Adult Neurogenesis Is Regulated by the Endocannabinoid and Kisspeptin Systems

Posted on by
Reply
pubmed logo

“Neurogenesis is considered the most robust form of plasticity in the adult brain. To better decipher this process, we evaluated the potential crosstalk of Kisspeptin and Endocannabinoid Systems (KPS and ECS, respectively) on hippocampal neurogenesis.

Male adolescent rats were exposed to kisspeptin-10 (KP10) and the endocannabinoid anandamide (AEA) administered alone or in combination with the type 1 cannabinoid receptor (CB1R) antagonist SR141716A. The expression of Kiss1 and Kisspeptin receptor (Kiss1R) has been characterized for the first time in rat hippocampus together with the expression of the CB1R and the Transient Receptor Potential Vanilloid 1 ion channel receptor (TRPV1).

Results show that both systems inhibit neurogenesis by reducing the extracellular signal-regulated kinase (ERK) signaling. Despite little differences in the expression of Kiss1R and CB1R, TRPV1 is enhanced by both KP10 and AEA treatments, suggesting TRPV1 as a common thread. KP10 administration reduces CB1R expression in the dentate gyrus, while AEA does not. KPS, unlike ECS, promotes the expression of estrogen receptor α (ER-α) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), also upregulating sirtuin 1 (SIRT1), brain-derived-neurotrophic factor (BDNF), and c-Jun.

These findings suggest that the interaction between ECS and KPS could be involved in the fine-tuning of neurogenesis, highlighting a novel role for KPS.”

https://pubmed.ncbi.nlm.nih.gov/40362219/

https://www.mdpi.com/1422-0067/26/9/3977

Cannabichromene, a key non-psychotropic phytocannabinoid in treatment of major depressive disorder: in silico and in vivo explorations

Posted on by
Reply
pubmed logo

“Cannabichromene, a non-psychotropic cannabinoid with antioxidant and neuroprotective properties, is hypothesized to possess antidepressant potential.

This study aimed to evaluate cannabichromene’s depression-alleviating effects in mice exposed to chronic unpredictable mild stress and unstressed mice using a combination of in silico and in vivo approaches.

Initially, gene targets associated with major depressive disorder were identified through GeneCards, while cannabichromene’s target genes were predicted using SwissTargetPrediction. Overlapping targets were visualized using Venny software, and protein-protein interaction networks were constructed with the STRING database.

The cannabinoid receptor two genes, encoding the cannabinoid 2 receptor, emerged as a key shared target. Molecular docking studies revealed that cannabichromene exhibited a strong binding affinity to cannabinoid 2 receptors (docking score: – 9.4) compared to cannabidiol (CBD) (- 8.8) and Δ9-tetrahydrocannabinol (- 9.1). For in vivo analysis, male Swiss albino mice were subjected to chronic unpredictable mild stress for 3 weeks to induce depression-like behavior. Cannabichromene (10 and 20 mg/kg) and imipramine (15 mg/kg) were administered for 21 days.

Cannabichromene at 20 mg/kg significantly reduced immobility in stressed mice, like imipramine, without affecting locomotor activity. Additionally, both cannabichromene and imipramine reduced elevated plasma nitrite and corticosterone levels and inhibited monoamine oxidase-A activity in the brain. Cannabichromene also reversed stress-induced catalase suppression.

In conclusion, cannabichromene revealed a relatively substantial antidepressant character with chronic unpredictable mild stress model of depression in Swiss albino male mice, likely through interaction with cannabinoid 2 receptors encoded by the cannabinoid 2 gene, as ratified via in silico modeling and in vivo findings. This highlights cannabichromene’s potential as a novel therapeutic agent for depression after further in vitro and clinical assessments in other models.”

https://pubmed.ncbi.nlm.nih.gov/40358684/

https://link.springer.com/article/10.1007/s00210-025-04236-2

Cannabidiol Pretreatment Reduces Status Epilepticus and Glutamate Uptake Induced by Kainic Acid in Adult Zebrafish

Posted on by
Reply
pubmed logo

“Background: Epilepsy is a neurological chronic disorder that affects about 70 million people worldwide. Status epilepticus (SE) are neural disturbances that cause intense glutamatergic excitatory discharges that modulate changes in normal brain physiological activity. Cannabidiol (CBD) is the main nonpsychomimetic compound present in Cannabis sativa and exhibits a wide spectrum of neuroprotective properties. The use of zebrafish (Danio rerio) is regarded as an important alternative animal model for studies on seizures, as it has neuronal mechanisms similar to humans. 

Objective: This study aims to evaluate the effects of CBD on SE induced by kainic acid (KA) in zebrafish. 

Methods: Animals received CBD (5, 10, or 40 mg·L-1 tank water) for 24 h followed by KA administration (5 mg/kg intraperitoneally). The convulsive pattern of alterations was then assessed. After 12 h, cerebral glutamate transport and oxidative stress were also verified. 

Results: CBD at 5 and 40 mg·L-1 induced a significant decrease in the seizure intensity (26.1% and 29.9%) and an increase in the latency to reach SE (from 10.71 min to 17.5 and 25 min), respectively. In addition, CBD administration (40 mg·L-1) attenuated the decrease in cerebral glutamate transport following 12 h KA-induced seizure. The KA-induced seizure was also able to alter the oxidative stress parameters 2′,7′-dichlorofluorescin, and catalase activity. However, CBD (40 mg·L-1) did not influence these markers.

The present study indicates that CBD promotes a neuroprotective response against the epileptic profile in zebrafish. These findings contribute to the understanding of the influence of CBD on the modulation of excitatory/inhibitory disruption on zebrafish seizure.”

https://pubmed.ncbi.nlm.nih.gov/40354278/

https://www.liebertpub.com/doi/10.1089/can.2024.0189

Microbial Biosynthesis of Rare Cannabinoids

Posted on by
Reply
pubmed logo

“∆9-tetrahydrocannabinol (∆9-THC) and cannabidiol (CBD) are the most abundant natural cannabinoids isolated from the different cultivars of the Cannabis plant. Other natural ∆9-THC analogs, especially those with different alkyl chain substitutions, display different and potent bioactivity. However, these rare cannabinoids are typically isolated at minuscule amounts and are difficult to synthesize. Targeted microbial biosynthesis can therefore be an attractive route to access such molecules.

Here, we report the development of a Saccharomyces cerevisiae host to biosynthesize two rare cannabinoids from simple sugars. The yeast host is engineered to accumulate excess geranyl pyrophosphate (GPP), to overexpress a fungal pathway to 2,4-dihydroxy-6-alkyl-benzoic acids, as well as the downstream UbiA-prenyltransferase and THCA synthase. Two rare cannabinoid acids, the C1-substituted ∆9-tetrahydrocannabiorcolic acid (∆9-THCCA, ∼16 mg/L) and the C7-substituted ∆9-tetrahydrocannabiphorolic acid (∆9-THCPA, ∼5 mg/L) were obtained from this host; the latter was thermally decarboxylated to give ∆9-tetrahydrocannabiphorol (∆9-THCP).

Given the diversity of fungal biosynthetic gene clusters (BGCs) that can produce resorcylic acids, this microbial platform offers potential to produce other rare and new-to-nature cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/40359163/

https://academic.oup.com/jimb/advance-article/doi/10.1093/jimb/kuaf013/8129704?login=false

Nucleolar sequestration of cannabinoid type-2 receptors in triple-negative breast cancer cells

Posted on by
Reply
pubmed logo

“Multiple investigations have shown that the different types of cannabinoids, phytocannabinoids, synthetic cannabinoids, and endocannabinoids, possess antiproliferative and anticancer properties.

The cannabinoid type-2 receptor (CB2R) has been proposed as a central player in tumor progression and has been correlated with the aggressiveness of breast cancer. Using immunocytochemistry and confocal microscopy, in the present work, we studied the expression level and subcellular localization of CB2R in two human triple-negative breast cancer (TNBC) cell lines, corresponding to early (stage I, HCC-1395) and metastatic (MDA-MB-231) stages, and they were compared with a non-tumoral mammary epithelial cell line (MCF-10A).

We found that although CB2R was detected at the plasma membrane, it was mainly localized intracellularly, with ~40-fold higher expression in both TNBC cell lines than in MCF-10A (P < 0.0001). Notably, double staining with DAPI or with the nucleoli-specific fluorescent marker (3xnls-mTurquoise2) showed that most of the CB2R overexpressed in the nucleoli of cancer cells.

This finding is supported by the fact that CB2R expression was markedly lower in mitotic cells compared to interphase cells (P < 0.0001). Interestingly, exposure of cancer cells to the specific agonist HU-308 reversed the nucleolar sequestration of CB2R while increasing the presence of the receptor in the nucleoplasm and cytoplasm (P < 0.0001). In addition, we found that this agonist reduced both the cell migration (P < 0.05-0.0001) and proliferation (P < 0.001) of TNBC cells. It remains to determine the function and signaling ability of CB2R in the nucleolus.

Although our study only includes cell lines (tumoral and non-tumoral), we consider that this feature of nucleolar sequestration of CB2R could be a potential diagnostic marker for TNBC from the early stage.”

https://pubmed.ncbi.nlm.nih.gov/40359210/

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0323554

Effect of hemp seed oil on accelerating wound healing: Evaluation of wound size reduction, epithelialization, granulation tissue formation, and vascularization in murine models

Posted on by
Reply
pubmed logo

“Essential oils have gained interest in wound management, with prior studies exploring combinations of hemp seed oil (Cannabis sativa) and other oils. However, single-oil strategies may offer simpler formulation, reducing the risk of interactions while preserving therapeutic benefits.

The aim of this study was to explore the effect of hemp seed oil on accelerating wound healing, focusing on wound size reduction, epithelialization, granulation tissue formation, and vascularization in murine models.

An in vivo with a post-test-only control group was conducted using 36 male Mus musculus mice (3-4 months, 150-250 grams) which were divided into three groups: negative control (NC), positive control (PC, treated with chloramphenicol ointment twice daily), and treatment group (TG, treated with hemp seed oil 400,000 mg/mL twice daily). Mice were euthanized on day 3, 7, 14, and 21 for wound healing assessment, including macroscopic evaluation (visual observation, wound size, and wound healing rate) and microscopic evaluation (epithelialization, granulation tissue formation, and vascularization).

The present study found that the TG group demonstrated smaller wound sizes on day 14 (p < 0.001) and day 21 (p < 0.001). This group also enhanced wound healing rates observed on day 14 (p < 0.001) and day 21 (p = 0.001) compared to PC and NC groups. Epithelialization was significantly higher in the TG group compared to PC and NC groups on day 14 (p = 0.007), while granulation tissue formation showed significant improvement on day 3 (p = 0.045), day 14 (p = 0.028), and day 21 (p = 0.003). Additionally, TG group showed significantly greater new blood vessel formation on day 21 (p = 0.001) compared to the PC and NC groups.

In conclusion, hemp seed oil demonstrated significant potential in accelerating wound healing processes suggesting a superior effect compared to chloramphenicol ointment. Therefore, hemp seed oil may serve as a promising natural and cost-effective adjunct for wound management.”

https://pubmed.ncbi.nlm.nih.gov/40352225/

In Vivo and In Vitro Crosstalk Among CBD, Aβ, and Endocannabinoid System Enzymes and Receptors

Posted on by
Reply
pubmed logo

“Cannabidiol (CBD), a non-psychotropic compound derived from Cannabis sativa, has garnered attention as a potential therapeutic agent for various neurodegenerative diseases, including Alzheimer’s disease (AD).

Despite growing interest, additional research is required to clarify the specific mechanisms by which CBD influences the pathological accumulation of β-amyloid (Aβ) associated with AD. Moreover, the interactions between CBD and the endocannabinoid system (ECS), both in the presence and absence of Aβ expression, remain a subject of active investigation.

Elucidating these mechanisms may provide valuable insights for advancing both our understanding and the development of targeted interventions in neurodegenerative disease management. Using a multifaceted approach that integrates pharmacological interventions, immunofluorescence imaging, flow cytometry, and biochemical assays, we examined the effects of CBD on Aβ40 and Aβ42. Additionally, we analyzed the modulation of cannabinoid receptor 1(CB1 receptor) and fatty acid amide hydrolase (FAAH) in the presence or absence of Aβ expression, uncovering the intricate regulatory mechanisms of CBD.

Our findings indicate a nuanced response to CBD; while it may produce side effects in non-pathological cells, it demonstrates an ability to induce autophagy and apoptosis in Aβ-expressing cells via the activation of the Microtubule-associated protein 1 light chain 3 B(LC3B) and Caspase-3 pathways. Furthermore, our investigation into faah-1 involvement highlighted its role in alleviating pharyngeal dysfunction and counteracting weight loss in Aβ-expressing Caenorhabditis elegans(C. elegans) strains. These insights advance our understanding of CBD’s therapeutic potential in addressing neurodegenerative pathologies.”

https://pubmed.ncbi.nlm.nih.gov/40350019/

https://www.sciencedirect.com/science/article/abs/pii/S0014299925004741?via%3Dihub

Cannabidiol-loaded-injectable depot formulation for the treatment of triple-negative breast cancer: design, development, in-vitro and in-ovo evaluation of its anticancer activity

Posted on by
Reply
pubmed logo

“Triple-negative breast cancer (TNBC) is an invasive and difficult-to-treat carcinoma that represents 15-20 % of breast malignancies and is frequently diagnosed in younger women. Chemotherapy is the mainstay treatment approach.

Cannabidiol (CBD), the main non-psychoactive cannabinoid, has shown a potential anticancer activity in TNBC, enhancing the effect of conventional antineoplastics.

This research aims to develop in situ forming implants (ISFIs) as a long-acting depot formulation of CBD with potential application in TNBC. This formulation is intended to be administered in the tumor site during neoadjuvant chemotherapeutic regimens, allowing a controlled CBD release. ISFIs were elaborated with 100 mg of polycaprolactone (PCL) and 2.5 mg (2.5-CB-ISFI), 5 mg (5-CB-ISFI) or 10 mg (10-CB-ISFI) of CBD dissolved in 400 µL of NMP. All the formulations exhibited a controlled drug release for around two months. 10-CB-ISFI formulation with the highest CBD content and the most suitable CBD release profile was selected for biological studies.

This formulation inhibited the proliferation and migration of MDA-MB-231 and 4T1 cells and exerted an antiangiogenic effect in ovo. Interestingly, the antiangiogenic activity of 10-CB-ISFI was higher compared with CBD in solution administered at the same concentration, showing vascular inhibition percentages of around 80 % and 60 %, respectively.

Finally, this formulation reduced the growth of MDA-MB-231-derived tumors developed in the chorioallantoic membrane (CAM) model. The single administration of 10-CB-ISFI exhibited a similar antitumor efficacy to the daily administration of CBD in solution (≈60 % tumor growth inhibition).

Therefore, the injectable depot formulation of CBD developed in this work showed a promising utility in TNBC treatment.”

https://pubmed.ncbi.nlm.nih.gov/40349999/

https://www.sciencedirect.com/science/article/pii/S0378517325005472?via%3Dihub

Optimization of the Extraction Process and Comprehensive Evaluation of the Antimicrobial and Antioxidant Properties of Different Polar Parts of the Ethanol Extracts of Cannabis sativa L

Posted on by
Reply
pubmed logo

“The total flavonoids of Cannabis sativa L. were selected as the research object, and the extraction process of C. sativa L. was optimized on the basis of a single factor experiment utilizing a five-factor, three-level response surface method. Subsequently, the vitro antimicrobial and antioxidant activities of the flavonoids were evaluated.

The optimized extraction conditions were as follows: ratio of liquid to solid, 24.69:1 mL/g; soaking time, 102.12 min; extraction time, 165.96 min; ethanol concentration, 46.59%; extraction temperature, 86.87 °C. The extraction rate of C. sativa L. flavonoids (CSF) was found to be 5.51 ± 0.04 mg/g. The extraction of crude flavonoid (i.e., flavonoids extracted under the optimal extraction process) was conducted using four solvents, resulting in five C. sativa L. flavonoid extracts (petroleum ether, CSFp; n-butanol, CSFb; ethyl acetate, CSFe; aqueous phase, CSFw; and crude flavonoid, CSF). CSF contains 10 flavonoid components.

In vitro, all five CSF samples demonstrated good total reducing power, effective scavenging capacity against DPPH and ABTS+ radicals, and pronounced inhibitory effects against Escherichia coli, Bacillus subtilis, and Bacillus pumilus. Analytic Hierarchy Process (AHP) was employed to evaluate the five CSF samples in terms of antibacterial and antioxidant activity.

The results indicated that petroleum-ether-extracted C. sativa L. flavonoids (CSFp) exhibited the most pronounced antibacterial and antioxidant effects.”

https://pubmed.ncbi.nlm.nih.gov/40352509/

“Cannabis sativa L. is an annual herbaceous plant belonging to the mulberry family. It has been demonstrated that the plant contains a variety of physiologically active substances, including antibacterial, antithrombotic, antiallergic, and analgesic properties.”

“The results demonstrate that flavonoids present in C. sativa L. possess significant potential for utilization in both medical and industrial applications.”

https://pubs.acs.org/doi/10.1021/acsomega.4c10986

Quantitative and qualitative imaging in marijuana users and smokers

Posted on by
Reply
pubmed logo

“Objective: To evaluate the effect of marijuana use compared to cigarette smoking on imaging findings in the lungs.

Methods: By searching the electronic medical record, we identified patients who were marijuana users who never smoked; current smokers; and non-marijuana never smokers, who underwent chest CT in our healthcare system in 2019. We generated a random sample of 100 marijuana users as well as 100 each age- and sex-matched controls from the current smoker and never-smoker groups. Patients with extensive airspace disease on CT were excluded. Quantitative CT analysis was performed to measure total lung volume (TLV). A thoracic radiologist reviewed chest CTs in a blinded fashion for the presence of emphysema, centrilobular ground glass opacities, mosaic attenuation, bronchial wall thickening, and coronary calcification.

Results: Our study included 285 participants, comprising 89 non-smokers, 97 smokers, and 99 marijuana users. Despite propensity score matching, the marijuana user group was slightly younger than the smokers and non-smokers (mean age 59 versus 62 and 64 years, respectively, p = 0.04), with similar sex distribution across all groups. TLV was higher in smokers than marijuana users and non-smokers (p<.01 for both).

By visual analysis, 62 % of smokers had emphysema versus 4 % of marijuana users (p<.001). Additionally, centrilobular ground glass opacities were more prevalent in smokers (15 %) than in marijuana users (2 %) (p = 0.0008). No significant difference was noted in the occurrence of mosaic attenuation between smokers and marijuana users. In terms of coronary artery calcification, more smokers had moderate to severe coronary artery calcifications compared to marijuana users (43 % versus 25 %, p = 0.01).

Conclusion: While emphysema and hyperinflation were common in smokers, they were rare in marijuana users.”

https://pubmed.ncbi.nlm.nih.gov/40318925/

“Visual assessment revealed a significantly higher prevalence of emphysema in smokers (62 %) compared to marijuana users”

https://www.sciencedirect.com/science/article/abs/pii/S0363018825000738