Author Archives: David Worrell

Synaptic Endocannabinoid Signaling in the Anterior Cingulate Cortex: Implications for Alzheimer’s Disease Pathology and Social Behavior

Posted on by

“Background: Alzheimer’s disease (AD) is a major contributor to neuropsychiatric disorders, exerting profound impacts on individuals and society. Social behavioral impairments associated with AD present significant challenges for both diagnosis and treatment, highlighting the urgent need to unravel their underlying mechanisms. Dysfunction of the anterior cingulate cortex (ACC) has been identified as a key factor driving the emergence of these behavioral deficits. Among its regulatory mechanisms, endocannabinoids play a critical role in modulating short-term synaptic plasticity in the ACC, thereby maintaining synaptic homeostasis. Endocannabinoid signaling is highly sensitive to environmental stimuli, demonstrating dynamic responses to external stressors. Despite these insights, the precise role of synaptic endocannabinoid signaling in the ACC, particularly its contribution to synaptic homeostasis and social behavioral regulation in the context of AD pathology, remains poorly understood.

Method: Using a multifaceted approach-including optogenetic, electrophysiological, pharmacological, and behavioral techniques-we characterized alterations in presynaptic CB1 receptors and endocannabinoid synthesis at excitatory and inhibitory synapses during AD progression.

Result: Our findings reveal a regulatory role of cannabinoid signaling at both pre- and post-synaptic terminals within the ACC, providing insights into its modulation of synaptic transmission in AD. We further examined the impact of disrupted endocannabinoid signaling on synaptic homeostasis, employing calcium signal recording and pharmacological interventions. Alterations in excitatory and inhibitory synaptic function were particularly evident in socially isolated mice, a condition that exacerbates AD-related behavioral deficits. These findings highlight the interplay between endocannabinoid dysregulation, synaptic dysfunction, and behavioral abnormalities in AD. Moreover, we explored therapeutic strategies targeting synaptic endocannabinoid signaling to mitigate AD-induced social behavioral deficits. Using cannabinoid receptor knockout models and pharmacological approaches, we dissected the distinct roles of cannabinoid signaling components in mediating behavioral outcomes. This work underscores the potential of modulating endocannabinoid signaling to alleviate neuropsychiatric symptoms associated with AD.

Conclusion: This comprehensive investigation sheds light on the intricate relationship between AD pathology, synaptic endocannabinoid signaling, and social behavior. By unraveling the molecular, cellular, and behavioral correlates of AD-induced alterations in cannabinoid signaling, our study provides valuable insights into the pathophysiology of AD-related neuropsychiatric disorders. It lays the foundation for innovative therapeutic approaches.”

https://pubmed.ncbi.nlm.nih.gov/41435339

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70855_097499

Cannabidiol-Mediated Neuroprotection in Aβ42-Induced Alzheimer’s Model of Drosophila: Behavioral and Morphological Evidence

Posted on by

“Background: Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by cognitive decline and neuropathological transformations, imposing a significant burden on individuals and healthcare systems globally. Despite ongoing research endeavors, effective treatments to halt AD progression remain elusive. Cannabidiol (CBD) is a natural compound derived from cannabis renowned for its anti-inflammatory, neuroprotective, and antioxidant properties. This study investigated the neuroprotective potential of CBD in mediating neurobehavioral and morphological changes in the Aβ42 transgenic model of AD.

Method: 150 flies were grouped into five. Group I & II are negative and positive control and were exposed to 10 g of diet only, group III is an experimental control and was exposed to 1 mM Donepezil. Group IV & V were subjected to 2 mg and 4 mg of CBD respectively for 2 weeks. Motor function, memory abilities, social interactions, and expression of amyloid beta (Aβ42) and glial fibrillary acidic protein (GFAP) were evaluated using climbing, aversive phototaxis suppression, social space assay, and immunostaining respectively.

Result: Findings revealed a significant decrease in motor coordination (0.31 ± 0.08, p = 0.007), memory function (7.00 ± 8.52, p = 0.008), and social behavior (3.09 ± 0.51, p = 0.0008) in the positive control compared to the negative control group, accompanied by elevated Aβ42 and GFAP expression (58.50 ± 8.000, p = 0.03). However, treatment with CBD effectively mitigated these deficits. Motor function was restored in the 4 mg CBD (0.69 ± 0.08, p = 0.028), memory abilities were improved in the 4 mg CBD (63.00 ± 7.35, p = 0.007), social interaction was increased in the 4 mg CBD group (1.19 ± 0.53, p = 0.0071). Furthermore, CBD treatment reduced Aβ42 and GFAP immunoreactivity (58.50 ± 8.000, p = 0.03).

Conclusion: This study provides compelling evidence for the therapeutic potential of CBD oil in mitigating motor and cognitive deficits and neuropathological changes associated with AD, underscoring the importance of further research into the mechanisms of action and optimization of treatment regimens for AD.”

https://pubmed.ncbi.nlm.nih.gov/41441546

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70856_096378

Evaluation of the effect of cannabidiol treatment on [18F]FDG and [11C]PK11195 uptake in an animal model for Alzheimer’s disease

Posted on by

“Background: Cannabidiol (CBD) has well-described anti-inflammatory and neuroprotective properties. Emerging preclinical research has explored the potential of this cannabinoid as a therapeutic agent to delay or prevent the onset of symptoms and pathophysiological features of neurodegenerative processes, such as Alzheimer’s disease (AD). Therefore, the aim of this study was to evaluate the effect of CBD treatment during aging of an animal model for AD using positron emission tomography (PET).

Method: Male and female 3xTg-AD mice (ethics committee 1811/2022) were divided into control and CBD groups. At 7 months-old, the animals were treated with CBD (20 mg/kg) or vehicle for 30 days. At 4, 8, 12 and 18 months-old, [18F]FDG and [11C]PK11195 PET images were acquired to assess brain metabolism and neuroinflammation. The standardized uptake value (SUV) was calculated for the whole brain. The behavioral tests of novel object recognition (NOR) and elevated plus maze (EPM) were performed to assess memory, exploratory behavior and anxiety.

Result: There was a sex effect on [18F]FDG uptake, with vehicle-males showing higher uptake than vehicle-females at 4 (p = 0.02), 8 (p = 0.007), and 18 months (p <0.0001). Vehicle-females had reduced [18F]FDG uptake at 18 months compared to all other ages (18 months vs: 4: p = 0.045; 8: p = 0.001; 12: p <0.0001). In the CBD group, [18F]FDG uptake was higher in males than in females at 8 months (p = 0.002). CBD-males also had increased uptake from 4 to 8 months (p <0.0001) and to 12 months (p = 0.002). In addition, CBD-females had higher [18F]FDG uptake than vehicle-females at 18 months (p = 0.024). No sex effect was observed for [11C]PK11195. Increased uptake was observed in the control group at 18 months compared to 4 months (p = 0.004) and 12 months (p = 0.02). No significant differences were observed in the behavioral assessments.

Conclusion: Our study demonstrated prominent sex differences in brain metabolism and provided evidence of a possible neuroprotective role of CBD in mitigating neuroinflammatory events associated with aging. Furthermore, PET proved to be a more sensitive tool for detecting aging-induced changes in the 3xTg-AD model compared to behavioral assessments.”

https://pubmed.ncbi.nlm.nih.gov/41442268

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70856_100426

Exploring the synergistic effects of physical exercise and cannabidiol treatment in a mouse model of Down syndrome using positron emission tomography

Posted on by

“Background: Down Syndrome (DS) is considered a genetic form of Alzheimer’s disease (AD) as it increases the expression of AD-related genes, leading to precocious neuroinflammation and cell death. Given the increasing longevity of the DS population, it is essential to look for alternatives to delay AD development and improve quality of life. Considering that physical exercise and cannabidiol (CBD) have recognized neuroprotective properties, the aim of this study was to evaluate the effects of these interventions alone and in combination, in a model of DS using positron emission tomography (PET).

Method: Ts65Dn trisomic mice (ethical approval: 1292/2019, 1811/2022, 2065/2024) were divided into four groups: control (no treatment); exercise; CBD; and exercise+CBD. The exercise group was subjected to physical exercise on a treadmill from 2 to 8 months of age, 3 times/week, and the CBD group was treated at 7 months of age for 30 days (20 mg/kg, ip). The exercise+CBD group received both treatments as described above. PET images with [11C]PK11195 and [18F]FDG were acquired to assess brain metabolism and neuroinflammation at 4 and 8 months of age using a small animal PET scanner. The average standardized uptake value (SUV) was calculated considering the whole brain (WB) and the hippocampus.

Result: At 4 months, exercise+CBD had higher [11C]PK11195 uptake in the WB and hippocampus compared to the other groups (control: p = 0.0006 in both; exercise: p = 0.009 and p = 0.005; CBD: p = 0.0007 and p = 0.0006). At 8 months, CBD and CBD+exercise had higher radiotracer uptake compared to the control (WB: p = 0.0005 and p = 0.0003, respectively; hippocampus: p = 0.0002 and p = 0.0003, respectively) and exercise groups (WB: p = 0.0009 and p = 0.0005, respectively; hippocampus: p <0.0001 for both). The CBD group showed increased [11C]PK11195 uptake in the WB (p <0.0001) and hippocampus (p <0.0001) at 8 months of age. Regarding [18F]FDG, the exercise+CBD group had an increase in uptake from 4 to 8 months in both regions (WB: p = 0.03; hippocampus: p = 0.04).

Conclusion: Our data suggest that CBD treatment induced a higher glial response that was not present when CBD was associated with physical exercise. Indeed, this association increased brain metabolism, suggesting a neuroprotective mechanism.”

https://pubmed.ncbi.nlm.nih.gov/41447104

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70856_099067

Natural cannabinoids effects on glutamatergic and dopaminergic neurotransmission in a transgenic model of Alzheimer’s disease

Posted on by

“Background: Previous results demonstrated that chronic treatment with a combination of two natural cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), at non-psychotropic doses reduces cognitive decline, as well as the extracellular glutamate levels and the basal excitability in the hippocampus of APP/PS1 mice. In the present study, we aimed to elucidate whether this modulation of hippocampal excitability exerted by natural cannabinoids could affect the dopaminergic activity in limbic areas related to non-cognitive symptoms of Alzheimer’s disease (AD) in our animal model.

Method: We used glutamate and dopamine biosensors, along with fiber photometry techniques, to evaluate the levels of these neurotransmitters in the hippocampus and nucleus accumbens (NAcc), respectively. Experiments were conducted in anaesthetized animals for recording under an electrical hippocampal stimulation protocol, or in awake animals for recording during behavioral evaluations (novel object recognition, open field, sociability and prepulse inhibition tests).

Result: Chronic treatment with THC and CBD reversed the increased prominence and frequency of glutamate peaks observed in the hippocampus of APP/PS1 animals during the novel object recognition test at early stages of the AD-like process. At more advanced stages, APP/PS1 mice exhibited alterations in dopamine dynamics in the NAcc, which were compatible with psychotic-like traits observed in this animal model of AD. Interestingly, these alterations were partially modulated by chronic treatment with these natural cannabinoids.

Conclusion: Our results reveal that the combination of THC and CBD modulates glutamatergic activity in the hippocampus at early stages of the AD process and that, likely related to this, reduces dopaminergic alterations in limbic areas at advanced stages. Thus, these natural cannabinoids may alleviate both cognitive and non-cognitive symptoms occurring in AD, supporting their clinical development as a pleiotropic therapeutic alternative for this neurodegenerative disease.”

https://pubmed.ncbi.nlm.nih.gov/41454444

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70855_102846

Therapeutic potential of chronic CBD:THC co-treatment on disease-relevant behaviors of female TAU58/2 mice

Posted on by

“Background: Limited therapeutic success and side effect profile of traditional but also novel antibody-based therapies for Alzheimer’s disease (AD) underline the need for alternatives. Cannabinoids have anti-inflammatory effects, are easily accessible and generally well tolerated. A dosage-dependent “entourage” effect has been described for phytocannabinoids such as cannabidiol (CBD) administered in combination with delta-9-tetrahydrocannabinol (THC). The effects of cannabinoid combination treatment on tau pathology, one of the major neuropathological hallmarks of AD, is poorly understood. Here, the effects of chronic treatment with CBD and THC on disease-relevant behaviors of female TAU58/2 transgenic mice were evaluated for the first time.

Method: Six-month-old TAU58/2 transgenic females (n = 28) and wild type-like control littermates (n = 22) were chronically treated with CBD+THC (50:3 mg/kg/day, i.p.) or vehicle for five weeks. Behavioral testing started after three weeks of treatment and included assessment of motor function, spatial and social recognition memory, anxiety and sensorimotor gating.

Result: Treatment and genotype effects on individual behavioral tests are summarized in Table 1. TAU58/2 transgenic females exhibited pronounced deficits in motor function, sensorimotor gating impairments, a prominent anxiolytic-like phenotype and subtle spatial memory deficits. Chronic CBD:THC co-treatment significantly improved aspects of motor function in pole test and accelerod. Moreover, anxiolytic-like behavior of TAU58/2 mice was partially reduced by cannabinoid treatment. Cannabinoids also showed the potential to improve spatial memory impairment of transgenic mice, though not confirmed by a significant treatment effect. Social recognition memory and sensorimotor gating were not affected by the treatment.

Conclusion: Here, long-term CBD:THC treatment at 50:3 mg/kg/day shows subtle but promising therapeutic effects in middle-aged TAU58/2 mice. Thereby, this study is the first to provide evidence for the therapeutic potential of CBD:THC co-treatment on tauopathy-related behavioral symptoms. Since CBD alone did not improve deficits of adult TAU58/2 mice in a previous study, these findings underline the potential of multi-cannabinoid therapy for the treatment of AD and contribute to the evaluation of the most efficient cannabinoid ratio. Ongoing tissue analysis addressing tau and inflammatory markers will reveal further insights into the underlying molecular mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/41447176

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70859_099683

Therapeutic Potential of INM-901 in Mitigating Alzheimer’s Disease Pathology: Insights from a Long-term 5xFAD Mouse Model Study

Posted on by

“Background: Alzheimer’s Disease (AD) is a neurodegenerative condition characterized by cognitive and sensorimotor deficits, affecting over 6.9 million people in the US, with an annual economic impact of over $700 billion in direct and indirect healthcare costs. While current treatments such as donepezil, and memantine manage symptoms, they do not halt disease progression. Moreover, amyloid beta (Aβ) antibody therapy faces challenges, including limited efficacy in advanced disease stages, infusion-related reactions, and high treatment costs. Cannabinoids have shown potential in alleviating Aβ toxicity, reducing tau phosphorylation, and suppressing inflammation via CB1 and CB2 receptors, supporting neuronal viability. Therefore, in this study, we investigated the effects of a novel synthetic cannabinoid analogue INM-901 on Aβ-induced toxicity and disease progression using the 5xFAD mice.

Method: Male 5xFAD mice, which exhibit AD-like pathology, including accelerated Aβ-plaque accumulation, inflammation, neurodegeneration, and deficits in cognitive and motor functions, were treated (intra-peritoneally) with INM-901 at 15 or 30 mg/kg twice-weekly for 7 months. Control groups, including non-transgenic and 5xFAD mice, received vehicle-treatment. Behavioral tests, including the Open-field (OFT), Zero Maze, Barnes Maze, and Acoustic Startle Response, were conducted post-treatment. Brain tissue and plasma samples were collected and analyzed via RNAseq, immunohistochemistry, western blotting, and multiplex assay to assess the effects of INM-901 on AD-related genes and protein expression.

Result: INM-901 treatment reversed changes in anxiety-like behavior in the Zero Maze and OFT, as well as improved spatial learning and memory in the Barnes Maze. INM-901 treated mice also exhibited improved acoustic startle response (%PPI), indicating enhanced auditory function. RNAseq showed decreased expression of several inflammatory genes that were upregulated in the 5xFAD mice, while multiplex assays revealed reduced levels of pro-inflammatory cytokines and neurodegeneration marker neurofilament light chain (NfL). Immunohistochemistry demonstrated a reduction in Aβ-aggregation, as well as changes in CB2R expression, highlighting the neuroprotective and anti-inflammatory effects of INM-901.

Conclusion: INM-901 treatment reversed several behavioral changes, improved auditory deficits, decreased Aβ-aggregation, and modulated inflammatory and neuritogenesis markers in 5xFAD mice. These findings highlight the potential of INM-901 as a therapeutic candidate for AD and provide a basis for further evaluation in tauopathy and inflammatory neurodegenerative models.”

https://pubmed.ncbi.nlm.nih.gov/41449949

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70859_103609

Resurrected Ancestral Cannabis Enzymes Unveil the Origin and Functional Evolution of Cannabinoid Synthases

Posted on by

“Cannabinoids, such as tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) and cannabichromenic acid (CBCA), are bioactive and medicinally relevant compounds found in the cannabis plant (Cannabis sativa L.). These three compounds are synthesised from a single precursor, cannabigerolic acid (CBGA), through regioselective reactions catalysed by different cannabinoid oxidocyclase enzymes.

Despite the importance of cannabinoid oxidocyclases for determining cannabis chemotype and properties, the functional evolution and molecular mechanism of this enzyme family remain poorly understood. To address this gap, we combined ancestral sequence reconstruction and heterologous expression to resurrect and functionally characterise three ancestral cannabinoid oxidocyclases.

Results showed that the ability to metabolise CBGA originated in a recent ancestor of cannabis and that early cannabinoid oxidocyclases were promiscuous enzymes producing all three THCA, CBDA and CBCA. Gene duplication and diversification later facilitated enzyme subfunctionalisation, leading to extant, highly-specialised THCA and CBDA synthases. Through rational engineering of these ancestors, we designed hybrid enzymes which allowed identifying key amino acid mutations underlying the functional evolution of cannabinoid oxidocyclases. Ancestral and hybrid enzymes also displayed unique activities and proved to be easier to produce heterologously than their extant counterparts.

Overall, this study contributes to understanding the origin, evolution and molecular mechanism of cannabinoid oxidocyclases, which opens new perspectives for breeding, biotechnological and medicinal applications.”

https://pubmed.ncbi.nlm.nih.gov/41454532

“Cannabinoids are specialised metabolites produced by the plant Cannabis sativa L. (cannabis).”

https://onlinelibrary.wiley.com/doi/10.1111/pbi.70475

Cannabigerol Exerts In Vivo and In Vitro Anti-Inflammatory Effects via Inhibition of the MAPK and NF-κB Pathways

Posted on by

“Cannabis sativa L. has a long history of use and contains more than 80 cannabinoids. However, although cannabigerol (CBG), which acts as a biosynthetic precursor of its most abundant phytocannabinoids, has anti-inflammatory effects, the exact mechanism of action remains underexplored.

In this study, we explored the anti-inflammatory potential of CBG to assess its potential for therapeutic and industrial applications.

CBG was extracted from the cannabis cultivar ‘Pink Pepper’ In vitro assays were performed via RAW 264.7 mouse macrophages stimulated with lipopolysaccharide, and in vivo efficacy was evaluated through a carrageenan-induced paw edema mouse model to confirm the activity of CBG in acute inflammation.

Nitric oxide production, mRNA, and protein expression of inflammatory mediators were suppressed by CBG treatment in a process downregulated through the MAPK and NF-κB pathways. Although paw edema was not statistically significantly reduced, oral administration of CBG suppressed the expression of COX-2, iNOS, TNF-α, IL-1β, and IL-6 in the carrageenan-induced mouse model.

CBG has been demonstrated to exert significant anti-inflammatory effects via modulation of key inflammatory mediators and signaling pathways in both in vivo and in vitro models.

Our findings further support the potential of CBG as a bioactive compound for further anti-inflammatory research.”

https://pubmed.ncbi.nlm.nih.gov/41423277

https://www.jmb.or.kr/journal/view.html?doi=10.4014/jmb.2509.09034

Cannabidiol attenuates the LPS/D-Galactosamine-induced acute liver injury by inhibiting parkin-mediated ubiquitination of MFN2

Posted on by

“Ethnopharmacological relevance: Acute liver injury (A-LI) is a clinical syndrome that can rapidly progress to acute liver failure, resulting in high mortality and poor prognosis. Cannabis sativa L. is an important herbaceous plant that has been widely used in folk medicine since ancient times. Cannabidiol (CBD) is its most abundant non-psychoactive compound, exhibiting hepatoprotective, anti-inflammatory, and antioxidant properties. However, the protective effect of CBD against A-LI and its mechanism remain unclear.

Objective: This study aimed to investigate the protective effects of CBD on A-LI and elucidate the underlying molecular mechanisms.

Methods: In vivo, an A-LI mouse model was induced by LPS/D-GalN. Each group was treated with or without LPS/D-GalN or CBD. H&E staining, alanine aminotransferase (ALT), aspartate aminotransferase (AST) level assay, TUNEL staining, TEM, IF, RT-qPCR, Western blot, Co-IP and adeno-associated virus (AAV) infection were performed. In vitro, RAW264.7 cells were stimulated with LPS. CCK-8, ELISA, MMP, mitochondrial ROS assay, siRNA knockdown and plasmid overexpression were performed.

Results: CBD (2.5 or 5 mg kg-1) mitigated LPS/D-GalN-induced liver damage, suppressed inflammatory cytokine expression, reduced hepatocellular apoptosis, and inhibited oxidative stress. CBD treatment increased hepatic mitofusin-2 (MFN2) protein while decreasing Parkin-MFN2 binding and MFN2 ubiquitination. In RAW264.7 cells, CBD pretreatment (2.5 or 5 μM) dose-dependently attenuated LPS-induced inflammation, apoptosis, and mitochondrial dysfunction and likewise elevated MFN2 levels while limiting its ubiquitination. MFN2 knockdown abolished CBD’s protective effects, whereas MFN2 overexpression restored them. Consistently, AAV-mediated delivery of MFN2-targeting short hairpin RNA reversed the hepatoprotective action of CBD in vivo.

Conclusion: CBD mediates anti-inflammatory and hepatoprotective effects by inhibiting MFN2 degradation through disrupting the interaction between Parkin and MFN2. These results provide molecular evidence for application of CBD in treatment of A-LI and provide references to the drug development for A-LI.”

https://pubmed.ncbi.nlm.nih.gov/41419044

“The natural plant extract cannabidiol (CBD) attenuates acute liver injury.”

“Cannabis sativa L. (family Cannabaceae) is a valuable natural plant resource that has been used as a folk medicine since ancient times.”

https://www.sciencedirect.com/science/article/abs/pii/S037887412501760X?via%3Dihub