“Prostate cancer is the second most frequently occurring carcinoma in males worldwide and one of the leading causes of death in men around the world. Recent studies estimate that over 1.4 million males are diagnosed with prostate cancer on an annual basis, with approximately 375 000 succumbing to the disease annually. With current treatments continuing to show severe side effects, there is a need for new treatments. In this study we looked at the effect of cannabis sativa extract, cannabidiol and cisplatin on prostate cancer cells, PC3.
Methods: In addressing the above questions, we employed the MTT assay to measure the antiproliferative effect on PC3 cells following treatment with varying concentrations of Cannabis sativa extract, cisplatin and cannabidiol. xCELLigence was also used to confirm the IC50 activity in which cells were grown in a 16 well plate coated with gold and monitor cell. Caspase 3/7 activity was also measured using 96 well-plate following treatment. Western-blot and qRT-PCR was also used to measure the gene expression of tumor suppressor genes, p53, Bax and Bcl2. Animal studies were employed to measure the growth of PC3-mouse derived cancer to evaluate the effect of compounds in vivo.
Results: From the treatment with varying concentrations of Cannabis sativa extract, cannabidiol and cisplatin, we have observed that the three compounds induced antiproliferation of PC3 cancer cell lines through the activation of caspase 3/7 activity. We also observed induction of apoptosis in these cells following silencing of retinoblastoma binding protein 6 (RBBP6), with upregulation of p53 and bax mRNA expression, and a reduction in Bcl2 gene expression. The growth of tumors in the mouse models were reduced following treatment with cisplatin and cannabidiol.
Conclusion: We demonstrated that cannabidiol is a viable therapy to treat prostate cancer cells, in combination with silencing of RBBP6. This suggests that cannabidiol rather Cannabis sativa extract may play an important role in reducing cancer progression.”
“Subarachnoid hemorrhage (SAH) is a major health burden that accounts for approximately 5% of all strokes. The most common cause of a non-traumatic SAH is the rupture of a cerebral aneurysm. The most common symptom associated with SAH is a headache, often described as “the worst headache of my life.” Delayed cerebral ischemia (DCI) is a major factor associated with patient mortality following SAH and is often associated with SAH-induced cerebral vasospasm (CV).
Cannabidiol (CBD) is emerging as a potential drug for many therapeutic purposes, including epilepsy, anxiety, and pain relief. We aim to review the potential use of CBD as a treatment option for post-SAH critically ill patients. Through a literature review, we evaluated the known pharmacology and physiological effects of CBD and correlated those with the pathophysiological outcomes associated with cerebral vasospasm following subarachnoid hemorrhage. Although overlap exists, data were formatted into three major categories: anti-inflammatory, vascular, and neuroprotective effects.
Based on the amount of information known about the actions of CBD, we hypothesize the anti-inflammatory effects are likely to be the most promising therapeutic mechanism. However, its cardiovascular effects through calcium regulation and its neuroprotective effects against cell death, excitotoxicity, and oxidative stress are all plausible mechanisms by which post-SAH critically ill patients may benefit from both early and late intervention with CBD. More research is needed to better understand if and how CBD might affect neurological and vascular functions in the brain following injury such as subarachnoid hemorrhage.”
“Parkinson disease (PD) is the second most progressive neurodegenerative disorder of the central nervous system (CNS) in the elderly, causing motor impediments and cognitive dysfunctions. Dopaminergic (DA) neuron degeneration and α-synuclein (α-Syn) accumulation in substantia nigra pars compacta (SNPc) are the major contributor to this disease. At present, the disease has no effective treatment. Many recent studies focus on identifying novel therapeutics that provide benefits to stop disease advancement in PD patients.
Cannabidiol (CBD) is a cannabinoid derived from the Cannabis Sativa plant and possesses anti-depressive, anti-inflammatory, and antioxidative effects. The present study aims to evaluate the neuroprotective effect of CBD in transgenic C. elegans PD models.
We observed that CBD at 0.025mM (24.66%), 0.05mM (52.41%) and 0.1mM (71.36%) diminished DA neuron degenerations induced by 6-hydroxydopamine (6-OHDA), reduced (0.025, 27.1%), (0.05, 38.9%), (0.1, 51.3%) food-sensing behavioural disabilities in BZ555, reduced 40.6%, 56.3%, 70.2% the aggregative toxicity of α-Syn and expanded the nematodes’ lifespan up to 11.5%, 23.1%, 28.8%, dose-dependently. Moreover, CBD augmented the ubiquitin-like proteasomes 28.11%, 43.27, 61.33% and SOD-3 expressions by about 16.4%, 21.2%, 44.8% in transgenic models. Further, we observed the antioxidative role of CBD by reducing 33.2%, 41.4%, 56.7% reactive oxygen species in 6-OHDA intoxicated worms.
Together, these findings supported CBD as an anti-parkinsonian drug and may exert its effects by raising lipid depositions to enhance proteasome activity and reduce oxidative stress via the antioxidative pathway.”
“CBD neuroprotective effects were assessed in pharmacological transgenic models of PD. According to our assessment, CBD promoted neuroprotection via recovery of degenerated DA neurons in 6-OHDA-exposed C. elegans and significantly reduced the α-Syn accumulations. Furthermore, CBD enhanced the lipid depositions, ubiquitin-like proteasome activities, food sensing behavior, and lifespan in the treated animals. CBD could restrain PD patients’ inflammations and decline DA neuron damage via leading.”
“Background: Early invasion of the central nervous system (CNS) by human immunodeficiency virus (HIV) (Gray et al. in Brain Pathol 6:1-15, 1996; An et al. in Ann Neurol 40:611-6172, 1996), results in neuroinflammation, potentially through extracellular vesicles (EVs) and their micro RNAs (miRNA) cargoes (Sharma et al. in FASEB J 32:5174-5185, 2018; Hu et al. in Cell Death Dis 3:e381, 2012). Although the basal ganglia (BG) is a major target and reservoir of HIV in the CNS (Chaganti et al. in Aids 33:1843-1852, 2019; Mintzopoulos et al. in Magn Reson Med 81:2896-2904, 2019), whether BG produces EVs and the effect of HIV and/or the phytocannabinoid-delta-9-tetrahydrocannabinol (THC) on BG-EVs and HIV neuropathogenesis remain unknown.
Methods: We used the simian immunodeficiency virus (SIV) model of HIV and THC treatment in rhesus macaques (Molina et al. in AIDS Res Hum Retroviruses 27:585-592, 2011) to demonstrate for the first time that BG contains EVs (BG-EVs), and that BG-EVs cargo and function are modulated by SIV and THC. We also used primary astrocytes from the brains of wild type (WT) and CX3CR1+/GFP mice to investigate the significance of BG-EVs in CNS cells.
Results: Significant changes in BG-EV-associated miRNA specific to SIV infection and THC treatment were observed. BG-EVs from SIV-infected rhesus macaques (SIV EVs) contained 11 significantly downregulated miRNAs. Remarkably, intervention with THC led to significant upregulation of 37 miRNAs in BG-EVs (SIV-THC EVs). Most of these miRNAs are predicted to regulate pathways related to inflammation/immune regulation, TLR signaling, Neurotrophin TRK receptor signaling, and cell death/response. BG-EVs activated WT and CX3CR1+/GFP astrocytes and altered the expression of CD40, TNFα, MMP-2, and MMP-2 gene products in primary mouse astrocytes in an EV and CX3CR1 dependent manners.
Conclusions: Our findings reveal a role for BG-EVs as a vehicle with potential to disseminate HIV- and THC-induced changes within the CNS.”
“In summary, the findings of this study suggest that HIV/SIV infection reprograms the BG leading to the release of pathogenic EVs that may potentially promote CNS inflammation and toxicity. However, cannabinoid mediated modulation of EV cargo composition as shown in this study maybe a mechanism for the regulation of HIV/SIV-induced changes. This is significant, because exploration of the potential of THC EVs in a preclinical animal model may be logical to investigate whether the clinical advantages of THC EVs will result in beneficial outcomes. The findings of this study also pave the way for investigation into the effects of the combined administration of THC:CBD [1:1 or 1:3 ratio] on neuroinflammation and their effects on BG-EV composition and function. The implication of our findings goes beyond HIV-induced inflammation. Glia cells (microglia and astrocytes) are involved in the pathogenesis of pain. Activated/reactive astrocytes play a role in neuropathic pain, inflammatory pain, as well as bone cancer pain. Activated astrocytes are also involved in Parkinson’s disease, spinal cord injury, and traumatic brain injury. In line with their role in the pathogenesis of pain, studies are warranted to assess the effect of CNS EVs in mediating the development and maintenance of pain.”
“Substances from the Cannabis sativa species, especially cannabidiol (CBD) and Delta-9-tetrahydrocannabinol (Δ9-THC), have attracted medical attention in recent years. The actions of these two main cannabinoids modulate the cholinergic nervous system (CholNS) involving development, synaptic plasticity, and response to endogenous and environmental damage, as a characteristic of many neurodegenerative diseases.
The dynamics of these diseases are mediated by specific neurotransmitters, such as the GABAergic nervous system (GNS) and the CholNS. The nematode Caenorhabditis elegans is an important experimental model, which has different neurotransmitter systems that coordinate its behavior and has a transgene strain that encodes the human β-amyloid 1-42 peptide in body wall muscle, one of the main proteins involved in Alzheimer´s disease.
Therefore, the objective of this study was to evaluate the protective potential of terpenoids found in C. sativa in the GNS and CholNS of C. elegans. The effect of two C. sativa oils with variations in CBD and THC concentrations on acetylcholinesterase (AChE) activity, lipid peroxidation, and behavior of C. elegans was evaluated.
C. sativa oils were efficient in increasing pharyngeal pumping rate and reducing defecation cycle, AChE activity, and ROS levels in N2 strains. In the muscle:Abeta1-42 strain, mainly when using CBD oil, worm movement, body bends, and pharyngeal pumping were increased, with a reduced AChE activity.
Consequently, greater investments in scientific research are needed, in addition to breaking the taboo on the use of the C. sativa plant as an alternative for medicinal use, especially in neurodegenerative diseases, which have already shown positive initial results.”
“Purpose of review: There have been many debates, discussions, and published writings about the therapeutic value of cannabis plant and the hundreds of cannabinoids it contains. Many states and countries have attempted, are attempting, or have already passed bills to allow legal use of cannabinoids, especially cannabidiol (CBD), as medicines to treat a wide range of clinical conditions without having been approved by a regulatory body. Therefore, by using PubMed and Google Scholar databases, we have reviewed published papers during the past 30 years on cannabinoids as medicines and comment on whether there is sufficient clinical evidence from well-designed clinical studies and trials to support the use of CBD or any other cannabinoids as medicines.
Recent findings: Current research shows that CBD and other cannabinoids currently are not ready for formal indications as medicines to treat a wide range of clinical conditions as promoted except for several exceptions including limited use of CBD for treating two rare forms of epilepsy in young children and CBD in combination with THC for treating multiple-sclerosis-associated spasticity.
Summary: Research indicates that CBD and several other cannabinoids have potential to treat multiple clinical conditions, but more preclinical, and clinical studies and clinical trials, which follow regulatory guidelines, are needed to formally recommend CBD and other cannabinoids as medicines.”
“Based on preliminary preclinical and clinical research, cannabinoids could be further investigated for their potential in treating a wide range of clinical conditions. For their effects on neuroinflammation, inflammatory cytokines, psychosis, fibrosis, and immunomodulation, many of these cannabinoids may be further investigated for treating clinical indications ranging from seizures/epilepsy in adults, schizophrenia, obesity, nausea, neuropathy, retinopathy nephropathy, pain, and dermal conditions like dermatitis and acne.”
“Cannabis has been used in even the oldest traditional medicines available. In the last century, negative attention has prevailed regarding the psychotropic and abuse potential. For this reason, Cannabis has been banned and declared illegal in many countries. In recent years, however, there has been a more in-depth evaluation of the legalization of cannabinoids for medical use in several countries following heightened media attention and reports of effectiveness, although not always thoroughly backed up by scientific evidence. The official introduction of pharmaceutical-grade Cannabis inflorescences for medicinal purposes has allowed physicians and pharmacists, to prescribe and prepare several Cannabis preparations legally. Such products are currently being administered to patients without their efficacy being evaluated in controlled studies: for each patient the composition and route of administration may differ. In addition, many advanced administration systems have been developed or are still under development, but few clinical trials have been completed.
In this context, this Research Topic focused on the in-depth analysis of the legal, technological and pharmacological aspects related to the medical use of Cannabis-based formulations.
Anil et al. have directed their research specifically on the activity of Cannabis for medical use in the context of inflammatory processes. Although activities in this area are plausible, the high number of active molecules produced by Cannabis and simultaneously administered through the extractive products normally used in therapy, has not yet made it possible to identify their specific mechanisms of action. Once the modalities of action of the active molecules have been clarified, it might be of interest to use purified mixtures to obtain a more significant activity potentially (Anil et al.).
Specific literature reviews were then done for some pathologies such as when Xin et al. investigated the potential therapeutic effect of CBD in bone diseases. Even in this case, further studies are needed to evaluate the benefits and risks of cannabinoids’ use (Xin et al.).
A large part of the clinical research relating to Cannabis for medical use concerns its use in the context of diseases of the central nervous system. Ortiz et al. examined evidence supporting the therapeutic utility of cannabinoids for treating neurodegenerative diseases, pain, mood disorders, and substance use disorders. Important considerations were also made on the methods of formulation and the routes of administration (Ortiz et al.). Lacroix et al. Also considered Cannabis in neurological disorders stressing that currently most of the scientific data supports the potential therapeutic use of Cannabis but, as much as patients request it, the knowledge is still too little in-depth. It is therefore certainly urgent to manage clinical trials to provide stronger and safer evidence (Lacroix et al.).
Procaccia et al. discussed how phytocannabinoid profiles differed between plants according to chemovar types and examined the main factors influencing the accumulation of secondary metabolites in the plant, including genotype, growing conditions, processing, storage and the delivery route; the authors highlighted how these factors make the use of Cannabis in therapy highly complex (Procaccia et al.).
In addition to the more well-known compounds such as THC and CBD, Cannabis produces over 120 other phytocannabinoids. The use of THC is associated with acute psychotropic effects that could potentially be avoided considering that minor cannabinoids and their chemical counterparts could offer the same potential benefits without the same adverse effects. In this regard, Walsh et al. reviewed the literature to provide an overview of the endocannabinoid system, phytocannabinoid biosynthesis and a discussion on molecular pharmacology. Potential therapeutic uses of minor cannabinoids underlining that future studies will have to rigorously evaluate these compounds’ risk/benefit ratio (Walsh et al.).
The interest in molecules other than cannabinoids such as terpenes is certainly relevant. This interest has grown even greater since the possibility of an “entourage” effect between the active molecules of Cannabis has been postulated. Accordingly, Finlay et al. in their study examined whether some terpenes acted directly on cannabinoid receptors. From the results obtained, it was not possible to exclude the existence of an entourage effect. Still, this cannot be linked to a direct action of the terpenes on the cannabinoid receptors. However, the pharmacological mechanism underlying this substances activity remains to be thoroughly investigated (Finlay et al.).
Maayah et al. pointed out that full-spectrum Cannabis extracts have been used in clinical trials to treat various diseases. However, despite their efficacy, their potential use in therapy may be limited by possible behavioural side effects. These researchers then successfully worked on experimental animals to identify a panel of blood metabolites predicting behavioural effects (Maayah et al.).
Pennypacker et al. have evaluated whether the products available on the market in the United States of America are consistent in the concentration of cannabinoids, with the literature indications for use in therapy. Overall, the results of this study have been defined by the authors as alarming as current product offerings do not reflect scientific evidence (Pennypacker et al.).
In the regulatory context MacPhail et al. have analysed the trend of prescriptions in Australia over the last 5 years, noting a substantial increase in prescriptions over time that does not actually reflect a worsening of the pathological conditions of the population but rather a greater prescription linked to greater knowledge and acceptance of this type of therapy (MacPhail et al.).
As regards the use in therapy of medical Cannabis, the current regulations have been analysed by Baratta et al. in those countries where clinical studies have recently been conducted. The results of the trials have been crossed with the pathologies for which the current legislation provides that it is possible to prescribe Cannabis allowing relevant considerations (Baratta et al.).
From all the publications collected, it is clear that there is a great interest in the enormous potential of Cannabis in the medical field but also a widespread awareness of the extreme need to conduct in-depth research that clarifies the mechanisms of action of the quantity of components present in the phytocomplex of this plant species.”
“Cannabis sativa contains more than 120 cannabinoids and 400 terpene compounds (i.e., phytomolecules) present in varying amounts. Cannabis is increasingly available for legal medicinal and non-medicinal use globally, and with increased access comes the need for a more comprehensive understanding of the pharmacology of phytomolecules. The main transducer of the intoxicating effects of Cannabis is the type 1 cannabinoid receptor (CB1R). ∆9-tetrahydrocannabinolic acid (∆9-THCa) is often the most abundant cannabinoid present in many cultivars of Cannabis. Decarboxylation converts ∆9-THCa to ∆9-THC, which is a CB1R partial agonist. Understanding the complex interplay of phytomolecules-often referred to as “the entourage effect”-has become a recent and major line of inquiry in cannabinoid research. Additionally, this interest is extending to other non-Cannabis phytomolecules, as the diversity of available Cannabis products grows. Here, we chose to focus on whether 10 phytomolecules (∆8-THC, ∆6a,10a-THC, 11-OH-∆9-THC, cannabinol, curcumin, epigallocatechin gallate, olivetol, palmitoylethanolamide, piperine, and quercetin) alter CB1R-dependent signaling with or without a co-treatment of ∆9-THC. Phytomolecules were screened for their binding to CB1R, inhibition of forskolin-stimulated cAMP accumulation, and βarrestin2 recruitment in Chinese hamster ovary cells stably expressing human CB1R. Select compounds were assessed further for cataleptic, hypothermic, and anti-nociceptive effects on male mice. Our data revealed partial agonist activity for the cannabinoids tested, as well as modulation of ∆9-THC-dependent binding and signaling properties of phytomolecules in vitro and in vivo. These data represent a first step in understanding the complex pharmacology of Cannabis– and non-Cannabis-derived phytomolecules at CB1R and determining whether these interactions may affect the physiological outcomes, adverse effects, and abuse liabilities associated with the use of these compounds.”
“While blockade of cannabinoid receptor 1 (CB1) has been shown to attenuate diet-induced obesity (DIO), its relative role in different cell types has not been tested. The current study investigated the role of CB1 in immune vs non-immune cells during DIO by generating radiation-induced bone marrow chimeric mice that expressed functional CB1 in all cells except the immune cells or expressed CB1 only in immune cells. CB1-/- recipient hosts were resistant to DIO, indicating that CB1 in non-immune cells is necessary for induction of DIO. Interestingly, chimeras with CB1-/- in immune cells showed exacerbation in DIO combined with infiltration of bone-marrow-derived macrophages to the brain and visceral adipose tissue, elevated food intake, and increased glucose intolerance. These results demonstrate the opposing role of CB1 in hematopoietic versus non-hematopoietic cells during DIO and suggests that targeting immune CB1 receptors provides a new pathway to ameliorate obesity and related metabolic disorders.”
“Peripheral inputs continuously shape brain function and can influence memory acquisition, but the underlying mechanisms have not been fully understood. Cannabinoid type-1 receptor (CB1R) is a well-recognized player in memory performance, and its systemic modulation significantly influences memory function. By assessing low arousal/non-emotional recognition memory in mice, we found a relevant role of peripheral CB1R in memory persistence. Indeed, the peripherally-restricted CB1R specific antagonist AM6545 showed significant mnemonic effects that were occluded in adrenalectomized mice, and after peripheral adrenergic blockade. AM6545 also transiently impaired contextual fear memory extinction. Vagus nerve chemogenetic inhibition reduced AM6545-induced mnemonic effect. Genetic CB1R deletion in dopamine β-hydroxylase-expressing cells enhanced recognition memory persistence. These observations support a role of peripheral CB1R modulating adrenergic tone relevant for cognition. Furthermore, AM6545 acutely improved brain connectivity and enhanced extracellular hippocampal norepinephrine. In agreement, intra-hippocampal β-adrenergic blockade prevented AM6545 mnemonic effects. Altogether, we disclose a novel CB1R-dependent peripheral mechanism with implications relevant for lengthening the duration of non-emotional memory.”
