extract (b) that demonstrated the most efficient inhibition of AChE and BChE, and tyrosinase was inhibited the most significantly by the Białobrzeskie inflorescences extract (b). Multidimensional comparative analysis enrolled all assays and revealed that the Henola inflorescences extract (b) showed the most substantial neuroprotective potential.”