Discovery and structure-activity relationship of cannabidiol aminoquinones as anti-Alzheimer’s agents via dual modulation of Nrf2/HO-1 and TLR4/NF-κB pathways

Posted on by

“Neuroinflammation and oxidative stress are recognized as key drivers of neuronal death and the progression of neurodegenerative diseases. At the same time, they serve as central hubs linking the major pathological hallmarks of Alzheimer’s disease (AD), including Aβ aggregation, tau protein hyperphosphorylation, neurofibrillary tangle formation, and neuronal injury.

In this study, we screened natural active molecules of cannabidiol (CBD) and its derivatives, and conducted molecular docking simulations. A class of CBD aminoquinone scaffolds with potential anti-AD activity was identified, and 32 CBD aminoquinone derivatives were synthesized for comprehensive in vitro and in vivo evaluation.

Among them, compound G-12 with p-F-aniline moiety exhibited potent anti-inflammatory activity (IC50 = 1.39 μM), outstanding neuroprotective effects (IC50 = 1.29 μM), and prominent behavioral manifestations. In addition, G-12 displayed acceptable in vivo pharmacokinetic (PK) properties. The superior performance of G-12 indicated that through the Nrf2/HO-1 oxidative stress pathway, it affected the TLR4/NF-κB inflammatory pathway, inhibited neuroinflammation, and thereby influenced Aβ aggregation, protecting neurons.

This strategy that links several major pathological features of AD is effective in combating AD.

G-12 is also a lead compound with the potential to be developed into a multifunctional drug for AD.”

https://pubmed.ncbi.nlm.nih.gov/41643512

“Cannabidiol (CBD) is one of non-psychoactive cannabinoids derived from cannabis plants. CBD and its structural analogues modulate a broad spectrum of pharmacological targets, including multiple orphan receptors, GPCRs, 5-HT1A receptors, and PPARγ and TRPV1 channels, thus show potential therapeutic effects such as neuroprotection, anti-epilepsy, anti-inflammation, antioxidation. CBD exhibits neuroprotective properties through multiple mechanisms in the treatment of neurodegenerative disorders, including AD, multiple sclerosis, epilepsy, Parkinson’s disease. Currently, CBD has been approved as an orphan drug by the FDA for the treatment of Lennox-Gastaut syndrome and Dravet.”

https://www.sciencedirect.com/science/article/abs/pii/S0045206826001264?via%3Dihub

Involvement of Keap1/Nrf2 and the antioxidant defence in cytoprotective effects induced by cannabis polyphenols in SH-SY5Y neuronal cells

Posted on by

“Oxidative stress (OS) is widely recognized as a central promoter to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS).

Cannabis sativa L. synthesizes a complex array of bioactive compounds that extends well beyond the well-known cannabinoids to include a diverse suite of polyphenols, terpenes, fatty acids, tocopherols, and proteins. The non-cannabinoid polyphenolic fraction is composed primarily of flavonoids, stilbenoids, lignans, and lignanamides, which contribute substantially to the plant’s antioxidant, anti-inflammatory, and neuroprotective properties.

This study investigates the redox-modulating and cytoprotective properties of a polyphenolic fraction derived from Cannabis sativa L. in SH-SY5Y neuroblastoma cells.

Neurons were treated with various concentrations of the aqueous polyphenolic cannabis extract and exposed to oxidative stress using hydrogen peroxide (100 µM). Protein and gene expression related to redox signalling were analyzed via Western blot and qPCR, and molecular docking studies were performed in silico. Furthermore, antioxidant enzymes activity was measured by spectrophotometry.

Results revealed that the phenolic fraction significantly activated the Keap1/Nrf2 pathway, increased expression of PRDX1 and PRDX3, and enhanced endogenous antioxidant defences. Simultaneously, it reduced endoplasmic reticulum stress-induced apoptosis (via Bax/Bcl-2 modulation) and attenuated inflammatory markers, including NO, NF-κB2, IL-6, and IL-8. In silico docking studies identified Leu583 as a key residue in Nrf2-ligand interactions.

These findings suggest that Cannabis sativa L. polyphenols are key bioactive compounds modulating redox homeostasis and inflammation, and offering neuroprotective benefits with potential relevance in diseases involving mitochondrial dysfunction and oxidative damage.”

https://pubmed.ncbi.nlm.nih.gov/41643607

“Collectively, these results position phenolic compounds present in Cannabis sativa as promising and essential key candidates for targeting mitochondrial dysfunction and oxidative neurotoxicity, although further studies are needed to fully the therapeutic and clinical potential.”

https://www.sciencedirect.com/science/article/pii/S0753332226000806?via%3Dihub

Synergistic Neuroprotection by Cannabis sativa and Tilia × viridis: Attenuation of Hippocampal Neurons Glutamate-Induced Oxidative Stress and LPS-Driven Microglial Inflammation

Posted on by

“Throughout history, Cannabis sativa has been linked to the therapeutic management of epilepsy and Tilia × viridis has a tradition of use as a sedative.

This study aimed to evaluate the protective effect of an ethanolic extract of C. sativa (CSRD), an aqueous extract of T. × viridis (TE), and their combination against oxidative stress induced by glutamate in a murine hippocampal neuronal (HT-22) cell line, as well as their anti-inflammatory activity in male Wistar rats’ microglial cells stimulated with LPS.

A phytochemical analysis was also conducted. Glutamate-induced reactive oxygen species (ROS) were quantified using 2′,7′-dichlorodihydrofluorescein diacetate via fluorescence microscopy. Cell viability was assessed using the MTT assay. Distinct microglial cell phenotypes were identified via immunofluorescence.

Extracts partially reversed glutamate-induced loss of cell viability (52% to 200% for CSRD; 22% to 82% for TE). Their combination produced a greater effect, reversing glutamate-induced toxicity by 133% to 284% and fully restoring cell viability to control levels. Moreover, the combined treatment reduced intracellular ROS levels (52% to 58%).

Notably, the combination also exhibited the most pronounced anti-inflammatory effects, significantly reducing the proportion of reactive phenotype 1 cells, while increasing the population of anti-inflammatory phenotype 2 cells and preserving the trophic phenotype 3 subpopulation.

In conclusion, this study not only validates the ethnobotanical uses of C. sativa and T. × viridis but also reveals a potent synergy when combined. This provides a strong foundation for the development of phytomedicines with translational potential for managing complex pathologies like epilepsy or neuroinflammation associated with neurodegenerative diseases.”

https://pubmed.ncbi.nlm.nih.gov/41628619

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2751-0171

Integrative therapies for chronic insomnia: A randomized controlled trial of a traditional Thai Herbal Remedy and Cannabis sativa oil

Posted on by

“Background: This study compared the efficacy and safety of integrative and conventional therapies for chronic insomnia.

Objective: To evaluate the effects of the Suk-Sai-Yat traditional Thai herbal remedy, Cannabis sativa oil (Deja formula) and lorazepam on sleep quality and quality of life in patients with chronic insomnia.

Methods: In a randomized controlled parallel-group trial, 60 adults with chronic insomnia received Suk-Sai-Yat, Cannabis sativa oil, or lorazepam for four weeks. Sleep quality was assessed using the Pittsburgh leep Quality Index (PSQI) and quality of life was evaluated using EQ-5D-5L and EQ-VAS. Safety was monitored throughout the study.

Results: After four weeks, PSQI scores significantly improved in all groups: Suk-Sai-Yat (12.3-6.6), Cannabis sativa oil (13.6-3.68) and lorazepam (14.4-5.8) (all p < 0.001), with no significant differences between groups. Quality-of-life scores improved significantly in the integrative therapy groups. Only mild adverse events were reported.

Conclusion: Suk-Sai-Yat and Cannabis sativa oil demonstrated comparable efficacy to lorazepam with favorable safety profiles, supporting their role as integrative, non-benzodiazepine options for chronic insomnia management.”

https://pubmed.ncbi.nlm.nih.gov/41623556

“Suk-Sai-Yat and Cannabis sativa oil significantly improved chronic insomnia symptoms.”

https://www.sciencedirect.com/science/article/pii/S2590142726000017?via%3Dihub

Health-related quality of life in patients receiving medicinal cannabis: systematic review and meta-analysis of primary research findings 2015-2025

Posted on by

“Purpose: The global burden of chronic health conditions is significant. Medicinal cannabis (MC) is a legalised treatment option for patients with chronic health conditions in some countries. Health-related quality of life (HRQL) is an important patient-reported outcome across all chronic health conditions. We aimed to determine how studies of MC therapy justify, measure, and report HRQL, and assess the current evidence for HRQL following MC treatment.

Methods: Systematic review searching AMED, Medline, Web of Science, Scopus, Embase, Cinahl, and PsycINFO from Jan 2015 to Apr 2025. Studies using validated HRQL measures pre-, and post-MC treatment for any chronic health condition were included. Screening and data extraction were performed independently by two reviewers. Completeness of HRQL reporting was evaluated. Meta-analyses for short-term (2-weeks to 3-months), medium-term (> 3 to < 12-months), and long-term (≥ 12-months) HRQL outcomes were conducted, with Risk of Bias (RoB) assessed in randomised control trials (RCTs).

Results: Of 16,674 retrieved citations, 64 studies were retained for analysis:12 RCTs; 38 cohort studies; 13 case series; 1 non-randomised experimental study. Thirty-nine studies (61%) provided justification for assessing HRQL and five (8%) provided HRQL definitions. Studies used generic (n = 52, 81%) or condition-specific (n = 12, 19%) HRQL measures, with EQ-5D-5L most commonly used. Meta-analyses: RCTs showed small short-term HRQL improvements (Cohen’s d = 0.30, p = 0.03), with some concerns or low RoB. For observational studies, HRQL improved in all follow-up periods (d = 0.43 to 0.74; all p < 0.001). HRQL improvement varied between, and within, different health conditions.

Conclusion: This systematic review and meta-analyses of studies published between 2015 and 2025 found that few studies provided HRQL definitions, and a third of studies did not explain why they measured HRQL. To ensure appropriate measures are used for this important treatment outcome, future studies should define HRQL and justify the HRQL assessment in the context of research objectives.

Overall, improvements in HRQL were observed across studies of patients using MC.”

https://pubmed.ncbi.nlm.nih.gov/41621036

Plain language summary

“Medicinal cannabis (MC) is a treatment option for patients in countries where prescribing MC is legal. Health-related Quality of Life (HRQL) can mean different things to different people but remains an important treatment outcome for all patients, regardless of their specific health condition. HRQL varies depending on the context and measurement tool (questionnaire) used. We aimed to find out (1) how HRQL assessment is justified, defined and measured in MC research, and (2) if HRQL improves in patients prescribed MC. We looked at studies published over the past decade that reported HRQL in patients before and after MC treatment. Most studies (81%) used generic HRQL questionnaires (e.g., EuroQol Group: EQ-5D) and others used condition-specific questionnaires (e.g. Multiple Sclerosis Quality of Life: MSQoL-52).

Overall, HRQL improved in patients using MC.

However, only a few studies provided HRQL definitions, and a third of studies didn’t explain why they measured HRQL. This information is needed to ensure HRQL is measured and interpreted appropriately in future studies.”

https://link.springer.com/article/10.1007/s11136-026-04170-7

Beyond neurons: Impact of cannabidiol on glial cells in ischemic stroke

Posted on by

“Ischemic stroke triggers a complex cascade of events involving inflammation, oxidative stress, and glial cell dysfunction, all of which contribute to neuronal damage and impaired recovery. Glial cells (e.g., astrocytes, microglia, and oligodendrocytes) play key roles in neuroinflammatory responses, making them attractive targets for therapeutic modulation.

Cannabidiol, a non-psychoactive phytocannabinoid from Cannabis sativa, exhibits anti-inflammatory, antioxidant, and neuroprotective properties.

Preclinical evidence indicates that cannabidiol attenuates glial reactivity, reduces pro-inflammatory signaling, mitigates oxidative stress, and preserves blood-brain and intestinal barrier integrity in stroke models. Moreover, cannabidiol modulates key molecular pathways (e.g., nuclear factor-κB, tumor necrosis factor, and calcium-related signaling), contributing to reduced infarct volume and improved neurological function. Despite these promising effects, clinical translation is hindered by a lack of standardized formulations, dosing regimens, and human trials.

This review highlights the impact of cannabidiol on glial cell activity in ischemic stroke, proposing it as a multi-target agent with therapeutic potential in post-stroke recovery and neuroprotection.”

https://pubmed.ncbi.nlm.nih.gov/41622458

https://journals.lww.com/nrronline/abstract/9900/beyond_neurons__impact_of_cannabidiol_on_glial.1148.aspx

Hemp seed extract exerts cytostatic effects through metabolic stress and autophagy modulation in malignant cells

Posted on by

“Phytocannabinoids from Cannabis sativa L. exhibit anticancer activity, but how the polar fraction from cold-pressed hemp seed oil derived from industrial cultivars lacking Δ9-THC affects cell proliferation remains unclear.

Here, we characterized the phenolic composition of the Oil Polar Extract (OPE) from the Codimono cultivar and evaluated its effects on cancer cells. In HT-29 colorectal cells, OPE induced metabolic stress, decreasing ATP by ~ 40%, activating AMPK, and disrupting autophagic flux. This stress led to G1 phase cell cycle arrest without triggering apoptosis.

Notably, pharmacological inhibition of autophagy with chloroquine enhanced the antiproliferative effects of the extract by ~ 30%, indicating that autophagy serves a cytoprotective role.

These findings identify OPE as a metabolic modulator capable of inducing an AMPK-dependent cytostatic effect in colorectal cancer cells, supporting its potential as a non-psychotropic, plant-derived anticancer strategy and as a candidate for combination therapies with autophagy inhibitors.”

https://pubmed.ncbi.nlm.nih.gov/41620507

https://www.nature.com/articles/s41598-026-37119-4

HER2-dependent paraptosis and ferroptosis induction by cannabidiol in breast cancer cells

Posted on by

“HER2 (human epidermal growth factor receptor 2) is a well-established oncogenic driver and therapeutic target in breast cancer.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has demonstrated anticancer potential, yet its mechanisms of action in HER2-positive breast cancer remain insufficiently characterized.

In this study, we examined the effects of CBD on HER2-positive (SK-BR-3, BT-474) and HER2-negative (MCF-7, MDA-MB-231) breast cancer cell lines, with a focus on its interaction with HER2.

CBD selectively reduced the viability of HER2-positive cells, an effect associated with increased intracellular reactive oxygen species (ROS) and a marked reduction in HER2 protein levels. Mechanistically, CBD triggered non-apoptotic cell death pathways, including paraptosis and ferroptosis, as indicated by the modulation of specific molecular markers such as reduced Alix and elevated ATF4 and CHOP for paraptosis, and downregulated GPX4 and SLC7A11 with upregulated TFRC for ferroptosis. HER2 knockdown attenuated CBD-induced cytotoxicity, while HER2 overexpression sensitized cells to CBD, underscoring the HER2-dependence of these effects. Molecular docking predicts the binding conformation and key interactions of ligand with target proteins providing initial insights into potential molecular recognition. Subsequently, molecular dynamics simulations extend this analysis by assessing the stability, flexibility, and energetic characteristics of the ligand-protein complex within a dynamic biological environment.

These findings support a model in which CBD downregulates HER2 and, in a HER2-dependent context, promotes paraptosis and ferroptosis. In addition, docking and molecular dynamics analyses suggested a potential interaction between CBD and HER2, providing mechanistic insights into possible molecular recognition relevant to HER2-positive breast cancer.”

https://pubmed.ncbi.nlm.nih.gov/41621547

“These results suggest that CBD targets HER2, offering a new therapeutic strategy for HER2-positive breast cancer management.”

https://www.sciencedirect.com/science/article/abs/pii/S0925443926000256?via%3Dihub


Cannabinoids and skin cancer: Mechanistic insights, therapeutic potential, and translational perspectives

Posted on by

“Skin cancer represents a significant global healthcare challenge, with rising incidence and persistent gaps in effective long-term management.

Recent evidence has identified the endocannabinoid system as an emerging therapeutic target offering novel pharmacological approaches for the prevention and treatment of various skin cancers.

Cannabinoids, through modulation of the endocannabinoid system, have demonstrated antitumor activity by inhibiting tumor proliferation, angiogenesis, invasion, and metastasis and by inducing apoptosis and autophagy in malignant cells.

This review synthesizes the most recent preclinical evidence on phytocannabinoids, endocannabinoids, and synthetic cannabinoids in melanoma and non-melanoma skin cancers, delineating receptor-dependent and receptor-independent mechanisms. Additionally, emerging cannabinoid-based delivery strategies, particularly cannabidiol formulations designed to enhance skin penetration and therapeutic efficacy, are critically examined. Despite encouraging preclinical findings, clinical translation remains limited by scarce skin-cancer-specific trials, variability in cannabinoid preparations, and uncertainties around dosing and safety. Consequently, robust mechanistic studies and well-designed clinical trials are required to validate cannabinoids’ therapeutic potential and guide their integration into future skin cancer treatment paradigms.”

https://pubmed.ncbi.nlm.nih.gov/41621140

“Cannabinoids show anticancer effects in melanoma and non-melanoma skin cancers.”

https://www.sciencedirect.com/science/article/pii/S0014480026000067?via%3Dihub


Cannabis sativa in the fight against drug-resistant bacteria and fungi

Posted on by

“Drug resistance in bacteria and fungi is a global threat to public health. The purpose of this publication is to review the latest scientific achievements, mainly from 2020-2025, concerning the use of hemp compounds from Cannabis sativa in combating drug-resistant bacterial and fungal infections.

The literature review confirms that C.sativa, a plant with a documented centuries-old therapeutic history, is a rich source of cannabinoids and terpenes that combat drug-resistant bacteria: Mycobacterium tuberculosis, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, and fungi: Cryptococcus neoformans, as well as species from the Candida and Aspergillus.

The potential of hemp compounds is based on their activity in interacting directly with pathogens by disrupting cell membrane integrity, eradicating biofilm, having a bactericidal effect on bacterial spores, acting synergistically, affecting host inflammatory pathways, and the human endocannabinoid system.”

https://pubmed.ncbi.nlm.nih.gov/41607163