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Evaluation of Cytoprotective Effects of Cannabidiol on Neuroinflammation and Neurogenesis Process in Rat Offsprings

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“Natural compounds include complex chemical compounds that exist in plants, animals and microbes. Due to their broad spectrum of pharmacological and biochemical actions, they have been widely used to treat multifactorial diseases, including cancer. In addition, their demonstrated neuroprotective properties strongly support their use in the treatment of neurological diseases.

The present study investigated the effect of CBD, which can easily cross the placental barrier and is known to have anti-inflammatory effects, on fetal neuroinflammation and neurogenesis in a systemic inflammation model during pregnancy.

Herein, 12 weeks adult pregnant rats (n=30) were randomly divided into 5 groups with 6 rats in each group as follows: Control, LPS (lipopolysaccharide, i.p.), LPS+CBD 5mg/kg (i.p.), LPS+CBD10 mg/kg (i.p.) and LPS+CBD30 mg/kg (i.p.). After the injections, blood samples of rats were collected, fetuses and placentas were taken by hysterectomy. Histopathological analysis, immunohistochemical staining, ELISA and immunoblotting analysis were performed to investigate neuroinflammatory and neurogenesis parameters in fetal brain and placenta tissues.

Our findings indicated that CBD administration importantly suppressed the inflammatory process in the rat fetal brain by decreasing interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels and diminishing nuclear factor kappa B (NF-κB) activation. Moreover, CBD inhibited lipopolysaccharide (LPS)-induced increasing levels of neuroinflammation-associated proteins, including glial fibrillary acidic protein (GFAP), S100B and cAMP-response element binding protein (CREB).

These results suggest that CBD usage in pregnancy with inflammation conditions may be an effective therapeutic option for preventing conditions that may cause neuroinflammation in the fetal brain and adversely affect neurogenesis.”

https://pubmed.ncbi.nlm.nih.gov/39615608/

“Cannabidiol suppresses LPS-induced systemic inflammation in the fetal brain and placenta tissues. Cannabidiol reduces the level of neuroinflammatory markers in fetal brain tissues.”

https://www.sciencedirect.com/science/article/abs/pii/S0890623824002284?via%3Dihub


Novel fluorinated cannabinoid analogs modulate cytokine expression in human C20 microglial cells

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“Background: Phytochemicals derived from the plant Cannabis sativa hold promise in terms of medicinal value. Cannabinoids such as Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are arguably the best characterized and known to possess wide-ranging therapeutic benefits. The mechanism of action for these therapeutic effects remains to be fully elucidated, however, the anti-inflammatory actions are of particular interest. Maximizing therapeutic effects while limiting adverse effects is crucial in pharmaceutical development. Fluorination of natural products often yields molecules with enhanced biological properties and provides opportunities for intellectual property protection not available to the natural product.

Methods: Herein, we describe four novel cannabinoids (a deoxy trifluoroCBN analog (F3CBN), the racemic cis-deoxy-trifluoro-THC (F3THC), and truncated pyridine analogs of an intermediate in route to the THC and CBN, SG126 and SG154. Importantly, we provide the initial assessment of the biologic activity of these molecules, by investigating the in vitro effects on metabolic activity (via 3-[4,5-dimethylthiazol-2-yl]-2,5,-diphenyltetrazolium bromide, MTT assay) and cytokine expression (via enzyme linked immunosorbent assay, ELISA) in human C20 microglial cells.

Results: The cannabinoids examined had minimal to no effect on metabolic activity up to 10 µM. Notably, F3CBN and F3THC potentiated interleukin-1 β (IL-1β)-induced expression of interferon-γ inducible protein 10 (CXCL10) and IL-6 expression whereas, SG126 and SG154 were inhibitory.

Conclusions: These findings are foundational for new lines of investigation into the therapeutic potential of four novel fluorinated cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/39612133/

https://link.springer.com/article/10.1007/s43440-024-00680-8

A Review of Sturge-Weber Syndrome Brain Involvement, Cannabidiol Treatment and Molecular Pathways

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“Sturge-Weber syndrome (SWS) is a rare congenital neurocutaneous disorder typically caused by a somatic mosaic mutation in R183Q GNAQ. At-risk children present at birth with a capillary malformation port-wine birthmark.

The primary diagnostic characteristic of the disorder includes leptomeningeal enhancement of the brain, which demonstrates abnormal blood vessels and results in impaired venous drainage and impaired local cerebral perfusion. Impaired cerebral blood flow is complicated by seizures resulting in strokes, hemiparesis and visual field deficits, hormonal deficiencies, behavioral impairments, and intellectual disability. Therefore, anti-seizure medication in combination with low-dose aspirin is a common therapeutic treatment strategy. Recently published data indicate that the underlying mutation in endothelial cells results in the hyperactivation of downstream pathways and impairment of the blood-brain barrier.

Cannabidiol (CBD) has been used to treat medically refractory seizures in SWS due to its anti-seizure, anti-inflammatory, and neuroprotective properties. Pilot research suggests that CBD improves cognitive impairment, emotional regulation, and quality of life in patients with SWS.

Recent preclinical studies also suggest overlapping molecular pathways in SWS and in CBD, suggesting that CBD may be uniquely effective for SWS brain involvement.

This review aims to summarize early data on CBD’s efficacy for preventing and treating epilepsy and neuro-cognitive impairments in patients with SWS, likely molecular pathways impacted, and provide insights for future translational research to improve clinical treatment for patients with SWS.”

https://pubmed.ncbi.nlm.nih.gov/39598668/

https://www.mdpi.com/1420-3049/29/22/5279

Cannabidiol, a Strategy in Aging to Improve Redox State and Immunity in Male Rats

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“Aging is characterized by oxidative stress and immune function impairment, and is associated with increased morbidity. Cannabidiol (CBD) has anti-oxidant properties, but its role in aging has been scarcely studied.

This work aims to test the effect of CBD on the redox state and immunity during aging in rats. In this study, 15-month-old male Long Evans rats received 10 mg/kg b.w/day of CBD in their diet for 10 weeks and were compared with same-age control and 2-month-old rats serving as a young control group, both following a standard diet.

After treatment, they were sacrificed, and the spleen, thymus, and total blood cells were collected. Redox parameters such as glutathione reductase and peroxidase activities, reduced (GSH) and oxidized (GSSG) glutathione concentration, GSSG/GSH ratio, and lipid peroxidation were evaluated. Moreover, immune functions (chemotaxis, natural killer activity, and lymphoproliferation) were analyzed in the spleen.

Results show that the 15-month-old control rats exhibited increased oxidative stress and immunosenescence compared to the 2-month-old rats. However, the CBD-treated animals showed higher anti-oxidant defenses, lower oxidants in the spleen, thymus, and blood cells, and better immunity in the spleen than the corresponding age-matched controls.

Therefore, CBD administration neutralizes oxidative stress and improves immunity, suggesting it is a strategy for achieving healthy aging.”

https://pubmed.ncbi.nlm.nih.gov/39596353/

“CBD could be suggested as a candidate to slow down aging and achieve a healthier longevity.”

https://www.mdpi.com/1422-0067/25/22/12288

Cannabinoids as Antibacterial Agents: A Systematic and Critical Review of In Vitro Efficacy Against Streptococcus and Staphylococcus

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“Background: Two major bacterial pathogens, Staphylococcus aureus and Streptococcus pyogenes, are becoming increasingly antibiotic-resistant. Despite the urgency, only a few new antibiotics have been approved to address these infections. Although cannabinoids have been noted for their antibacterial properties, a comprehensive review of their effects on these bacteria has been lacking.

Objective: This systematic review examines the antibacterial activity of cannabinoids against S. aureus, including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) strains, and S. pyogenes.

Methods: Databases, including CINAHL, Cochrane, Medline, Scopus, Web of Science, and LILACS, were searched. Of 3510 records, 24 studies met the inclusion criteria, reporting on the minimum inhibitory concentration (MIC) and minimum bactericidal concentration of cannabinoids.

Results: Cannabidiol (CBD) emerged as the most effective cannabinoid, with MICs ranging from 0.65 to 32 mg/L against S. aureus, 0.5 to 4 mg/L for MRSA, and 1 to 2 mg/L for VRSA. Other cannabinoids, such as cannabichromene, cannabigerol (CBG), and delta-9-tetrahydrocannabinol (Δ9-THC), also exhibited significant antistaphylococcal activity. CBD, CBG, and Δ9-THC also showed efficacy against S. pyogenes, with MICs between 0.6 and 50 mg/L. Synergistic effects were observed when CBD and essential oils from Cannabis sativa when combined with other antibacterial agents.

Conclusion: Cannabinoids’ antibacterial potency is closely linked to their structure-activity relationships, with features like the monoterpene region, aromatic alkyl side chain, and aromatic carboxylic groups enhancing efficacy, particularly in CBD and its cyclic forms. These results highlight the potential of cannabinoids in developing therapies for resistant strains, though further research is needed to confirm their clinical effectiveness.”

https://pubmed.ncbi.nlm.nih.gov/39596719/

“In conclusion, cannabinoids such as CBD, CBG, and Δ9-THC offer significant promise as alternatives or adjuncts to traditional antibiotics, particularly for targeting S. aureus, MRSA, and S. pyogenes. Their favourable safety profile positions them as potential candidates for antibacterial therapies, though rigorous clinical trials, standardised testing, and long-term safety studies are crucial to fully unlock their potential in combating AMR.”

https://www.mdpi.com/2079-6382/13/11/1023

Prenatal cannabinoid exposure and early language development

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“Introduction: The effect of prenatal cannabis exposure (PCE) on childhood neurodevelopment remains poorly understood. There is a paucity of studies describing the neurodevelopment impact of PCE in infancy. The Mullen Scale of Early Learning (MSEL) is a cognitive screening tool that can be used from birth to 68 months and includes language and motor domains. Here we aim to explore the association between PCE during pregnancy and neurodevelopmental outcomes at 12 months of age.

Methods: Participants were pregnant persons/infant pairs enrolled in The Safe Passage Study, a large prospective cohort study. Inclusion criteria included data available on PCE with associated MSEL scores at 12 months of age. Exposed participants were defined as early exposure (1st trimester only) or late exposure (2nd or 3rd trimester) and were randomly matched with unexposed participants. Multiple linear regression models were performed to test associations between prenatal cannabis exposure and the five Mullen subscales: gross motor, fine motor, expressive language, receptive language, and visual reception.

Results: Sixty-nine exposed and 138 randomly matched unexposed infants were included in the analyses. Mothers of children with PCE were younger with the mean age 23.7 years for early exposure (n = 51) and 22.8 years for late exposure (n = 18). Maternal characteristics with prenatal cannabis use include a high-school education, American Indian or Alaska Native descent, lower socioeconomic status and co-use of tobacco. There were no gestational age or sex difference among the groups. Expressive (95% CI: 2.54-12.76; p = 0.0036,) and receptive language scores (95% CI: 0.39-8.72; p = 0.0322) were significantly increased between late-exposed infants compared to unexposed infants following adjustment for covariates. Gross motor scores (95% CI: 1.75-13; p = 0.0105) were also significantly increased for early-exposed infants with no difference in visual reception scores.

Conclusion: Preclinical studies have shown abnormal brain connectivity in offspring exposed to cannabis affecting emotional regulation, hyperactivity, and language development. Results from this study link PCE to altered early language development within the first year of life. Exposed infants demonstrated increased expressive and receptive language scores at 12 months of age, which can translate to better performance in school. However, further research is needed to determine the implications of these results later in childhood.”

https://pubmed.ncbi.nlm.nih.gov/38078314/

https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2023.1290707/full

Cannabidiol/cannabidiolic acid-rich hemp (Cannabis sativa L.) extract attenuates cognitive impairments and glial activations in rats exposed to chronic stress

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“Ethnopharmacological relevance: Hemp (Cannabis sativa L.) is increasingly being recognized for its medicinal properties beside utilizing it for food, oil, and textile fibers. The high level of cannabidiol (CBD) content in hemp’s flowers shows promising neuroprotective properties without causing psychotomimetic or addictive effects. Recently, products containing CBD and its precursor, cannabidiolic acid (CBDA), have been used to treat stress-related cognitive impairment. However, the therapeutic potential of hemp extract remains inadequately explored.

Aim of the study: To investigate the effect of CBD/CBDA-rich hemp extract on learning and memory, neuroendocrine alterations, and hippocampal neuropathological changes in the chronic restraint stress model.

Materials and methods: Chronic restraint stress (CRS) was induced in male Wistar rats by immobilizing them in a restrainer for 6 hours per day for 21 consecutive days. CBD/CBDA-rich hemp extract (10 and 30 mg/kg, intraperitoneal injection) was administered daily, 1 hour before restraint. After the last day of CRS, behavioral tests for cognition were conducted using the Y-maze and object recognition tests. Serum corticosterone (CORT) levels were measured by ELISA. Histopathological changes, neuronal density, and the activation of microglia and astrocytes were visualized using cresyl violet and immunohistochemical staining.

Results: A high dose of CBD/CBDA-rich hemp extract effectively ameliorated CRS-induced cognitive impairment and reversed HPA axis hyperactivity in CRS rats by reducing CORT levels and adrenal gland weight. Additionally, CBD/CBDA-rich hemp extract protected CRS-induced damage to hippocampal neurons. Further analysis showed that CBD/CBDA-rich hemp extract reduced specific markers of microglial activation (ionized calcium-binding adaptor molecule-1, Iba-1) and astrocytic structural protein (glial fibrillary acidic protein, GFAP) in CRS rats.

Conclusion: CBD/CBDA-rich hemp extracts remarkably reversed the stress-induced behavioral perturbations and hippocampal damage, suggesting its ameliorative effect on stress response.”

https://pubmed.ncbi.nlm.nih.gov/39551282/

“Cannabidiol (CBD) and cannabidiolic acid (CBDA) is the major constituent in hemp (Cannabis sativa L.) extract”

“CBD/CBDA-rich hemp extract is effective in relieving the chronic stress-induced cognitive impairment.”

https://linkinghub.elsevier.com/retrieve/pii/S0378874124014120

Cannabis Use and Age-Related Changes in Cognitive Function From Early Adulthood to Late Midlife in 5162 Danish Men

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“Introduction: Cannabis is by far the most widely used and abused drug listed on the Drug Enforcement Administration’s Schedule I, which includes drugs with a high potential for abuse. There is evidence of short-term negative effects of cannabis use on cognition, but only a limited number of studies have explored the association between cannabis use and age-related cognitive decline. The aim of the present study was to investigate the relationship between cannabis use and age-related cognitive decline from early adulthood to late midlife.

Methods: The study population consisted of 5162 men who had participated in Danish follow-up studies on cognitive aging. These studies included scores on the military intelligence test Børge Prien’s Prøve from both the conscription assessment (mean age = 20 years; p1 and p99: 18 and 26 years) and from the follow-up (mean age = 64 years; p1 and p99: 55 and 72 years) as well as extensive data on lifestyle and health from the follow-up questionnaires. The association between cannabis use and age-related cognitive decline was investigated in linear regression models.

Results: Men with a history of cannabis use had less cognitive decline from early adulthood to late midlife compared to men without a history of cannabis use. Among cannabis users, neither age of initiation of cannabis use nor frequent use was significantly associated with a greater age-related cognitive decline.

Discussion and conclusions: In a sample of more than 5000 men followed for a mean of 44 years, we found no significant harmful effects of cannabis use on age-related cognitive decline.”

https://pubmed.ncbi.nlm.nih.gov/39508467/

“In the present study, we aimed to investigate the relationship between cannabis use and age-related cognitive decline from early adulthood to late midlife. This study contributes to the sparse knowledge on this subject and aligns with most existing studies, suggesting no association between cannabis use and greater cognitive decline. More specifically, in the present study, cannabis users experienced slightly less cognitive decline compared to nonusers, and the association remained significant when controlling for potential confounders. Among cannabis users, no significant association was found with cognitive decline for either age of initiation of cannabis use or frequent cannabis use. Further studies are needed to investigate whether these findings reflect that there are no adverse effects on cognitive decline or that the effects of cannabis are temporary and disappear after a prolonged period of time.”

https://onlinelibrary.wiley.com/doi/10.1002/brb3.70136

CB1 Receptors In NG2 CELLS MEDIATE CANNABINOID-EVOKED FUNCTIONAL MYELIN REGENERATION

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“Defects in myelin homeostasis have been reported in many neuropathological conditions. Cannabinoid compounds have been shown to efficiently promote myelin regeneration in animal models of demyelination. However, it is still unknown whether this action relies mostly on a cell autonomous effect on oligodendroglial-lineage-NG2 cells.

By using conditional genetic mouse models, here we found that cannabinoid CB1 receptors located on NG2 cells are required for oligodendroglial differentiation and myelin regeneration after demyelination. Selective CB1 receptor gene depletion in NG2 cells following toxin-induced demyelination disrupted oligodendrocyte regeneration and functional remyelination and exacerbated axonal damage. These deficits were rescued by pharmacological blockade of the RhoA/ROCK/Cofilin pathway.

Conversely, tetrahydrocannabinol administration promoted oligodendrocyte regeneration and functional remyelination in wild-type but not Ng2-CB1-deficient mice.

Overall, this study identifies CB1 receptors as essential modulators of remyelination and support the therapeutic potential of cannabinoids for promoting remyelination in neurological disorders.”

https://pubmed.ncbi.nlm.nih.gov/39528076/

“Cannabinoids have been shown to modulate myelin development and regeneration in mice. Here, using OPC-specific reporter mouse lines in combination with models of toxin-induced demyelination, we found that CB1 receptors located on NG2 cells, by modulating RhoA/ROCK/cofilin and mTORC1 signaling in a coordinated manner, exert an essential function in controlling NG2 cell differentiation, OL regeneration, myelin regeneration and functional recovery following demyelination, thus supporting the therapeutic potential of cannabinoids for promoting remyelination in neurological disorders.”

https://www.sciencedirect.com/science/article/abs/pii/S0301008224001199?via%3Dihub

Effects of cannabidiol on AMPKα2 /HIF-1α/BNIP3/NIX signaling pathway in skeletal muscle injury

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“Cannabidiol: (CBD) is a non-psychoactive natural active ingredient from cannabis plant, which has many pharmacological effects, including neuroprotection, antiemetic, anti-inflammatory and anti-skeletal muscle injury. However, the mechanism of its effect on skeletal muscle injury still needs further research.

In order to seek a scientifically effective way to combat skeletal muscle injury during exercise, we used healthy SD rats to establish an exercise-induced skeletal muscle injury model by treadmill training, and systematically investigated the effects and mechanisms of CBD, a natural compound in the traditional Chinese medicine Cannabis sativa L., on combating skeletal muscle injury during exercise.

CBD effectively improved the fracture of skeletal muscle tissue and reduced the degree of inflammatory cell infiltration. Biochemical indexes such as CK, T, Cor, LDH, SOD, MDA, and GSH-Px in serum of rats returned to normal. Combining transcriptome and network analysis results, CBD may play a protective role in exercise-induced skeletal muscle injury through HIF-1 signaling pathway. The experimental results implied that CBD could down-regulate the expression of IL-6, NF-κB, TNF-α, Keap1, AMPKα2, HIF-1α, BNIP3 and NIX, and raised the protein expression of IL-10, Nrf2 and HO-1.

These results indicate that the protective effect of CBD on exercise-induced skeletal muscle injury may be related to the inhibition of oxidative stress and inflammation, thus inhibiting skeletal muscle injury through AMPKα2/HIF-1α/BNIP3/NIX signal pathways.”

https://pubmed.ncbi.nlm.nih.gov/39502531/

“This study preliminarily explored the protective effect of CBD on skeletal muscle in the rat model of acute exercise-induced skeletal muscle injury. The CBD intervention can reduce CK and LDH levels and increase T/COR ratio. The MDA content in the low-dose and high-dose groups of CBD was declined, while the SOD and GSH-Px content were raised. The intervention of CBD can reduce the level of oxidative stress and inflammatory response, and then reduce the expressions of AMPKα2, HIF-1α, BNIP3 and NIX, thus protecting skeletal muscle from injury. This study could provide a new potential target for the treatment of exercise-induced skeletal muscle injury. It can provide new ideas for the basic research and clinical treatment of CBD repairing skeletal muscle injury in the future.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1450513/full