Potential of CBD Acting on Cannabinoid Receptors CB1 and CB2 in Ischemic Stroke

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“Stroke is one of the leading causes of death. It not only affects adult people but also many children. It is estimated that, every year, 15 million people suffer a stroke worldwide. Among them, 5 million people die, while 5 million people are left permanently disabled. In this sense, the research to find new treatments should be accompanied with new therapies to combat neuronal death and to avoid developing cognitive impairment and dementia.

Phytocannabinoids are among the compounds that have been used by mankind for the longest period of history. Their beneficial effects such as pain regulation or neuroprotection are widely known and make them possible therapeutic agents with high potential.

These compounds bind cannabinoid receptors CB1 and CB2. Unfortunately, the psychoactive side effect has displaced them in the vast majority of areas. Thus, progress in the research and development of new compounds that show efficiency as neuroprotectors without this psychoactive effect is essential.

On the one hand, these compounds could selectively bind the CB2 receptor that does not show psychoactive effects and, in glia, has opened new avenues in this field of research, shedding new light on the use of cannabinoid receptors as therapeutic targets to combat neurodegenerative diseases such as Alzheimer’s, Parkinson’s disease, or stroke.

On the other hand, a new possibility lies in the formation of heteromers containing cannabinoid receptors. Heteromers are new functional units that show new properties compared to the individual protomers. Thus, they represent a new possibility that may offer the beneficial effects of cannabinoids devoid of the unwanted psychoactive effect.

Nowadays, the approval of a mixture of CBD (cannabidiol) and Δ9-THC (tetrahydrocannabinol) to treat the neuropathic pain and spasticity in multiple sclerosis or purified cannabidiol to combat pediatric epilepsy have opened new therapeutic possibilities in the field of cannabinoids and returned these compounds to the front line of research to treat pathologies as relevant as stroke.”

https://pubmed.ncbi.nlm.nih.gov/38928415/

“Phytocannabinoids not presenting psychoactive effects such as cannabidiol show an interesting potential to decrease neuroinflammation and neurodegeneration in animal models of hypoxia-ischemia, becoming a new promising therapy to improve stroke.”

https://www.mdpi.com/1422-0067/25/12/6708

Cannabinoids: Potential for Modulation and Enhancement When Combined with Vitamin B12 in Case of Neurodegenerative Disorders

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“The enduring relationship between humanity and the cannabis plant has witnessed significant transformations, particularly with the widespread legalization of medical cannabis.

This has led to the recognition of diverse pharmacological formulations of medical cannabis, containing 545 identified natural compounds, including 144 phytocannabinoids like Δ9-THC and CBD. Cannabinoids exert distinct regulatory effects on physiological processes, prompting their investigation in neurodegenerative diseases. Recent research highlights their potential in modulating protein aggregation and mitochondrial dysfunction, crucial factors in conditions such as Alzheimer’s Disease, multiple sclerosis, or Parkinson’s disease.

The discussion emphasizes the importance of maintaining homeodynamics in neurodegenerative disorders and explores innovative therapeutic approaches such as nanoparticles and RNA aptamers. Moreover, cannabinoids, particularly CBD, demonstrate anti-inflammatory effects through the modulation of microglial activity, offering multifaceted neuroprotection including mitigating aggregation. Additionally, the potential integration of cannabinoids with vitamin B12 presents a holistic framework for addressing neurodegeneration, considering their roles in homeodynamics and nervous system functioning including the hippocampal neurogenesis.

The potential synergistic therapeutic benefits of combining CBD with vitamin B12 underscore a promising avenue for advancing treatment strategies in neurodegenerative diseases. However, further research is imperative to fully elucidate their effects and potential applications, emphasizing the dynamic nature of this field and its potential to reshape neurodegenerative disease treatment paradigms.”

https://pubmed.ncbi.nlm.nih.gov/38931480/

“Since neurodegenerative diseases like Alzheimer’s, Parkinson’s, multiple sclerosis, Huntington’s, and amyotrophic lateral sclerosis present significant healthcare and therapeutic challenges due to not only their complex etiology or pathophysiology but symptoms severity as well, it is important to keep the attention on improving constantly effective therapeutic methods devoted to neurodegenerative diseases treatment.

Recent studies indicate cannabinoids, particularly from Cannabis sativa, to hold promise in addressing key pathological processes associated with these disorders.

Cannabinoids, especially THC and CBD, demonstrate anti-aggregative effects, modulating the endocannabinoid system and interacting with cannabinoid receptors 1 and 2, offering potential in mitigating protein aggregation seen in disorders like multiple sclerosis. They also activate CBR1, protecting against mitochondrial dysfunction, crucial in diseases disrupting energy distribution, such as demyelination.

Emerging evidence suggests that vitamin B12, essential for cellular processes, could complement therapeutic strategies, potentially enhancing the effects of CBD. Additionally, CBD shows promise in reversing locomotor changes in Parkinson’s disease independently of NPR-19 receptors, while also protecting dopaminergic neurons and reducing reactive oxygen species accumulation. Thus, the integration of nanoparticles of β-caryophyllene, a CB2R binder, as explored by Alberti et al. (2020) [4], represents potential advancement in developing therapies that improve drug BBB crossing and enhance overall treatment efficacy, moreover, accordingly, the process aimed at combining RNA aptamers with cannabinoids and vitamin B12 may offer precise targeted therapies, but rigorous testing is necessary before clinical use.

This combined approach represents a promising frontier in neurodegenerative disease treatment, highlighting ongoing research into cannabinoids’ effects and applications across various disease contexts. Understanding their interaction with mitochondrial function and cellular communication holds potential for novel therapeutic strategies. Further investigation is needed to fully grasp cannabinoids’ effects and applications in diverse disease contexts.”

https://www.mdpi.com/1424-8247/17/6/813

Endocannabinoid System Changes throughout Life: Implications and Therapeutic Potential for Autism, ADHD, and Alzheimer’s Disease

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“The endocannabinoid system has been linked to various physiological and pathological processes, because it plays a neuromodulator role in the central nervous system.

In this sense, cannabinoids have been used off-label for neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHA), as well as in Alzheimer’s disease (AD), a more prevalent neurodegenerative disease. Thus, this study aims, through a comprehensive literature review, to arrive at a better understanding of the impact of cannabinoids in the therapeutic treatment of patients with ASD, ADHD, and Alzheimer’s disease (AD).

Overall, cannabis products rich in CBD displayed a higher therapeutic potential for ASD children, while cannabis products rich in THC have been tested more for AD therapy. For ADHD, the clinical studies are incipient and inconclusive, but promising. In general, the main limitations of the clinical studies are the lack of standardization of the cannabis-based products consumed by the participants, a lack of scientific rigor, and the small number of participants.”

https://pubmed.ncbi.nlm.nih.gov/38928592/

“Importantly, cannabinoid replacement, through exogenous cannabis derivates, for example, CBD and THC, is promising for these diseases.”

https://www.mdpi.com/2076-3425/14/6/592

Neuroprotective Effects of Cannabispirenone A against NMDA-Induced Excitotoxicity in Differentiated N2a Cells

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“The endocannabinoid system is found throughout the central nervous system, and its cannabinoids receptor 1 is critical in preventing neurotoxicity caused by N-methyl-D-aspartate receptor activation (NMDARs). The activity of NMDARs places demands on endogenous cannabinoids to regulate their calcium currents.

Endocannabinoids keep NMDAR activity within safe limits, protecting neural cells from excitotoxicity. Cannabinoids are remembered to deliver this outcome by repressing presynaptic glutamate discharge or obstructing postsynaptic NMDAR-managed flagging pathways.

The endocannabinoid system must exert a negative influence proportional to the strength of NMDAR signaling for such control to be effective. The goal of this paper is to draw the attention towards the neuroprotective mechanism of constituents of Cannabis sativa against NMDA-induced excitotoxic result.

Phytochemical investigation of the cannabis flowers led to the isolation of nine secondary metabolites. A spiro-compound, Cannabispirenone A, which on treatment of the cells prior to NMDA exposure significantly increases cell survival while decreasing ROS production, lipid peroxidation, and intracellular calcium.

Our findings showed that this compound showed neuroprotection against NMDA-induced excitotoxic insult, has antioxidative properties, and increased cannabinoid receptor 1 expression, which may be involved in the signaling pathway for this neuroprotection.”

https://pubmed.ncbi.nlm.nih.gov/38855429/

“In the current study, we assessed the flowers of the cannabis plant that showed ability to protect cells from NMDA-induced insult and discovered that it could prevent cell death. To our knowledge, we here reporting the first-time neuroprotective properties of the molecule isolated from the flowers of the cannabis plant.”

https://onlinelibrary.wiley.com/doi/10.1155/2024/3530499

The development of cannabinoids as therapeutic agents in the United States

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“Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis’ effects through interactions with the body’s endogenous cannabinoid system.

This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents, while underscoring the risks related to interfering with the endogenous system during non-medical use.

This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well-established, including analgesic effects after acute exposures and neurocognitive risks after acute and chronic use.

In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility, ultimately, to extend our knowledge of the risks and benefits of cannabinoids for patients and providers.

Significance Statement This work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development.”

https://pubmed.ncbi.nlm.nih.gov/38849155/

https://pharmrev.aspetjournals.org/content/early/2024/06/07/pharmrev.123.001121

Exploring the versatile roles of the endocannabinoid system and phytocannabinoids in modulating bacterial infections

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“The endocannabinoid system (ECS), initially identified for its role in maintaining homeostasis, particularly in regulating brain function, has evolved into a complex orchestrator influencing various physiological processes beyond its original association with the nervous system. Notably, an expanding body of evidence emphasizes the ECS’s crucial involvement in regulating immune responses.

While the specific role of the ECS in bacterial infections remains under ongoing investigation, compelling indications suggest its active participation in host-pathogen interactions. Incorporating the ECS into the framework of bacterial pathogen infections introduces a layer of complexity to our understanding of its functions.

While some studies propose the potential of cannabinoids to modulate bacterial function and immune responses, the outcomes inherently hinge on the specific infection and cannabinoid under consideration. Moreover, the bidirectional relationship between the ECS and the gut microbiota underscores the intricate interplay among diverse physiological processes.

The ECS extends its influence far beyond its initial discovery, emerging as a promising therapeutic target across a spectrum of medical conditions, encompassing bacterial infections, dysbiosis, and sepsis.

This review comprehensively explores the complex roles of the ECS in the modulation of bacteria, the host’s response to bacterial infections, and the dynamics of the microbiome. Special emphasis is placed on the roles of cannabinoid receptor types 1 and 2, whose signaling intricately influences immune cell function in microbe-host interactions.”

https://pubmed.ncbi.nlm.nih.gov/38775488/

https://journals.asm.org/doi/10.1128/iai.00020-24

The antitumor action of endocannabinoids in the tumor microenvironment of glioblastoma

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“Approximately 80% of all malignant brain tumors are gliomas, which are primary brain tumors. The most prevalent subtype of glioma, glioblastoma multiforme (GBM), is also the most deadly. Chemotherapy, immunotherapy, surgery, and conventional pharmacotherapy are currently available therapeutic options for GBM; unfortunately, these approaches only prolong the patient’s life by 5 years at most. Despite numerous intensive therapeutic options, GBM is considered incurable.

Accumulating preclinical data indicate that overt antitumoral effects can be induced by pharmacologically activating endocannabinoid receptors on glioma cells by modifying important intracellular signaling cascades. The complex mechanism underlying the endocannabinoid receptor-evoked antitumoral activity in experimental models of glioma may inhibit the ability of cancer cells to invade, proliferate, and exhibit stem cell-like characteristics, along with altering other aspects of the complex tumor microenvironment. The exact biological function of the endocannabinoid system in the development and spread of gliomas, however, is remains unclear and appears to rely heavily on context.

Previous studies have revealed that endocannabinoid receptors are present in the tumor microenvironment, suggesting that these receptors could be novel targets for the treatment of GBM. Additionally, endocannabinoids have demonstrated anticancer effects through signaling pathways linked to the classic features of cancer. Thus, the pharmacology of endocannabinoids in the glioblastoma microenvironment is the main topic of this review, which may promote the development of future GBM therapies.”

https://pubmed.ncbi.nlm.nih.gov/38720772/

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1395156/full

Cannabidiol ameliorates PTSD-like symptoms by inhibiting neuroinflammation through its action on CB2 receptors in the brain of male mice

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“Post-traumatic stress disorder (PTSD) is a debilitating mental health disease related to traumatic experience, and its treatment outcomes are unsatisfactory.

Accumulating research has indicated that cannabidiol (CBD) exhibits anti-PTSD effects, however, the underlying mechanism of CBD remains inadequately investigated. Although many studies pertaining to PTSD have primarily focused on aberrations in neuronal functioning, the present study aimed to elucidate the involvement and functionality of microglia/macrophages in PTSD while also investigated the modulatory effects of CBD on neuroinflammation associated with this condition.

We constructed a modified single-prolonged stress (SPS) mice PTSD model and verified the PTSD-related behaviors by various behavioral tests (contextual freezing test, elevated plus maze test, tail suspension test and novel object recognition test). We observed a significant upregulation of Iba-1 and alteration of microglial/macrophage morphology within the prefrontal cortex and hippocampus, but not the amygdala, two weeks after the PTSD-related stress, suggesting a persistent neuroinflammatory phenotype in the PTSD-modeled group.

CBD (10 mg/kg, i.p.) inhibited all PTSD-related behaviors and reversed the alterations in both microglial/macrophage quantity and morphology when administered prior to behavioral assessments. We further found increased pro-inflammatory factors, decreased PSD95 expression, and impaired synaptic density in the hippocampus of the modeled group, all of which were also restored by CBD treatment. CBD dramatically increased the level of anandamide, one of the endocannabinoids, and cannabinoid type 2 receptors (CB2Rs) transcripts in the hippocampus compared with PTSD-modeled group.

Importantly, we discovered the expression of CB2Rs mRNA in Arg-1-positive cells in vivo and found that the behavioral effects of CBD were diminished by CB2Rs antagonist AM630 (1 mg/kg, i.p.) and both the behavioral and molecular effects of CBD were abolished in CB2Rs knockout mice. These findings suggest that CBD would alleviate PTSD-like behaviors in mice by suppressing PTSD-related neuroinflammation and upregulation and activation of CB2Rs may serve as one of the underlying mechanisms for this therapeutic effect.

The present study offers innovative experimental evidence supporting the utilization of CBD in PTSD treatment from the perspective of its regulation of neuroinflammation, and paves the way for leveraging the endocannabinoid system to regulate neuroinflammation as a potential therapeutic approach for psychiatric disorders.”

https://pubmed.ncbi.nlm.nih.gov/38759736/

“Cannabidiol alleviated all PTSD-like behaviors in mice by suppressing PTSD-related neuroinflammation.”

https://www.sciencedirect.com/science/article/abs/pii/S0889159124004045?via%3Dihub

Cannabis and cancer: unveiling the potential of a green ally in breast, colorectal, and prostate cancer

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“Cancer comes in second place on the list of causes of death worldwide. In 2018, the 5-year prevalence of breast cancer (BC), prostate cancer (PC), and colorectal cancer (CRC) were 30%, 12.3%, and 10.9%, respectively.

Cannabinoids are chemicals derived from the Cannabis sativa plant; the most investigated cannabinoids are cannabinol, delta 9-tetrahydrocannabinol (Δ9-THC), and cannabidiol. In humans, the endogenous endocannabinoid system consists of endocannabinoids, cannabinoids receptors (CBs), and enzymes that degrade the endocannabinoids.

In this review, we will review the most recent literature for evidence that discusses the role of cannabis in the treatment of the three types of neoplasms mentioned.

Studies have proved that BC cells express CB receptors; many in-vivo studies showed that cannabinoids cause apoptosis and inhibit proliferation and migration. Also, researchers found that treating BC mice with THC and JWH-133 (CB2 receptor agonist) slowed the tumor growth.

Regarding CRC, cannabidiol was found to decrease the viability of chemotherapy-resistant CRC cells and inhibit metastasis by antagonizing the G-protein-coupled receptor 55 (GPR55; a novel cannabinoid receptor) necessary for metastasis. Moreover, cannabidiol had anti-angiogenetic effects by reducing the expression of vascular endothelial growth factor (VEGF) in addition to anti-inflammatory effects.

Finally, studies demonstrated that PC cells highly express CB1 and CB2 receptors and that cannabinoids are capable of inhibiting the release of exosomes and microvesicles related to cancer progression. Cannabinoids also have antiproliferative, anti-invasive, anti-fibroblastic, cell cycle arrest, and proapoptotic effects on PC cells.”

https://pubmed.ncbi.nlm.nih.gov/38755733/

“There is growing evidence supporting the role of Cannabinoids in numerous pathological conditions, including their role in several cancer types such as breast, colorectal, and prostate cancer. Accordingly, cannabinoids could have a promising potential as adjunctive therapy for the treatment of these types of cancers.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-024-00233-z

Unraveling the Endocannabinoid System: Exploring Its Therapeutic Potential in Autism Spectrum Disorder

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“The salient features of autism spectrum disorder (ASD) encompass persistent difficulties in social communication, as well as the presence of restricted and repetitive facets of behavior, hobbies, or pursuits, which are often accompanied with cognitive limitations.

Over the past few decades, a sizable number of studies have been conducted to enhance our understanding of the pathophysiology of ASD. Preclinical rat models have proven to be extremely valuable in simulating and analyzing the roles of a wide range of established environmental and genetic factors.

Recent research has also demonstrated the significant involvement of the endocannabinoid system (ECS) in the pathogenesis of several neuropsychiatric diseases, including ASD. In fact, the ECS has the potential to regulate a multitude of metabolic and cellular pathways associated with autism, including the immune system. Moreover, the ECS has emerged as a promising target for intervention with high predictive validity.

Particularly noteworthy are resent preclinical studies in rodents, which describe the onset of ASD-like symptoms after various genetic or pharmacological interventions targeting the ECS, providing encouraging evidence for further exploration in this area.”

https://pubmed.ncbi.nlm.nih.gov/38744725/

https://link.springer.com/article/10.1007/s12017-024-08781-6