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The effect cannabichromene on adult neural stem/progenitor cells

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... CBC also activates the TRPA1, TRPV3, and TRPV4 channels [210]. CBC has anti-inflammatory, anti-nociceptive, and neuroprotective activities [220][221][222][223][224][225]. CBC reduces the activity of both the ON and OFF Biomedicines 2022, 10, 631 9 of 48 neurons in the rostral ventromedial medulla (RVM) and elevates the endocannabinoid levels in the ventrolateral periaqueductal gray matter [221]. ...
... The anti-nociceptive activity of CBC is mediated by the adenosine A1 and TRPA1 receptors [221]. CBC increases the viability of neural stem progenitor cells through activation of the adenosine A1 receptor [224]. Moreover, it has been shown to suppress reactive astrocytes, thus offering a protective effect against neuro-inflammation and Alzheimer's disease [225]. ...
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Antibiotic resistance has become an increasing challenge in the treatment of various infectious diseases, especially those associated with biofilm formation on biotic and abiotic materials. There is an urgent need for new treatment protocols that can also target biofilm-embedded bacteria. Many secondary metabolites of plants possess anti-bacterial activities, and especially the phytocannabinoids of the Cannabis sativa L. varieties have reached a renaissance and attracted much attention for their anti-microbial and anti-biofilm activities at concentrations below the cytotoxic threshold on normal mammalian cells. Accordingly, many synthetic cannabinoids have been designed with the intention to increase the specificity and selectivity of the compounds. The structurally unrelated endocannabinoids have also been found to have anti-microbial and anti-biofilm activities. Recent data suggest for a mutual communication between the endocannabinoid system and the gut microbiota. The present review focuses on the anti-microbial activities of phytocannabinoids and endocannabinoids integrated with some selected issues of their many physiological and pharmacological activities.
... CBC is an abundant non-intoxicating cannabinoid due to a recessive gene [80] that modulates the vanilloid type-1 (TRPV1) and ankyrin type-1 (TRPA1) receptors and TRPV2,3,4 [45,81]. Briefly, TRP channels and the ECS are involved in inflammation and have a role in pain [81,82]. Modulation of these receptors can cause elevated endocannabinoid levels, thereby amplifying total cannabinoid availability via turning on more docile CB1 and CB2 receptors with more respectable affinity to the CB2 receptor. ...
... CBC also has the ability to potentiate the analgesic effects of THC [45,84,85]. In one study CBC shows promise in positively affecting the viability of mammalian adult neural stem cell progenitor cells, i.e., an essential component of brain function in health and disease [82]. This particular cannabinoid could then be what allows a patient's "high" to then proverbially stack or amplify if given more of the same medication. ...
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This two-part section helps the reader to achieve a better understanding of how cannabis works as a viable medication for the endocannabinoid system (ECS) and central nervous system (CNS) in humans by identifying individual synergies between cannabinoids, or cannabinoids and terpenes in their journey through the ECS and CNS in various mammalian patient indicators to unmask this paradoxical effect. The specific biphasic/paradoxical manner in question was researched and inevitably identifies cannabis use that manipulates tryptophan uptake, serotonin release, and dopamine actuation. Therefore, a patient’s diet may demand a higher tryptophan and dopa-L supplementation to avoid a paradoxical agitation on the receptor level. This chapter explains the pathology of how cannabis consistently reacts in the ECS for every individual, only separated by metabolism and disruption/trauma in the ECS and CNS, implying that there was no found paradoxical effect existing in cannabis, but in the patient, and thus is perceived the same in every individual, only mediated by metabolism, environment (surroundings), and the exception for individuals who process stimulants and tryptophan and/or serotonin in a disrupted manner causing a perceived paradoxical effect or the build-up to and/or what will be referred to as ASR/ATD. The cannabis industry, growers/breeders, interpeners/cannabis sommeliers/bud tenders, and dispensaries need to continue to constantly strive for more knowledge, just as the researchers and FDA need to continue their work to understand the benefits of cannabis, and most importantly, all must work together to remove cannabis from the Schedule I and Schedule 2 classification.
... The anti-inflammatory actions of CBC may be important in its ability to function as a neuroprotective drug. CBC increases the viability of neural stem progenitor cells (NSPCs) in vitro through an ERK dependent mechanism (Shinjyo and Di Marzo, 2013). In addition, CBC inhibits astroglial differentiation of the NSPCs (Shinjyo and Di Marzo, 2013). ...
... CBC increases the viability of neural stem progenitor cells (NSPCs) in vitro through an ERK dependent mechanism (Shinjyo and Di Marzo, 2013). In addition, CBC inhibits astroglial differentiation of the NSPCs (Shinjyo and Di Marzo, 2013). NSPCs are modulated by surrounding microglial cells, brain immune cells, and astrocytes, which produce both pro-and anti-inflammatory factors. ...
Article
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The medicinal use of Cannabis sativa L. can be traced back thousands of years to ancient China and Egypt. While marijuana has recently shown promise in managing chronic pain and nausea, scientific investigation of cannabis has been restricted due its classification as a schedule 1 controlled substance. A major breakthrough in understanding the pharmacology of cannabis came with the isolation and characterization of the phytocannabinoids trans-Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD). This was followed by the cloning of the cannabinoid CB1 and CB2 receptors in the 1990s and the subsequent discovery of the endocannabinoid system. In addition to the major phytocannabinoids, Δ⁹-THC and CBD, cannabis produces over 120 other cannabinoids that are referred to as minor and/or rare cannabinoids. These cannabinoids are produced in smaller amounts in the plant and are derived along with Δ⁹-THC and CBD from the parent cannabinoid cannabigerolic acid (CBGA). While our current knowledge of minor cannabinoid pharmacology is incomplete, studies demonstrate that they act as agonists and antagonists at multiple targets including CB1 and CB2 receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors (PPARs), serotonin 5-HT1a receptors and others. The resulting activation of multiple cell signaling pathways, combined with their putative synergistic activity, provides a mechanistic basis for their therapeutic actions. Initial clinical reports suggest that these cannabinoids may have potential benefits in the treatment of neuropathic pain, neurodegenerative diseases, epilepsy, cancer and skin disorders. This review focuses on the molecular pharmacology of the minor cannabinoids and highlights some important therapeutic uses of the compounds.
... In a model of electroshock seizure, CBC (10-75 mgÁkg −1 i.p. per day) significantly depressed motor activity during the first 10-min interval, but subsequently only the highest dose was effective (Davis & Hatoum, 1983). In vitro, Shinjyo and Di Marzo (2013) found that 1μM CBC increased viability of adult nestin-positive neuronal stem cells when applied in medium without growth factors (B27 medium), by inducing ERK phosphorylation. No antagonist data were presented in these studies. ...
... More recently CBC acted as a CB 2 receptor agonist in AtT20 cells transfected with these receptors and was confirmed by application of the CB 2 receptor antagonist AM630, which blocked the effects of CBC (Udoh et al., 2019). We found only two papers related to neuroprotective effects of CBC; in vivo CBC suppressed motor activity while in vitro CBC improved viability of neural stem cells (Davis & Hatoum, 1983;Shinjyo & Di Marzo, 2013). The anti-inflammatory effects of CBC may play a pivotal role in its ability to act as a neuroprotectant, as inflammation and overactivation of the immune response are important features of neurodegenerative conditions.Thus, further research should assess this compound in neuro-inflammatory conditions, where it may have potential. ...
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Embase and PubMed were systematically searched for articles addressing the neuroprotective properties of phytocannabinoids, apart from cannabidiol and Δ⁹‐tetrahydrocannabinol, including Δ⁹‐tetrahydrocannabinolic acid, Δ⁹‐tetrahydrocannabivarin, cannabidiolic acid, cannabidivarin, cannabichromene, cannabichromenic acid, cannabichromevarin, cannabigerol, cannabigerolic acid, cannabigerivarin, cannabigerovarinic acid, cannabichromevarinic acid, cannabidivarinic acid, and cannabinol. Out of 2,341 studies, 31 articles met inclusion criteria. Cannabigerol (range 5 to 20 mg·kg⁻¹) and cannabidivarin (range 0.2 to 400 mg·kg⁻¹) displayed efficacy in models of Huntington's disease and epilepsy. Cannabichromene (10–75 mg·kg⁻¹), Δ⁹‐tetrahydrocannabinolic acid (20 mg·kg⁻¹), and tetrahydrocannabivarin (range 0.025–2.5 mg·kg⁻¹) showed promise in models of seizure and hypomobility, Huntington's and Parkinson's disease. Limited mechanistic data showed cannabigerol, its derivatives VCE.003 and VCE.003.2, and Δ⁹‐tetrahydrocannabinolic acid mediated some of their effects through PPAR‐γ, but no other receptors were probed. Further studies with these phytocannabinoids, and their combinations, are warranted across a range of neurodegenerative disorders.
... However, other cannabinoids have not been extensively studied. Future research could focus on clinical trials to investigate the therapeutic potential of these lesser-known cannabinoids and their derivatives, which have proven in vitro or in vivo biological activity, such as the following: THCV-antiepileptic activity [347], potential against Parkinson's disease [348,349], antipsychotic effects [350], CBG-anticonvulsant activity [351], counteract neuroinflammation [352], neuroprotective in Huntington's disease [202], in multiple sclerosis [353], CBG derivatives-anti-inflammatory in multiple sclerosis [354], in amyotrophic lateral sclerosis [355], neuroprotective potential in Huntington's disease [356], in Parkinson's disease [357][358][359], CBC-promotes neural stem/progenitor cells viability [360], induces neuronal differentiation in NSC-34 Cells [361], antinociceptive activity [362], anti-inflammatory [363], CBN-neuroprotective activity [167], antiseizure potential [364]. ...
Article
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Neurological disorders present a wide range of symptoms and challenges in diagnosis and treatment. Cannabis sativa, with its diverse chemical composition, offers potential therapeutic benefits due to its anticonvulsive, analgesic, anti-inflammatory, and neuroprotective properties. Beyond cannabinoids, cannabis contains terpenes and polyphenols, which synergistically enhance its pharmacological effects. Various administration routes, including vaporization, oral ingestion, sub-lingual, and rectal, provide flexibility in treatment delivery. This review shows the therapeutic efficacy of cannabis in managing neurological disorders such as epilepsy, neurodegenerative diseases, neurodevelopmental disorders, psychiatric disorders, and painful pathologies. Drawing from surveys , patient studies, and clinical trials, it highlights the potential of cannabis in alleviating symptoms , slowing disease progression, and improving overall quality of life for patients. Understanding the diverse therapeutic mechanisms of cannabis can open up possibilities for using this plant for individual patient needs.
... On the other hand, CBD has gained attention for its potential anti-inflammatory, anticonvulsant, and anxiolytic properties, making it valuable in treating epilepsy, anxiety disorders, and inflammation-related conditions [3,4]. Although present in smaller quantities, CBG is recognized as a precursor to other cannabinoids and demonstrates neuroprotective and potential anti-inflammatory effects, making it an emerging target for research and medicinal applications [5,6]. ...
Article
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In the evolving field of cannabis research, scholars are exploring innovative methods to quantify cannabinoids rapidly and non-destructively. This study evaluates the effectiveness of a hand-held near-infrared (NIR) device for quantifying total cannabidiol (total CBD), total delta-9-tetrahydrocannabinol (total THC), and total cannabigerol (total CBG) in whole cannabis inflorescences. Employing pre-processing techniques, including standard normal variate (SNV) and Savitzky–Golay (SG) smoothing, we aim to optimize the portable NIR technology for rapid and non-destructive cannabinoid analysis. A partial least-squares regression (PLSR) model was utilized to predict cannabinoid concentration based on NIR spectra. The results indicated that SNV pre-processing exhibited superior performance in predicting total CBD concentration, yielding the lowest root mean square error of prediction (RMSEP) of 2.228 and the highest coefficient of determination for prediction (R2P) of 0.792. The ratio of performance to deviation (RPD) for total CBD was highest (2.195) with SNV. In contrast, raw data exhibited the least accurate predictions for total THC, with an R2P of 0.812, an RPD of 2.306, and an RMSEP of 1.651. Notably, total CBG prediction showed unique characteristics, with raw data yielding the highest R2P of 0.806. SNV pre-processing emerges as a robust method for precise total CBD quantification, offering valuable insights into the optimization of a hand-held NIR device for the rapid and non-destructive analysis of cannabinoid in whole inflorescence samples. These findings contribute to ongoing efforts in developing portable and efficient technologies for cannabinoid analysis, addressing the increasing demand for quick and accurate assessment methods in cannabis cultivation, pharmaceuticals, and regulatory compliance.
... This compound has anti-glaucoma properties and antiproliferative effects and it is effective in bladder pain (29). Cannabichromene (CBC), has a low affinity for CB1-R and CB2-R, but can inhibit the AEA uptake, thus, affecting the ECS (30). CBC interacts with TRPA1, TRPV3, TRPV4, and TRPV8. ...
Article
Pain is a debilitating phenomenon that dramatically impairs the quality of life of patients. Many chronic conditions, including cancer, are associated with chronic pain. Despite pharmacological efforts that have been conducted, many patients suffering from cancer pain remain without treatment. To date, opioids are considered the preferred therapeutic choice for cancer-related pain management. Unfortunately, opioid treatment causes side effects and inefficiently relieves patients from pain, therefore alternative therapies have been considered, including Cannabis Sativa and cannabinoids. Accumulating evidence has highlighted that an increasing number of patients are choosing to use cannabis and cannabinoids for the management of their soothing and non-palliative cancer pain and other cancer-related symptoms. However, their clinical application must be supported by convincing and reproducible clinical trials. In this review, we provide an update on cannabinoid use for cancer pain management. Moreover, we tried to turn a light on the potential use of cannabis as a possible therapeutic option for cancer-related pain relief.
... CBN has been reported to display anticonvulsant effects similar to that of CBD in a zebrafish model of Dravet syndrome [25]. CBC is one of the most abundant cannabinoids in cannabis but has not been well studied with respect to epilepsy, yet is known to exhibit neuroprotective effects in cultured mouse neural cells [26]. There is also evidence that CBC, when used in combination with CBD or ∆ 9 -THC, can help alleviate symptoms of insomnia and depression in humans and rats [27,28]. ...
Article
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Cannabis has demonstrated anticonvulsant properties, and about thirty percent of epileptic patients do not have satisfactory seizure management with standard treatment and could potentially benefit from cannabis-based intervention. Here, we report the use of cannabinoids to treat pentylenetetrazol (PTZ)-induced convulsions in a zebrafish model, their effect on gene expression, and a simple assay for assessing their uptake in zebrafish tissues. Using an optimized behavioral assay, we show that cannabidiol (CBD) and cannabichromene (CBC) and cannabinol (CBN) are effective at reducing seizures at low doses, with little evidence of sedation, and our novel HPLC assay indicates that CBC is effective with the lowest accumulation in larval tissues. All cannabinoids tested were effective at higher concentrations. Pharmacological manipulation of potential receptors demonstrates that Gpr55 partially mediates the anticonvulsant effects of CBD. Treatment of zebrafish larvae with endocannabinoids, such as 2-arachidonoylglycerol (2-AG) and anandamide (AEA), altered larvae movement, and the expression of genes that regulate their metabolism was affected by phytocannabinoid treatment, highlighting the possibility that changes to endocannabinoid levels may represent one facet of the anticonvulsant effect of phytocannabinoids.
... Upon binding to these receptors, CBC induces an antinociceptive effect within the brain. CBC positively influenced the viability of adult neural stem progenitor cells during in vitro differentiation, upregulating the marker nestin while downregulating the astrocyte marker Glial fibrillary acidic protein, possibly involving adenosine signaling and ATP modulation in the process [35]. CBC might be also a potential neuronal differentiation inducer for NSC-34 cells (a hybridoma between spinal cord cells from the embryos of mice and neuroblastoma) [36]. ...
Article
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Cannabinoids: cannabidiol (CBD), cannabidiolic acid (CBDA), and cannabichromene (CBC) are lipophilic compounds with limited water solubility, resulting in challenges related to their bioavailability and therapeutic efficacy upon oral administration. To overcome these limitations, we developed co-dispersion cannabinoid delivery systems with the biopolymer polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus) and magnesium aluminometasilicate (Neusilin US2) to improve solubility and permeability. Recognizing the potential therapeutic benefits arising from the entourage effect, we decided to work with an extract instead of isolated cannabinoids. Cannabis sativa inflorescences (Henola variety) with a confirming neuroprotective activity were subjected to dynamic supercritical CO2 (scCO2) extraction and next they were combined with carriers (1:1 mass ratio) to prepare the co-dispersion cannabinoid delivery systems (HiE). In vitro dissolution studies were conducted to evaluate the solubility of CBD, CBDA, and CBC in various media (pH 1.2, 6.8, fasted, and fed state simulated intestinal fluid). The HiE-Soluplus delivery systems consistently demonstrated the highest dissolution rate of cannabinoids. Additionally, HiE-Soluplus exhibited the highest permeability coefficients for cannabinoids in gastrointestinal tract conditions than it was during the permeability studies using model PAMPA GIT. All three cannabinoids exhibited promising blood-brain barrier (BBB) permeability (Papp higher than 4.0 × 10−6 cm/s), suggesting their potential to effectively cross into the central nervous system. The improved solubility and permeability of cannabinoids from the HiE-Soluplus delivery system hold promise for enhancement in their bioavailability.
... Anti-inflammatory effects have been reported for CBC (Izzo et al., 2012;Maione et al., 2011) and its positive action on brain health exerted on neural stem cells (Shinjyo and di Marzo, 2013). ...
Article
Cannabis sativa (L.) is characterized by great genetic and phenotypic diversity, also expressed in the array of bioactive compounds synthesized. Despite its great potential economic interest, knowledge of the biology and genetics of this crop is incomplete, and still many efforts are needed for a complete understanding of the molecular mechanisms regulating its key traits. To better understand the synthesis of these compounds, we analysed the transcription levels of cannabinoid pathway genes, during early phases of plant development, then comparing the transcriptional results with a chemical characterization of the same samples. The work was conducted on both industrial and medicinal C. sativa plants, using samples belonging to three different chemotypes. Genes coding for the cannabinoid synthases, involved in the last step of the cannabinoid biosynthetic pathway, were found to be already expressed in the seed, providing a measure of the importance of this metabolism for the plant. Cannabichromenic acid is known as the first cannabinoid accumulating in the seedlings, shortly after emergence, and it was found that there is a good correspondence between transcript accumulation of the cannabichromenic acid synthase gene and accumulation of the corresponding metabolite.
... The existence of a variety of secondary metabolites in hemp makes it a unique plant in the medicinal sector. For example, cannabis terpenol (CBG) has sedative, muscle relaxation and analgesic effects (Shinjyo and di Marzo, 2013). Cannabinoid phenol (CBC) can treat inflammatory bowel disease (Huang et al., 2019), and has potential effects on adult brain neural stem cells (Laun et al., 2019). ...
Article
Industrial hemp (Cannabis sativa L.) is an economic crop with high yield and stress resistance. Hemp metabolites have high medicinal value and development potential, which is applicable to treat a variety of incurable diseases particularly, phenolic and terpene compounds such as cannabidiol and cannabigerol. Due to the impact of these compounds on cytokine metabolism, cannabinoids are being investigated as a potential treatment against viral diseases. Light intensity greatly affects the synthesis of plant metabolites. In this study, the overall metabolic profile of industrial hemp 'Yunma 1′ was detected under 30 μmol.m − 2 s − 1 , 80 μmol.m − 2 s − 1 ,130 μmol.m − 2 s − 1 and 180 μmol.m − 2 s − 1 light intensity based on UPLC-MS /MS wide-target metabolomics technology. The results suggested that different light intensities have different impact on hemp metabolic profile; additionally, the composition of lipids, phenolic acids, flavonoids, amino acids and their derivatives, organic acids, alkaloids, nucleotides and their derivatives, sugars and alcohols, vitamins, cannabinoids, coumarins, lignans, and terpe-noidsannins and carbohydrates were found highest at 180 μmol.m − 2 s − 1 light intensity. The content differences of two secondary metabolites i.e., spirodienone and iso-spirodienone (cannabispiradienone) were compared and results showed that 80 μmol.m − 2 .s − 1 light intensity is most appropriate for the synthesis of spirodienone and iso-spirodienone. These findings provide a base for understanding the metabolic characteristics of specific secondary metabolites and the optimum conditions for their synthesis.
... CBC, the most abundant phytocannabinoid in the plant, displays a low affinity for CB1 and CB2 receptors, but affects the ECS by inhibiting AEA uptake (Fig. 6) [42,43,83]. It can cause strong anti-inflammatory effects in animal models of oedema through non-CB receptor mechanisms [84]. ...
Article
There has been an increased interest of the scientific community in cannabis and its constituents for therapeutic purposes. Although it is believed that cannabinoids can be effective for a few different conditions and syndromes, there are little objective data that clearly support the use of cannabis, cannabis extracts or even cannabidiol (CBD) oil. This review aims to explore the therapeutic potential of phytocannabinoids and synthetic cannabinoids for the treatment of several diseases. A broad search covering the past five years, was performed in PubMed and ClinicalTrial.gov databases, to identify papers focusing on the use of medical phytocannabinoids in terms of tolerability, efficacy and safety. Accordingly, there are preclinical data supporting the use of phytocannabinoids and synthetic cannabinoids for the management of neurological pathologies, acute and chronical pain, cancer, psychiatric disorders and chemotherapy-induced emetic symptoms. However, regarding the clinical trials, most of the collected data do not fully support the use of cannabinoids in the treatment of such conditions. Consequently, more studies are still needed to clarify ascertain if the use of these compounds is useful in the management of different pathologies.
... The plethora of biological effects induced by the properties of phytocannabinoids, and also by the effects that CBC exerts on adult neural stem progenitor cells (NSPCs), leading them to sustain their viability and differentiation [10], brought to our attention the possibility to use this compound on NSC-34 cell line. It is a hybridoma between spinal cord cells, taken from embryos of mice, and neuroblastoma. ...
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Phytocannabinoids, with their variety of beneficial effects, represent a valid group of substances that could be employed as neurogenesis-enhancers or neuronal differentiation inducers. We focused our attention on the neuronal-related potential of cannabichromene (CBC) when administered to undifferentiated NSC-34 for 24 h. Transcriptomic analysis showed an upregulation of several neuronal markers, such as Neurod1 and Tubb3, as well as indicators of neuronal differentiation process progression, such as Pax6. An in-depth investigation of the processes involved in neuronal differentiation indicates positive cytoskeleton remodeling by upregulation of Cfl2 and Tubg1, and active differentiation-targeted transcriptional program, suggested by Phox2b and Hes1. After 48 h of treatment, the markers previously examined in the transcriptomic analysis are still overexpressed, like Ache and Hes1, indicating that the differentiation process is still in progress. The lack of GFAP protein suggests that no astroglial differentiation is taking place, and it is reasonable to indicate the neuronal one as the ongoing one. These results indicate CBC as a potential neuronal differentiation inducer for NSC-34 cells.
... In adult mouse neural stem cells/progenitor cells, which are an essential component of brain function and pathology, CBC raised cell viability and inhibited differentiation into astroglia (Shinjyo & Di Marzo, 2013). Schubert et al. (2019) found that CBC prevented amyloid toxicity, blocked cell death, and could increase the degradation and elimination of preformed, aggregated Aβ from neurons. ...
Chapter
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Alzheimer's disease (AD) is the most common form of dementia, and currently there is no cure. New therapeutic strategies that have the potential to address the complex pathophysiology of AD are urgently required; medicinal cannabis offers this possibility. Several potential leads can be extracted from Cannabis sativa (cannabis) that can target AD pathophysiology and alleviate symptoms, making it a prime candidate for AD drug discovery research. To date, most cannabis and AD research has focused on the major cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), paying little attention to other plant constituents with therapeutic properties for AD. This chapter will highlight emerging evidence on the therapeutic potential of medicinal cannabis going beyond CBD and THC to discuss cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabinoid acids, and other cannabinoid homologs, terpenes, and flavonoids that may have relevance to AD therapy. Further, the entourage effect, clinical implications, and directions for future research will be discussed.
... The copyright holder for this preprint this version posted February 15, 2023. ; https://doi.org/10.1101/2023.02.15.528525 doi: bioRxiv preprint most abundant cannabinoids in cannabis but has not been well studied with respect to epilepsy, but is known to exhibit neuroprotective effects in cultured mouse neural cells 23 . There is also evidence that CBC when used in combination with CBD or Δ 9 -THC can help alleviate symptoms of insomnia and depression in humans and rats 24,25 . ...
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Background: Cannabis has demonstrated anticonvulsant properties, and cannabis-based medicines are approved to treat pediatric patients with severe pediatric epilepsies that are particularly refractive to approved anti-epileptic drugs (AEDs). About thirty percent of epileptic patients do not have satisfactory seizure management with AEDs and could potentially benefit from cannabis-based intervention. Here we report the use of single and combined cannabinoids to treat Pentylenetetrazol (PTZ) induced convulsions in a zebrafish model, their effect on gene expression, and a simple assay for assessing their uptake in zebrafish tissues. These data provide novel insights as to the potential of treating epilepsy with cannabinoids. Methods: Zebrafish larvae were treated with cannabinoids and their seizures measured through an optimized behaviour tracking method. Cannabinoid uptake was measured with a novel HPLC-UV method. Gene expression changes were assessed using quantitative PCR (qPCR), and chemical inhibitors of potential cannabinoid receptors were used to block activity. Results: Treatment with cannabinol (CBN), cannabichromene (CBC) and cannabigerol (CBG) decreased seizure intensity at lower doses than CBD when accounting for the amount of cannabinoid recovered from exposed larvae. Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC) were effective at higher doses. Synergistic effects were observed between CBD and other cannabinoids such as Δ9-THC, Δ8-THC, and CBG. The reduction of PTZ induced seizures via CBD is partially mediated by the G-protein coupled receptor GPR55, as pharmacological inhibition of the receptor reduced the therapeutic action of CBD. Changes in expression of endocannabinoid system (napepld, gde1, faah, ptgs2a) and neural (fosab, pyya) genes in response to phytocannabinoid treatment were observed and highlight novel mechanisms of phytocannabinoid action. Conclusions: CBD can be combined with additional cannabinoids for optimal reduction of seizure activity and requires the activity of GPR55. Changes in fosab regulation of gene expression and endocannabinoid signalling may influence the anticonvulsant effects of cannabis, however further investigation is required.
... in vitro CBC improved the viability of neural stem cells CBGA Anti-inflammatory, sedative and analgesic potential [29][30][31][32] Cannabidivarin (CBDV) Inhibits oxytosis and prevents loss of energy in HT22 cells (50% inhibition at 1.1 µM and 90 nM, respectively), as well as reducing Aβ toxicity (50% inhibition at 100 nM) and trophic withdrawal (50% inhibition 350 nM); Phytocannabinoids have gained significant attention due to their neuroactive, strong antioxidant, and anti-inflammatory properties. which may potentially treat different neurodegenerative diseases [38]. ...
Article
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Cannabis sativa is a medicinal plant that has been known for years and is used as an Ayurvedic medicine. This plant has great potential in treating various types of brain diseases. Phytochemicals present in this plant act as antioxidants by maintaining synaptic plasticity and preventing neuronal loss. Cannabidiol (CBD) and Tetrahydrocannabinol (THC) are both beneficial in treating Alzheimer’s disease by increasing the solubility of Aβ42 amyloid and Tau aggregation. Apart from these therapeutic effects, there are certain unknown functions of these phytochemicals in Alzheimer’s disease that we want to elucidate through this study. In this research, our approach is to analyze the effect of phytochemicals in Cannabis sativa on multiple culprit enzymes in Alzheimer’s disease, such as AChE (Acetylcholinesterase), BChE (Butyrylcholinesterase), γ-secretase, and BACE-1. In this study, the compounds were selected by Lipinski’s rule, ADMET, and ProTox based on toxicity. Molecular docking between the selected compounds (THCV, Cannabinol C2, and Cannabidiorcol) and enzymes mentioned above was obtained by various software programs including AutoDock Vina 4.2, AutoDock, and iGEMDOCK. In comparison to Donepezil (BA = −8.4 kcal/mol, Ki = 1.46 mM), Rivastigmine (BA = −7.0 kcal/mol, Ki = 0.02 mM), and Galantamine (BA = −7.1, Ki = 2.1 mM), Cannabidiorcol (BA = −9.4 kcal/mol, Ki = 4.61 mM) shows significant inhibition of AChE. On the other hand, Cannabinol C2 (BA = −9.2 kcal/mol, Ki = 4.32 mM) significantly inhibits Butyrylcholinesterase (BuChE) in comparison to Memantine (BA = −6.8 kcal/mol, Ki = 0.54 mM). This study sheds new light and opens new avenues for elucidating the role of bioactive compounds present in Cannabis sativa in treating Alzheimer’s disease.
... Moreover, they showed that the level of CBC was maintained comparable or lower in plants grown under daylight than light stressed conditions. CBC is particularly abundant in young plants or freshly harvested dry-type cannabis and is hypothesized to be a synergist for the psychoactive cannabinoids [26,[38][39][40]. ...
Article
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Interest in cultivating cannabis for medical and recreational purposes is increasing due to a dramatic shift in cannabis legislation worldwide. Therefore, a comprehensive understanding of the composition of secondary metabolites, cannabinoids, and terpenes grown in different environmental conditions is of primary importance for the medical and recreational use of cannabis. We compared the terpene and cannabinoid profiles using gas/liquid chromatography and mass spectrometry for commercial cannabis from genetically identical plants grown indoors using artificial light and artificially grown media or outdoors grown in living soil and natural sunlight. By analyzing the cannabinoids, we found significant variations in the metabolomic profile of cannabis for the different environments. Overall, for both cultivars, there were significantly greater oxidized and degraded cannabinoids in the indoor-grown samples. Moreover, the outdoor-grown samples had significantly more unusual cannabinoids, such as C4- and C6-THCA. There were also significant differences in the terpene profiles between indoor- and outdoor-grown cannabis. The outdoor samples had a greater preponderance of sesquiterpenes including β-caryophyllene, α-humulene, α-bergamotene, α-guaiene, and germacrene B relative to the indoor samples.
... CBC may also exert antidepressant-like actions and thus may contribute to the overall mood-elevating properties of cannabis [130]. In addition, CBD may induce apoptosis and inhibit the growth of several cancer cell lines including breast cancer cells, suggesting that CBC could be further developed for treating cancer [131].CBC has positive effects on mouse neural stem/progenitor cells (essential for brain function) and could possibly be investigated to treat neuroinflammatory conditions including seizures/epilepsy [132]. Based on its action on inflammatory cytokines like MCP-2 [monocyte chemotactic protein], intraleukin-6 (IL-6), intraleukin-8 (IL-8) and tumor necrosis factor (TNF-alpha), it could be developed for treating allergic contact dermatitis [133]. ...
Article
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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.
... In addition, CBN, CBG, CBC, CBDV, and THCA prevented oxytosis, which in the case of CBN, was later confirmed to be via direct targeting of mitochondria and promotion of antioxidant defenses, indirectly of CB receptors (Liang et al., 2022). CBC has also been suggested to have pro-neurogenic benefits via suppression of reactive astrocytes (Shinjyo and Di Marzo, 2013), and THCA has demonstrated numerous PPARγ-dependent neuroprotective properties both in vitro and in vivo (Nadal et al., 2017). ...
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Alzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by declining cognition and behavioral impairment, and hallmarked by extracellular amyloid-β plaques, intracellular neurofibrillary tangles (NFT), oxidative stress, neuroinflammation, and neurodegeneration. There is currently no cure for AD and approved treatments do not halt or slow disease progression, highlighting the need for novel therapeutic strategies. Importantly, the endocannabinoid system (ECS) is affected in AD. Phytocannabinoids, including cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), interact with the ECS, have anti-inflammatory, antioxidant, and neuroprotective properties, can ameliorate amyloid-β and NFT-related pathologies, and promote neurogenesis. Thus, in recent years, purified CBD and THC have been evaluated for their therapeutic potential. CBD reversed and prevented the development of cognitive deficits in AD rodent models, and low-dose THC improved cognition in aging mice. Importantly, CBD, THC, and other phytochemicals present in Cannabis sativa interact with each other in a synergistic fashion (the “entourage effect”) and have greater therapeutic potential when administered together, rather than individually. Thus, treatment of AD using a multi-cannabinoid strategy (such as whole plant cannabis extracts or particular CBD:THC combinations) may be more efficacious compared to cannabinoid isolate treatment strategies. Here, we review the current evidence for the validity of using multi-cannabinoid formulations for AD therapy. We discuss that such treatment strategies appear valid for AD therapy but further investigations, particularly clinical studies, are required to determine optimal dose and ratio of cannabinoids for superior effectiveness and limiting potential side effects. Furthermore, it is pertinent that future in vivo and clinical investigations consider sex effects.
... Regarding differentiation, the endocannabinoid anandamide (AEA) proved to be efficient in the differentiation of NSCs [17] while VCE-003.2, the synthetic cannabigerol derivative proved to be able to induce a neuronal-like differentiation in P19 cells [18]. Another cannabinoid, cannabichromene (CBC), seems to have an effect on NSCs, in particular to inhibit their differentiation toward astroglia, indicating that CBC might assist neuronal differentiation [19]. ...
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Cannabis sativa L. proved to be a source of several phytocompounds able to help patients facing different diseases. Moreover, these phytocompounds can help ameliorate general conditions and control certain unpleasant effects of diseases. Some cannabinoids, however, provided more benefits applicable to settings other than palliative care. Using the NSC-34 cell line, we evaluated the barely known phytocompound named cannabinerol (CBNR) at different doses, in order to understand its unique characteristics and the ones shared with other cannabinoids. The transcriptomic analysis suggests a possible ongoing neuronal differentiation, principally due to the activation of cannabinoid receptor 1 (CB1), to which the phosphorylation of serine–threonine protein kinase (Akt) followed, especially between 20 and 7.5 µM. The increase of Neurod1 and Map2 genes at 7.5 µM, accompanied by a decrease of Vim, as well as the increase of Syp at all the other doses, point toward the initiation of differentiation signals. Our preliminary results indicate CBNR as a promising candidate to be added to the list of cannabinoids with neuronal differentiation-enhancer properties. However, further studies are needed to confirm this initial insight.
... CBC can have profound therapeutic effects on inflammation and pain through CB2 receptor activity and stimulation and desensitization of TRP ankyrin-type 1 (TRPA1) cation channels, interactions with TRPV3 and TRPV4 cation channels, and desensitization of TRPV2 and TRPV4 channels (De Petrocellis et al., 2012;. CBC has also been shown to relieve pain in mice by augmenting the analgesic effects of THC when the two are co-administered (Davis & Hatoum, 1983;Maione et al., 2011;, and can increase concentrations and prolong the duration of endocannabinoids like anandamide through its interactions with TRP channels (Shinjyo & Di Marzo, 2013;De Petrocellis et al., 2011. CBN is being investigated for several topical therapeutic targets for skin conditions like psoriasis, burns, and MRSA infections, via inhibition of keratinocyte proliferation, TRPV2 agonism, and direct antimicrobial activity, respectively (Wilkinson & Williamson, 2007;Appendio et al., 2008;Qin et al., 2008;Russo, 2014). ...
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“Hemp” refers to non-intoxicating, low delta-9 tetrahydrocannabinol (Δ9-THC) cultivars of Cannabis sativa L. “Marijuana” refers to cultivars with high levels of Δ9-THC, the primary psychoactive cannabinoid found in the plant and a federally controlled substance used for both recreational and therapeutic purposes. Although marijuana and hemp belong to the same genus and species, they differ in terms of chemical and genetic composition, production practices, product uses, and regulatory status. Hemp seed and hemp seed oil have been shown to have valuable nutritional capacity. Cannabidiol (CBD), a non-intoxicating phytocannabinoid with a wide therapeutic index and acceptable side effect profile, has demonstrated high medicinal potential in some conditions. Several countries and states have facilitated the use of THC-dominant medical cannabis for certain conditions, while other countries continue to ban all forms of cannabis regardless of cannabinoid profile or low psychoactive potential. Today, differentiating between hemp and marijuana in the laboratory is no longer a difficult process. Certain thin layer chromatography (TLC) methods can rapidly screen for cannabinoids, and several gas and liquid chromatography techniques have been developed for precise quantification of phytocannabinoids in plant extracts and biological samples. Geographic regulations and testing guidelines for cannabis continue to evolve. As they are improved and clarified, we can better employ the appropriate applications of this uniquely versatile plant from an informed scientific perspective.
... However, THC is well-documented having anti-inflammatory effects, including for arthritic and inflammatory conditions [15], Alzheimer's disease [16], Parkinson's [17] and diabetes [18]. However, cannabigerol (CBG) However, cannabigerol (CBG) and cannabichromene (CBC) have antibacterial and antifungal effects [19], and can act as antidepressants [20]. In contrast, cannabinol (CBN) has a potential effect on insomnia and sleep disorder [21]. ...
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The traditional Cannabis plant as a medicinal crop has been explored for many thousands of years. The Cannabis industry is rapidly growing; therefore, optimising drying methods and producing high-quality medical products have been a hot topic in recent years. We systemically analysed the current literature and drew a critical summary of the drying methods implemented thus far to preserve the quality of bioactive compounds from medicinal Cannabis. Different drying techniques have been one of the focal points during the post-harvesting operations, as drying preserves these Cannabis products with increased shelf life. We followed or even highlighted the most popular methods used. Drying methods have advanced from traditional hot air and oven drying methods to microwave-assisted hot air drying or freeze-drying. In this review, traditional and modern drying technologies are reviewed. Each technology will have different pros and cons of its own. Moreover, this review outlines the quality of the Cannabis plant component harvested plays a major role in drying efficiency and preserving the chemical constituents. The emergence of medical Cannabis, and cannabinoid research requires optimal post-harvesting processes for different Cannabis strains. We proposed the most suitable method for drying medicinal Cannabis to produce consistent, reliable and potent medicinal Cannabis. In addition, drying temperature, rate of drying, mode and storage conditions after drying influenced the Cannabis component retention and quality
... THCV exhibits high affinity for cannabinoid receptors and acts as a neutral CB1 antagonist and partial CB2 agonist with efficacy in an animal model of Parkinson's disease [98]. CBC influences adult neural stem cell differentiation by reducing generation of new astrocytes potentially involved in neuro-inflammation [99,100]. CBDV and, to a far smaller extent, THCV produce anticonvulsant effects in animal models of epilepsy, likely via non-CB1/CB2 mechanisms. ...
Chapter
Ageratum houstonianum leaves are a common poisonous weeds found on the vast valley of Kangra in Palampur, Himachal Pradesh State, India. Freshly harvested leaves sample of Ageratum houstonionum were dried under shade and powdered. Leaf sample of A. houstonionum was extracted by process of hydrodistillation using a Clevenger-type apparatus for the preparation of essential oil. Extract from A. houstonianum was prepared by dissolving 5 μL of the essential oil in 10 mL methanol. All the sample was filtered through a Whatman (Maidstone, England) stainless steel syringe assembly using a 0.22 μm Durapore (Millipore: Milford, USA) membrane filter. Purification processes via column chromatography, thin layer chromatography and preparative thin layer chromatography were done. Reverse phase HPLC analysis was carried out via a Waters HPLC system consisting of model 510 and 515 pumps, a Rheodyne injector, a Novapak C18 column (250 x 4.6 mm i.d.; 4 μm), a model 490E multi-channel detector and Millennium 2010 sata manager. The mobile phase constituents were filtered using a Durapore 0.22 μm membrane filter. The elution was carried out with a linear gradient of acetonitrile: water (40:60) to pure acetonitrile in 60 min at a flow rate of 1 mL/min. detection was at 210, 240, 280 and 320 nm. The precocene was eluted within 25 min, the peak areas showed good reproducibility (average relative standard deviation were 0.78%), and the calibration curves (i.e. mass of precocene standard injected vs. peak area detected at 210 nm) were linear over the range of 0.05- 10 μg (for precocene I, y = 6654454 x + 176626, r2 = 0.99 and for precocene II, y = 4618457 x + 133472, r2 = 0.99). Standard sample containing precocene I (1 mg/mL) and precocene II (1 mg/mL) obtained from Sigma (St Louis, MO, USA) were prepared in methanol. Identified precocene I was screened against Trypanosoma evansi for trypanocidal activity on Vero cells grown in Dulbecco's Modified Eagle Medium (DMEM) and supplemented with foetal calf serum (FCS) 20-40% at appropriate conditions. In vitro cytotoxicity test of precocene I at concentrations (1.56-100 μg ml-1) was done on Vero cells but without FCS. In vitro trypanocidal activity varied from immobilization, reduction and to the killing of trypanosomes in corresponding ELISA plate wells. At 250 μg ml-1of purified precocene I, there was drastic reduction of average mean trypanosomes count to complete killing of trypanosomes (40.±0.0 to 0.00±0.00) at 9 h of incubation, which was statistically the same as diminazine aceturate (50 μg ml-1) at 4 h. Trypanosomes counts decreased in concentration and time –dependent manner with significant difference (P ≤ 0.05 to 0. 01)). During in vitro cytotoxicity test, Purified precocene I and diminazine aceturate standard drug, were cytotoxic to Vero cells at all concentrations except at concentrations of 6.25-1.56 μg ml-1 and 1.56 μg ml-1, respectively. Precocene I was responsible for higher anti-trypanosomal activity. Precocene I could be near futurtrypanocidal compound for a new trypanocide. To attest its full and firm trypanocidal activity potential, in vivo test need to be conducted alongside the in vitro method.
... Preclinical research has identified several avenues of therapeutic potential that generally corroborate with in vitro pharmacological data. In vitro functional data show that CBC increases viability of adult neural progenitor cells and inhibited their differentiation into astroglia, suggesting that CBC may be a candidate for treating neuroinflammatory diseases [12]. In rodents, CBC has displayed anti-microbial, anti-inflammatory, analgesic, and anti-depressant-like activity [13][14][15][16][17][18][19][20][21]. ...
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Purpose Cannabichromene (CBC) is a phytocannabinoid commonly found in cannabis, yet its acute post-dose pharmacokinetics (PK) have not been examined in humans. This is a secondary data analysis from a trial investigating Spectrum Yellow oil, an oral cannabis product used for medical purposes that contained 20 mg cannabidiol (CBD), 0.9 mg Δ⁹-tetrahydrocannabinol (THC), and 1.1 mg CBC, per 1 mL of oil. Methods Participants (N = 43) were randomized to one of 5 groups: 120 mg CBD, 5.4 mg THC, and 6.6 mg CBC daily; 240 mg CBD, 10.8 mg THC, and 13.2 mg CBC daily; 360 mg CBD, 16.2 mg THC, and 19.8 mg CBC daily; 480 mg CBD, 21.6 mg THC, and 26.4 mg CBC daily; or placebo. Study medication was administered every 12 h for 7 days. Plasma CBC concentrations were analyzed by a validated two-dimensional high-performance liquid chromatography–tandem mass spectrometry assay. Results After a single dose and after the final dose, the Cmax of CBC increased by 1.3–1.8-fold for each twofold increase in dose; the tmax range was 1.6–4.3 h. Based on the ratio of administered CBD, THC, and CBC to the plasma concentration, the dose of CBD was 18 times higher than the dose of CBC, yet the AUC0–t of CBD was only 6.6–9.8-fold higher than the AUC0–t of CBC; the dose of THC was similar to the dose of CBC, yet THC was quantifiable in fewer plasma samples than was CBC. Conclusions CBC may have preferential absorption over CBD and THC when administered together. Trial Registration: Australian New Zealand Clinical Trials Registry #ACTRN12619001450101, registered 18 October 2019.
... We tested CBC at 1 μM, a concentration chosen for CBC and other phytocannabinoids because it represents a likely physiological ceiling concentration that consumers might encounter (discussed in [13]). It is also a concentration that has been shown to affect the activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and viability of neuronal stem cells [33]. At 1 μM, CBC did not alter excitatory post-synaptic current (EPSC) amplitudes (Figure 2A, EPSC charge relative to baseline (1.0 = no effect) CBC: 1.04 ± 0.02, n = 4; p = 0.23 by onesample t-test vs. baseline 1.0), indicating that CBC does not directly alter excitatory neurotransmission in this system. ...
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Cannabis contains more than 100 phytocannabinoids. Most of these remain poorly characterized, particularly in neurons. We tested a panel of five phytocannabinoids—cannabichromene (CBC), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), and Δ9-tetrahydrocannabivarin (THCV) in two neuronal models, autaptic hippocampal neurons and dorsal root ganglion (DRG) neurons. Autaptic neurons expressed a form of CB1-dependent retrograde plasticity while DRGs expressed a variety of transient receptor potential (TRP) channels. CBC, CBDA, and CBDVA had little or no effect on neuronal cannabinoid signaling. CBDV and THCV differentially inhibited cannabinoid signaling. THCV inhibited CB1 receptors presynaptically while CBDV acted post-synaptically, perhaps by inhibiting 2-AG production. None of the compounds elicited a consistent DRG response. In summary, we find that two of five ‘minor’ phytocannabinoids tested antagonized CB1-based signaling in a neuronal model, but with very different mechanisms. Our findings highlight the diversity of potential actions of phytocannabinoids and the importance of fully evaluating these compounds in neuronal models.
... Additionally, CBC, CBN, THC, THCV, THCA, CBDA, and CBG all induced intracellular Ca 2+ increases in HEK293 and rat DRG neurons through TRPA1 [202,200]. CBC has also shown promise in increasing neural stem cell viability in animal models (in vitro), mediated through ERK phosphorylation [346]. However, it is concerning that large amounts of CBC are required to produce pharmacological effects [90], which implies that CBC may be difficult to implement in a human health context. ...
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Cannabis sativa (Cannabis) is one of the world’s most well-known, yet maligned plant species. However, significant recent research is starting to unveil the potential of Cannabis to produce secondary compounds that may offer a suite of medical benefits, elevating this unique plant species from its illicit narcotic status into a genuine biopharmaceutical. This review summarises the lengthy history of Cannabis and details the molecular pathways that underpin the production of key secondary metabolites that may confer medical efficacy. We also provide an up-to-date summary of the molecular targets and potential of the relatively unknown minor compounds offered by the Cannabis plant. Furthermore, we detail the recent advances in plant science, as well as synthetic biology, and the pharmacology surrounding Cannabis. Given the relative infancy of Cannabis research, we go on to highlight the parallels to previous research conducted in another medically relevant and versatile plant, Papaver somniferum (opium poppy), as an indicator of the possible future direction of Cannabis plant biology. Overall, this review highlights the future directions of cannabis research outside of the medical biology aspects of its well-characterised constituents and explores additional avenues for the potential improvement of the medical potential of the Cannabis plant.
... CBC in combination with THC has a greater antiinflammatory effect (5). It showed potential in vitro effects on adult neural stem progenitor cells (42), but the in vivo medical research needs to be done to account for various physiological and pathological variations. ...
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Cannabigerol and cannabichromene in Cannabis sativa L. In addition to delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), other phytocannabinoids, such as can-nabigerol (CBG) and cannabichromene (CBC), also have beneficial effects on human health. A high content of CBG is found in plants with the B 0 genotype, whereas CBC is independent of the allelic chemotype locus B. In basic research models such as mice or rats, CBG has demonstrated anticancer properties, particularly against breast cancer. CBG has shown anti-inflammatory effects on murine colitis and on inflammatory bowel disease as well as stimulatory effects on the feeding behaviors of mice. It has also exhibited inhibition of aldose reductase, which is known to cause an accumulation of sorbitol and increase glucose levels in the blood, which may lead to diabetes. Cannabinoid CBC has also shown anti-inflammatory effects and reduced hy-permobility in the gut and has displayed potential in vitro effect on adult neural stem progenitor cells. CBC also exerts modest analgesic properties in rodents, as well as anti-fungal , anti-bacterial, pro-apoptotic, and anti-proliferative effects in tumor cells.
... This provided new insights on the chromosome arrangement and the cannabinoid biosynthetic genes. Another milestone from the Laverty et al. (2019) study is the identification of an important gene involved in the biosynthesis of cannabichromene, a cannabinoid with a weak activity on the CB1 and CB2 receptors (involved in the neural and psychoactive effect of THC and CBD) that could be possibly used in medical therapies against pain and gastro-inflammatory diseases (Maione et al., 2011;Izzo et al., 2012;Shinjyo and Di Marzo, 2013). ...
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Cannabis (Cannabis sativa L.) is an influential yet controversial agricultural plant with a very long and prominent history of recreational, medicinal, and industrial usages. Given the importance of this species, we deepened some of the main challenges—along with potential solutions—behind the breeding of new cannabis cultivars. One of the main issues that should be fixed before starting new breeding programs is the uncertain taxonomic classification of the two main taxa (e.g., indica and sativa) of the Cannabis genus. We tried therefore to examine this topic from a molecular perspective through the use of DNA barcoding. Our findings seem to support a unique species system (C. sativa) based on two subspecies: C. sativa subsp. sativa and C. sativa subsp. indica. The second key issue in a breeding program is related to the dioecy behavior of this species and to the comprehension of those molecular mechanisms underlying flower development, the main cannabis product. Given the role of MADS box genes in flower identity, we analyzed and reorganized all the genomic and transcriptomic data available for homeotic genes, trying to decipher the applicability of the ABCDE model in Cannabis. Finally, reviewing the limits of the conventional breeding methods traditionally applied for developing new varieties, we proposed a new breeding scheme for the constitution of F1 hybrids, without ignoring the indisputable contribution offered by genomics. In this sense, in parallel, we resumed the main advances in the genomic field of this species and, ascertained the lack of a robust set of SNP markers, provided a discriminant and polymorphic panel of SSR markers as a valuable tool for future marker assisted breeding programs.
... While the degree to which they may interact within cannabis or elicit their own pharmacological effects is unclear, it is possible that these cannabinoids may play a role in modulating cannabis' function in the brain. A few rodent studies have indicated that these cannabinoids may have some anti-inflammatory, analgesic, and neuroprotective properties similar to CBD (122)(123)(124)(125). THCV, for example, acts as a neutral antagonist of the CB 1 receptor at a low dose and acts as an agonist at a high dose (6,126). ...
Article
Cannabis and cannabinoid-based products are increasingly being accepted and commodified globally. Yet there is currently limited understanding of the effect of the varied cannabinoid compounds on the brain. Exogenous cannabinoids interact with the endogenous cannabinoid system that underpins vital functions in the brain and body, and are thought to perturb key brain and cognitive function. However, much neuroimaging research has been confined to observational studies of cannabis users, without examining the specific role of the various cannabinoids (THC, CBD etc.). This narrative review summarises the brain structural imaging evidence to date associated with cannabis use, its major cannabinoids (e.g. THC, CBD), and synthetic cannabinoid products that have emerged as recreational drugs. In doing so, we seek to highlight some of the key issues to consider in understanding cannabinoid-related brain effects, emphasizing the dual neurotoxic and neuroprotective role of cannabinoids, and the need to consider the distinct role of the varied cannabinoids in establishing their effect on the brain.
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Cannabis sativa L. is a multipurpose crop with high value for food, textiles, and other industries. Its secondary metabolites, including cannabidiol (CBD), have potential for broad application in medicine. With the CBD market expanding, traditional production may not be sufficient. Here we review the potential for the production of CBD using biotechnology. We describe the chemical and biological synthesis of cannabinoids, the associated enzymes, and the application of metabolic engineering, synthetic biology, and heterologous expression to increasing production of CBD.
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Cannabichromene (CBC) is a nonpsychoactive phytocannabinoid well-known for its wide-ranging health advantages. However, there is limited knowledge regarding its human metabolism following CBC consumption. This research aimed to explore the metabolic pathways of CBC by various human liver cytochrome P450 (CYP) enzymes and support the outcomes using in vivo data from mice. The results unveiled two principal CBC metabolites generated by CYPs: 8′-hydroxy-CBC and 6′,7′-epoxy-CBC, along with a minor quantity of 1″-hydroxy-CBC. Notably, among the examined CYPs, CYP2C9 demonstrated the highest efficiency in producing these metabolites. Moreover, through a molecular dynamics simulation spanning 1 μs, it was observed that CBC attains stability at the active site of CYP2J2 by forming hydrogen bonds with I487 and N379, facilitated by water molecules, which specifically promotes the hydroxy metabolite’s formation. Additionally, the presence of cytochrome P450 reductase (CPR) amplified CBC’s binding affinity to CYPs, particularly with CYP2C8 and CYP3A4. Furthermore, the metabolites derived from CBC reduced cytokine levels, such as IL6 and NO, by approximately 50% in microglia cells. This investigation offers valuable insights into the biotransformation of CBC, underscoring the physiological importance and the potential significance of these metabolites.
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Cannabis, renowned for its historical medicinal use, harbours various bioactive compounds—cannabinoids, terpenes, and flavonoids. While major cannabinoids like delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have received extensive scrutiny for their pharmacological properties, emerging evidence underscores the collaborative interactions among these constituents, suggesting a collective therapeutic potential. This comprehensive review explores the intricate relationships and synergies between cannabinoids, terpenes, and flavonoids in cannabis. Cannabinoids, pivotal in cannabis’s bioactivity, exhibit well-documented analgesic, anti-inflammatory, and neuroprotective effects. Terpenes, aromatic compounds imbuing distinct flavours, not only contribute to cannabis’s sensory profile but also modulate cannabinoid effects through diverse molecular mechanisms. Flavonoids, another cannabis component, demonstrate anti-inflammatory, antioxidant, and neuroprotective properties, particularly relevant to neuroinflammation. The entourage hypothesis posits that combined cannabinoid, terpene, and flavonoid action yields synergistic or additive effects, surpassing individual compound efficacy. Recognizing the nuanced interactions is crucial for unravelling cannabis’s complete therapeutic potential. Tailoring treatments based on the holistic composition of cannabis strains allows optimization of therapeutic outcomes while minimizing potential side effects. This review underscores the imperative to delve into the intricate roles of cannabinoids, terpenes, and flavonoids, offering promising prospects for innovative therapeutic interventions and advocating continued research to unlock cannabis’s full therapeutic potential within the realm of natural plant-based medicine.
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In recent years, the enantiomeric ratio of cannabichromene (CBC) within the cannabis plant has attracted significant attention. Cannabichromene is one of the well-known cannabinoids found in cannabis, along with THC (tetrahydrocannabinol) and CBD (cannabidiol). Cannabichromene exists as a scalemic mixture, meaning it has two enantiomers, (S)-cannabichromene and (R)-cannabichromene, with the ratio between these enantiomers varying among different cannabis strains and even within individual plants. This study presents an accurate and robust chiral NMR method for analyzing cannabichromene’s enantiomeric ratio, a well-investigated cannabinoid with numerous pharmacological targets. The use of Pirkle’s alcohol as the chiral solvating agent (CSA) or, alternatively, the use of (S)-ibuprofen as a chiral derivatizing agent (CDA) facilitated this analysis. Moreover, the chiral NMR method proves to be a user-friendly tool, easily applicable within any NMR facility, and an expanded investigation of cannabichromene chirality may provide insights into the origin, cultivation, treatment, and processing of Cannabis sativa plants. This study also undertakes a pharmacological examination of the (R)- and (S)-cannabichromenes concerning their most extensively studied pharmacological target, the TRPA1 channels, with the two enantiomers showing the same strong agonistic effect as the racemic mixture.
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Chapter
Cannabis products and Cannabis use are inherently variable. Given the difficulty in standardizing Cannabis products and Cannabis use patterns, studies are often impacted by differences in the participants’ exposure to Cannabis or even specific cannabinoids, especially in medical use. Although it is clear that chronic recreational use impacts brain function, albeit subtly, future researches exploring moderating factors, including the age of onset, recovery of function after abstinence, frequency and magnitude of Cannabis use, high- versus low-potency products, mode of use, and the unique effects of specific cannabinoids, are all needed to understand the impact of Cannabis fully. As legalization efforts expand, overall use rates continue to rise, and questions regarding Cannabis and public policy measures remain crucial.
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Cannabis spp. are some of the most controversial medicinal plants in the world. They contain great amounts of biologically active secondary metabolites, including the typical phenolic compounds called cannabinoids. Because of their low toxicity and complex biological activities, cannabinoids can be useful in the therapy of various diseases, but adverse psychological effects (of Δ9-THC in particular) raise concerns. This review summarizes the current knowledge of selected active C. indica compounds and their therapeutic potential. We summarize the main compounds contained in cannabis, the mechanisms of their effects, and their potential therapeutic applications. Further, we mention some of the clinical tests used to evaluate the efficacy of cannabinoids in therapy.
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Cannabis refers to a genus of flowering plants and includes three major species Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Phytocannabinoids (plant-based cannabinoids) include cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC). Endocannabinoids are endogenous chemicals which act on the cannabinoid receptors (CBR). Synthetic medications such as nabilone, dronabinol, and rimonabant are also commercially available. The phytocannabinoids are chemicals extracted from the cannabis plant either interacting directly with cannabinoid receptors or sharing chemical similarity with endocannabinoids or both. While Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most studied phytocannabinoids, other phytocannabinoids that require special mention include cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), and tetrahydrocannabivarin (THCV). These minor cannabinoids have demonstrated anticonvulsant, anti-inflammatory, antibacterial, and antidepressant properties apart from showing promise in pain relief and muscle relaxation. Evidence of anticancer and cytotoxic properties on human epithelioid carcinoma and breast cancer in basic research models highlights the need for further research in this arena, to validate their use.
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In the last decades, cannabinoid receptor 2 (CB2R) has continued to receive attention as a key therapeutic target in neuroprotection. Indeed, several findings highlight the neuroprotective effects of CB2R through suppression of both neuronal excitability and reactive microglia. Additionally, CB2R seems to be a more promising target than cannabinoid receptor 1 (CB1R) thanks to the lack of central side effects, its lower expression levels in the central nervous system (CNS), and its inducibility, since its expression enhances quickly in the brain following pathological conditions. This review aims to provide a thorough overview of the main natural and synthetic selective CB2R modulators, their chemical classification and their potential therapeutic usefulness in neuroprotection, a crucial aspect for the treatment of neurodegenerative diseases.
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The discovery of the endocannabinoid system (ECS) has not only increased our understanding of the effects of plant cannabinoids, but also increased our understanding of human biochemistry as well as opened up avenues towards new therapeutic targets. Phytocannabinoids as well as their synthetic counterparts are known to engage with our endocannabinoid system ; hence our understanding of the basic biochemistry of this pivotal signaling system offers insights into beneficial and therapeutic uses of these molecules. There is a plethora of research data and scientific peer-reviewed papers on the topic of cannabinoids, the ECS and health/disease. Much data has been gathered from epidemiological and biomedical research, thus providing patients and medical professionals with good foundations for the use of cannabinoids in medicine. But understanding the biochemistry of the ECS and the role this signaling system plays in human physiology is the key to the proper use of these potent molecules.
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Geçmişte pek çok bitki, bitki parçası, meyvesi, tohumu ve bunlardan hazırlanan ürünler (iksirler ve karışımlar) tedavi amaçlı olarak kullanılmıştır. Bugün farmasötik sanayide gelinen aşamadan dolayı geçmişe bakıldığında, kullanılan birçok iksirlerin ve karışımların işe yaramadığı, hatta bazılarının zararlı bile olduğu bilinmektedir. Bununla birlikte, bazı bitkilerin bazı hastalıklara farklı mekanizmalarla olumlu etkileri olabildiği bilimsel olarak kanıtlanırken aynı zamanda bir kısmı ilaç etken maddesi olarak eczanelerde de yer alabilmektedir. Bu bitkilerden biri olan kenevir, insanlar tarafından yüzyıllar boyunca tekstil lifi, ilaç, keyif verici madde, tıbbı tedavi amaçlı olarak ve dini ritüellerde günlük adanma işlemleri sırasında kullanılmıştır.
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Plant-based therapies date back centuries. Cannabis sativa is one such plant that was used medicinally up until the early part of the 20th century. Although rich in diverse and interesting phytochemicals, cannabis was largely ignored by the modern scientific community due to its designation as a schedule 1 narcotic and restrictions on access for research purposes. There was renewed interest in the early 1990s when the endocannabinoid system (ECS) was discovered, a complex network of signaling pathways responsible for physiological homeostasis. Two key components of the ECS, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), were identified as the molecular targets of the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC). Restrictions on access to cannabis have eased worldwide, leading to a resurgence in interest in the therapeutic potential of cannabis. Much of the focus has been on the two major constituents, Δ9-THC and cannabidiol (CBD). Cannabis contains over 140 phytocannabinoids, although only a handful have been tested for pharmacological activity. Many of these minor cannabinoids potently modulate receptors, ionotropic channels, and enzymes associated with the ECS and show therapeutic potential individually or synergistically with other phytocannabinoids. The following review will focus on the pharmacological developments of the next generation of phytocannabinoid therapeutics.
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Most of our current understanding of the neuromolecular mechanisms of Cannabis action focusses on two plant cannabinoids, THC and CBD. THC acts primarily through presynaptic CB cannabinoid receptors to regulate neurotransmitter release in the brain, spinal cord and peripheral nerves. CBD action, on the other hand, is probably mediated through multiple molecular targets.
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The Cannabis sativa plant contains more than 120 cannabinoids. With the exceptions of ∆⁹-tetrahydrocannabinol (∆⁹-THC) and cannabidiol (CBD), comparatively little is known about the pharmacology of the less-abundant plant-derived (phyto) cannabinoids. The best-studied transducers of cannabinoid-dependent effects are type 1 and type 2 cannabinoid receptors (CB1R, CB2R). Partial agonism of CB1R by ∆⁹-THC is known to bring about the ‘high’ associated with Cannabis use, as well as the pain-, appetite-, and anxiety-modulating effects that are potentially therapeutic. CB2R activation by certain cannabinoids has been associated with anti-inflammatory activities. We assessed the activity of 8 phytocannabinoids at human CB1R, and CB2R in Chinese hamster ovary (CHO) cells stably expressing these receptors and in C57BL/6 mice in an attempt to better understand their pharmacodynamics. Specifically, ∆⁹-THC, ∆⁹-tetrahydrocannabinolic acid (∆⁹-THCa), ∆⁹-tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDa), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC) were evaluated. Compounds were assessed for their affinity to receptors, ability to inhibit cAMP accumulation, βarrestin2 recruitment, receptor selectivity, and ligand bias in cell culture; and cataleptic, hypothermic, anti-nociceptive, hypolocomotive, and anxiolytic effects in mice. Our data reveal partial agonist activity for many phytocannabinoids tested at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids and are critical in understanding the complex and interactive pharmacology of Cannabis-derived molecules.
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Cannabis is an annual plant with a long history of use as food, feed, fiber, oil, medicine, and narcotics. Despite realizing its true value, it has not yet found its true place. Cannabis has had a long history with many ups and downs, and now it is our turn to promote it. Cannabis contains approximately 600 identified and many yet unidentified potentially useful compounds. Cannabinoids, phenolic compounds, terpenoids, and alkaloids are some of the secondary metabolites present in cannabis. However, among a plethora of unique chemical compounds found in this plant, the most important ones are phytocannabinoids (PCs). Over hundreds of 21-22-carbon compounds exclusively produce in cannabis glandular hairs through either polyketide and or deoxyxylulose phosphate/methylerythritol phosphate (DOXP/MEP) pathways. Trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are those that first come to mind while talking about cannabis. Nevertheless, despite the low concentration, cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabinodiol (CBND), and cannabinidiol (CBDL) may have potentially some medical effects. PCs and endocannabinoids (ECs) mediate their effects mainly through CB1 and CB2 receptors. Despite all concerns regarding cannabis, nobody can ignore the use of cannabinoids as promising tonic, analgesic, antipyretic, antiemetic, anti-inflammatory, anti-epileptic, anticancer agents, which are effective for pain relief, depression, anxiety, sleep disorders, nausea and vomiting, multiple sclerosis, cardiovascular disorders, and appetite stimulation. The scientific community and public society have now increasingly accepted cannabis specifically hemp as much more than a recreational drug. There are growing demands for cannabinoids, mainly CBD, with many diverse therapeutic and nutritional properties in veterinary or human medicine. The main objective of this review article is to historically summarize findings concerning cannabinoids, mainly THC and CBD, towards putting these valuable compounds into food, feed and health baskets and current and future trends in the consumption of products derived from cannabis.
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In the last few decades great thrust has been put in the area of regenerative neurobiology research to combat brain injuries and neurodegenerative diseases. The recent discovery of neurogenic niches in the adult brain has led researchers to study how to mobilize these cells to orchestrate an endogenous repair mechanism. The brain can minimize injury-induced damage by means of an immediate glial response and by initiating repair mechanisms that involve the generation and mobilization of new neurons to the site of injury where they can integrate into the existing circuit. This review highlights the current status of research in this field. Here, we discuss the changes that take place in the neurogenic milieu following injury. We will focus, in particular, on the cellular and molecular controls that lead to increased proliferation in the Sub ventricular Zone (SVZ) as well as neurogenesis. We will also concentrate on how these cellular and molecular mechanisms influence the migration of new cells to the affected area and their differentiation into neuronal/glial lineage that initiate the repair mechanism. Next, we will discuss some of the different factors that limit/retard the repair process and highlight future lines of research that can help to overcome these limitations. A clear understanding of the underlying molecular mechanisms and physiological changes following brain damage and the subsequent endogenous repair should help us develop better strategies to repair damaged brains.
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Microglial activation is an invariant feature of Alzheimer's disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing β-amyloid (Aβ)-induced microglial activation both in vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms. In the present study, we compared the effects of CBD with those of other cannabinoids on microglial cell functions in vitro and on learning behavior and cytokine expression after Aβ intraventricular administration to mice. CBD, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone [WIN 55,212-2 (WIN)], a mixed CB(1)/CB(2) agonist, and 1,1-dimethylbutyl-1-deoxy-Δ(9)-tetrahydrocannabinol [JWH-133 (JWH)], a CB(2)-selective agonist, concentration-dependently decreased ATP-induced (400 μM) increase in intracellular calcium ([Ca(2+)](i)) in cultured N13 microglial cells and in rat primary microglia. In contrast, 4-[4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl]-6,6-dimethyl-bicyclo[3.1.1]hept-2-ene-2-methanol [HU-308 (HU)], another CB(2) agonist, was without effect. Cannabinoid and adenosine A(2A) receptors may be involved in the CBD action. CBD- and WIN-promoted primary microglia migration was blocked by CB(1) and/or CB(2) antagonists. JWH and HU-induced migration was blocked by a CB(2) antagonist only. All of the cannabinoids decreased lipopolysaccharide-induced nitrite generation, which was insensitive to cannabinoid antagonism. Finally, both CBD and WIN, after subchronic administration for 3 weeks, were able to prevent learning of a spatial navigation task and cytokine gene expression in β-amyloid-injected mice. In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD. Given that CBD lacks psychoactivity, it may represent a novel therapeutic approach for this neurological disease.
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Two non-psychoactive cannabinoids, cannabidiol (CBD) and cannabichromene (CBC), are known to modulate in vitro the activity of proteins involved in nociceptive mechanisms, including transient receptor potential (TRP) channels of vanilloid type-1 (TRPV1) and of ankyrin type-1 (TRPA1), the equilibrative nucleoside transporter and proteins facilitating endocannabinoid inactivation. Here we have tested these two cannabinoids on the activity of the descending pathway of antinociception. Electrical activity of ON and OFF neurons of the rostral ventromedial medulla in anaesthetized rats was recorded extracellularly and tail flick latencies to thermal stimuli were measured. CBD or CBC along with various antagonists were injected into the ventrolateral periaqueductal grey. Cannabidiol and CBC dose-dependently reduced the ongoing activity of ON and OFF neurons in anaesthetized rats, whilst inducing antinociceptive responses in the tail flick-test. These effects were maximal with 3 nmol CBD and 6 nmol CBC, and were antagonized by selective antagonists of cannabinoid CB(1) adenosine A(1) and TRPA1, but not of TRPV1, receptors. Both CBC and CBD also significantly elevated endocannabinoid levels in the ventrolateral periaqueductal grey. A specific agonist at TRPA1 channels and a synthetic inhibitor of endocannabinoid cellular reuptake exerted effects similar to those of CBC and CBD. CBD and CBC stimulated descending pathways of antinociception and caused analgesia by interacting with several target proteins involved in nociceptive control. These compounds might represent useful therapeutic agents with multiple mechanisms of action.
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The G-protein coupled receptors for Δ⁹-tetrahydrocannabinol, the major psychoactive principle of marijuana, are known as cannabinoid receptors of type 1 (CB₁) and 2 (CB₂) and play important functions in degenerative and inflammatory disorders of the central nervous system. Whilst CB₁ receptors are mostly expressed in neurons, where they regulate neurotransmitter release and synaptic strength, CB₂ receptors are found mostly in glial cells and microglia, which become activated and over-express these receptors during disorders such as Alzheimer's disease, multiple sclerosis, amyotropic lateral sclerosis, Parkinson's disease, and Huntington's chorea. The neuromodulatory actions at CB₁ receptors by endogenous agonists ('endocannabinoids'), of which anandamide and 2-arachidonoylglycerol are the two most studied representatives, allows them to counteract the neurochemical unbalances arising during these disorders. In contrast, the immunomodulatory effects of these lipophilic mediators at CB₂ receptors regulate the activity and function of glia and microglia. Indeed, the level of expression of CB₁ and CB₂ receptors or of enzymes controlling endocannabinoid levels, and hence the concentrations of endocannabinoids, undergo time- and brain region-specific changes during neurodegenerative and neuroinflammatory disorders, with the initial attempt to counteract excitotoxicity and inflammation. Here we discuss this plasticity of the endocannabinoid system during the aforementioned central nervous system disorders, as well as its dysregulation, both of which have opened the way to the use of either direct and indirect activators or blockers of CB₁ and CB₂ receptors for the treatment of the symptoms or progression of these diseases.
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Numerous evidence demonstrates that astrocytes, a type of glial cell, are integral functional elements of the synapses, responding to neuronal activity and regulating synaptic transmission and plasticity. Consequently, they are actively involved in the processing, transfer and storage of information by the nervous system, which challenges the accepted paradigm that brain function results exclusively from neuronal network activity, and suggests that nervous system function actually arises from the activity of neuron-glia networks. Most of our knowledge of the properties and physiological consequences of the bidirectional communication between astrocytes and neurons resides at cellular and molecular levels. In contrast, much less is known at higher level of complexity, i.e. networks of cells, and the actual impact of astrocytes in the neuronal network function remains largely unexplored. In the present article, we summarize the current evidence that supports the notion that astrocytes are integral components of nervous system networks and we discuss some functional properties of intercellular signalling in neuron-glia networks.
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Adult neurogenesis is a particular example of brain plasticity that is partially modulated by the endocannabinoid system. Whereas the impact of synthetic cannabinoids on the neuronal progenitor cells has been described, there has been lack of information about the action of plant-derived extracts on neurogenesis. Therefore we here focused on the effects of Delta9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) fed to female C57Bl/6 and Nestin-GFP-reporter mice on proliferation and maturation of neuronal progenitor cells and spatial learning performance. In addition we used cannabinoid receptor 1 (CB1) deficient mice and treatment with CB1 antagonist AM251 in Nestin-GFP-reporter mice to investigate the role of the CB1 receptor in adult neurogenesis in detail. THC and CBD differed in their effects on spatial learning and adult neurogenesis. CBD did not impair learning but increased adult neurogenesis, whereas THC reduced learning without affecting adult neurogenesis. We found the neurogenic effect of CBD to be dependent on the CB1 receptor, which is expressed over the whole dentate gyrus. Similarly, the neurogenic effect of environmental enrichment and voluntary wheel running depends on the presence of the CB1 receptor. We found that in the absence of CB1 receptors, cell proliferation was increased and neuronal differentiation reduced, which could be related to CB1 receptor mediated signaling in Doublecortin (DCX)-expressing intermediate progenitor cells. CB1 affected the stages of adult neurogenesis that involve intermediate highly proliferative progenitor cells and the survival and maturation of new neurons. The pro-neurogenic effects of CBD might explain some of the positive therapeutic features of CBD-based compounds.
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Adenosine is a signalling molecule that modulates cellular activity in the central nervous system and peripheral organs via four G protein-coupled receptors designated A(1), A(2A), A(2B), and A(3). This review surveys the literature on the role of adenosine in auditory function, particularly cochlear function and its protection from oxidative stress. The specific tissue distribution of adenosine receptors in the mammalian cochlea implicates adenosine signalling in sensory transduction and auditory neurotransmission although functional studies have demonstrated that adenosine stimulates cochlear blood flow, but does not alter the resting and sound-evoked auditory potentials. An interest in a potential otoprotective role for adenosine has recently evolved, fuelled by the capacity of A(1) adenosine receptors to prevent cochlear injury caused by acoustic trauma and ototoxic drugs. The balance between A(1) and A(2A) receptors is conceived as critical for cochlear response to oxidative stress, which is an underlying mechanism of the most common inner ear pathologies (e.g. noise-induced and age-related hearing loss, drug ototoxicity). Enzymes involved in adenosine metabolism, adenosine kinase and adenosine deaminase, are also emerging as attractive targets for controlling oxidative stress in the cochlea. Other possible targets include ectonucleotidases that generate adenosine from extracellular ATP, and nucleoside transporters, which regulate adenosine concentrations on both sides of the plasma membrane. Developments of selective adenosine receptor agonists and antagonists that can cross the blood-cochlea barrier are bolstering efforts to develop therapeutic interventions aimed at ameliorating cochlear injury. Manipulations of the adenosine signalling system thus hold significant promise in the therapeutic management of oxidative stress in the cochlea.
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The regenerative capacity of the CNS is extremely limited. The reason for this is unclear, but glial cell involvement has been suspected, and oligodendrocytes have been implicated as inhibitors of neuroregeneration (Chen et al., 2000, GrandPre et al., 2000; Fournier et al., 2001). The role of astrocytes in this process was proposed but remains incompletely understood (Silver and Miller, 2004). Astrocyte activation (reactive gliosis) accompanies neurotrauma, stroke, neurodegenerative diseases, or tumors. Two prominent hallmarks of reactive gliosis are hypertrophy of astrocytic processes and upregulation of intermediate filaments. Using the entorhinal cortex lesion model in mice, we found that reactive astrocytes devoid of the intermediate filament proteins glial fibrillary acidic protein and vimentin (GFAP-/-Vim-/-), and consequently lacking intermediate filaments (Colucci-Guyon et al., 1994; Pekny et al., 1995; Eliasson et al., 1999), showed only a limited hypertrophy of cell processes. Instead, many processes were shorter and not straight, albeit the volume of neuropil reached by a single astrocyte was the same as in wild-type mice. This was accompanied by remarkable synaptic regeneration in the hippocampus. On a molecular level, GFAP-/-Vim-/- reactive astrocytes could not upregulate endothelin B receptors, suggesting that the upregulation is intermediate filament dependent. These findings show a novel role for intermediate filaments in astrocytes and implicate reactive astrocytes as potent inhibitors of neuroregeneration.
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Endocannabinoids exert an important neuromodulatory role via presynaptic cannabinoid CB1 receptors and may also participate in the control of neural cell death and survival. The function of the endocannabinoid system has been extensively studied in differentiated neurons, but its potential role in neural progenitor cells remains to be elucidated. Here we show that the CB1 receptor and the endocannabinoid-inactivating enzyme fatty acid amide hydrolase are expressed, both in vitro and in vivo, in postnatal radial glia (RC2+ cells) and in adult nestin type I (nestin(+)GFAP+) neural progenitor cells. Cell culture experiments show that CB1 receptor activation increases progenitor proliferation and differentiation into astroglial cells in vitro. In vivo analysis evidences that, in postnatal CB1(-/-) mouse brain, progenitor proliferation and astrogliogenesis are impaired. Likewise, in adult CB1-deficient mice, neural progenitor proliferation is decreased but is increased in fatty acid amide hydrolase-deficient mice. In addition, endocannabinoid signaling controls neural progenitor differentiation in the adult brain by promoting astroglial differentiation of newly born cells. These results show a novel physiological role of endocannabinoids, which constitute a new family of signaling cues involved in the regulation of neural progenitor cell function.
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Multipotent neural stem/progenitor cells (NSPCs) can be isolated from many regions of the adult central nervous system (CNS), yet neurogenesis is restricted to the hippocampus and subventricular zone in vivo. Identification of the molecular cues that modulate NSPC fate choice is a prerequisite for their therapeutic applications. Previously, we demonstrated that primary astrocytes isolated from regions with higher neuroplasticity, such as newborn and adult hippocampus and newborn spinal cord, promoted neuronal differentiation of adult NSPCs, whereas astrocytes isolated from the nonneurogenic region of the adult spinal cord inhibited neural differentiation. To identify the factors expressed by these astrocytes that could modulate NSPC differentiation, we performed gene expression profiling analysis using Affymetrix rat genome arrays. Our results demonstrated that these astrocytes had distinct gene expression profiles. We further tested the functional effects of candidate factors that were differentially expressed in neurogenesis-promoting and -inhibiting astrocytes using in vitro NSPC differentiation assays. Our results indicated that two interleukins, IL-1beta and IL-6, and a combination of factors that included these two interleukins could promote NSPC neuronal differentiation, whereas insulin-like growth factor binding protein 6 (IGFBP6) and decorin inhibited neuronal differentiation of adult NSPCs. Our results have provided further evidence to support the ongoing hypothesis that, in adult mammalian brains, astrocytes play critical roles in modulating NSPC differentiation. The finding that cytokines and chemokines expressed by astrocytes could promote NSPC neuronal differentiation may help us to understand how injuries induce neurogenesis in adult brains.
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Cannabinoids, the active components of marijuana and their endogenous counterparts, act on the brain and many other organs through the widely expressed CB1 cannabinoid receptor. In contrast, the CB2 cannabinoid receptor is abundant in the immune system and shows a restricted expression pattern in brain cells. CB2-selective agonists are, therefore, very attractive therapeutic agents as they do not cause CB1-mediated psychoactive effects. CB2 receptor expression in brain has been partially examined in differentiated cells, while its presence and function in neural progenitor cells remain unknown. Here we show that the CB2 receptor is expressed, both in vitro and in vivo, in neural progenitors from late embryonic stages to adult brain. Selective pharmacological activation of the CB2 receptor in vitro promotes neural progenitor cell proliferation and neurosphere generation, an action that is impaired in CB2-deficient cells. Accordingly, in vivo experiments evidence that hippocampal progenitor proliferation is increased by administration of the CB2-selective agonist HU-308. Moreover, impaired progenitor proliferation was observed in CB2-deficient mice both in normal conditions and on kainate-induced excitotoxicity. These findings provide a novel physiological role for the CB2 cannabinoid receptor and open a novel therapeutic avenue for manipulating neural progenitor cell fate.
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Adenosine, a modulator of neuronal function in the mammalian central nervous system, exerts a neuropro- tective effect via the adenosine A1 receptor; however, its effect on neural stem cells (NSCs) remains unclear. Because adenosine is released in response to patho- logical conditions and NSCs play a key role in neurore- generation, we tested the hypothesis that adenosine is capable of stimulating NSC proliferation. We demon- strated that NSCs dominantly express adenosine A1 and A2B receptors. Adenosine and the adenosine A1 re- ceptor agonist cyclopentyladenosine (CPA) increased proliferation of NSCs, and this CPA-induced cell prolif- eration was attenuated by the A1 antagonist 8-cyclo- pentyl-1,3-dipropylxanthine (DPCPA). CPA also induced phosphorylation of extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase/ERK kinase (MEK), and Akt, and their phosphorylation was inhibited by DPCPA. In addition, CPA-induced cell proliferation was inhibited by MEK and Akt inhibitors. These results suggest that activation of adenosine A1 receptor-stimu- lated proliferation of NSCs occurs via MEK/ERK and Akt signaling pathways. V V C 2008 Wiley-Liss, Inc.
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Background and purpose: The non-psychotropic cannabinoid cannabichromene is known to activate the transient receptor potential ankyrin-type1 (TRPA1) and to inhibit endocannabinoid inactivation, both of which are involved in inflammatory processes. We examined here the effects of this phytocannabinoid on peritoneal macrophages and its efficacy in an experimental model of colitis. Experimental approach: Murine peritoneal macrophages were activated in vitro by LPS. Nitrite levels were measured using a fluorescent assay; inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2) and cannabinoid (CB1 and CB2 ) receptors were analysed by RT-PCR (and/or Western blot analysis); colitis was induced by dinitrobenzene sulphonic acid (DNBS). Endocannabinoid (anandamide and 2-arachidonoylglycerol), palmitoylethanolamide and oleoylethanolamide levels were measured by liquid chromatography-mass spectrometry. Colonic inflammation was assessed by evaluating the myeloperoxidase activity as well as by histology and immunohistochemistry. Key results: LPS caused a significant production of nitrites, associated to up-regulation of anandamide, iNOS, COX-2, CB1 receptors and down-regulation of CB2 receptors mRNA expression. Cannabichromene significantly reduced LPS-stimulated nitrite levels, and its effect was mimicked by cannabinoid receptor and TRPA1 agonists (carvacrol and cinnamaldehyde) and enhanced by CB1 receptor antagonists. LPS-induced anandamide, iNOS, COX-2 and cannabinoid receptor changes were not significantly modified by cannabichromene, which, however, increased oleoylethanolamide levels. In vivo, cannabichromene ameliorated DNBS-induced colonic inflammation, as revealed by histology, immunohistochemistry and myeloperoxidase activity. Conclusion and implications: Cannabichromene exerts anti-inflammatory actions in activated macrophages - with tonic CB1 cannabinoid signalling being negatively coupled to this effect - and ameliorates experimental murine colitis.
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Background and purpose: Cannabis extracts and several cannabinoids have been shown to exert broad anti-inflammatory activities in experimental models of inflammatory CNS degenerative diseases. Clinical use of many cannabinoids is limited by their psychotropic effects. However, phytocannabinoids like cannabidiol (CBD), devoid of psychoactive activity, are, potentially, safe and effective alternatives for alleviating neuroinflammation and neurodegeneration. Experimental approach: We used experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice, as a model of multiple sclerosis. Using immunocytochemistry and cell proliferation assays we evaluated the effects of CBD on microglial activation in MOG-immunized animals and on MOG-specific T-cell proliferation. Key results: Treatment with CBD during disease onset ameliorated the severity of the clinical signs of EAE. This effect of CBD was accompanied by diminished axonal damage and inflammation as well as microglial activation and T-cell recruitment in the spinal cord of MOG-injected mice. Moreover, CBD inhibited MOG-induced T-cell proliferation in vitro at both low and high concentrations of the myelin antigen. This effect was not mediated via the known cannabinoid CB(1) and CB(2) receptors. Conclusions and implications: CBD, a non-psychoactive cannabinoid, ameliorates clinical signs of EAE in mice, immunized against MOG. Suppression of microglial activity and T-cell proliferation by CBD appeared to contribute to these beneficial effects.
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There has been tremendous progress in understanding neural stem cell (NSC) biology, with genetic and cell biological methods identifying sequential gene expression and molecular interactions guiding NSC specification into distinct neuronal and glial populations during development. Data has emerged on the possible exploitation of NSC-based strategies to repair adult diseased brain. However, despite increased information on lineage specific transcription factors, cell-cycle regulators and epigenetic factors involved in the fate and plasticity of NSCs, understanding of extracellular cues driving the behavior of embryonic and adult NSCs is still very limited. Knowledge of factors regulating brain development is crucial in understanding the pathogenetic mechanisms of brain dysfunction. Since injury-activated repair mechanisms in adult brain often recapitulate ontogenetic events, the identification of these players will also reveal novel regenerative strategies. Here, we highlight the purinergic system as a key emerging player in the endogenous control of NSCs. Purinergic signalling molecules (ATP, UTP and adenosine) act with growth factors in regulating the synchronized proliferation, migration, differentiation and death of NSCs during brain and spinal cord development. At early stages of development, transient and time-specific release of ATP is critical for initiating eye formation; once anatomical CNS structures are defined, purinergic molecules participate in calcium-dependent neuron-glia communication controlling NSC behaviour. When development is complete, some purinergic mechanisms are silenced, but can be re-activated in adult brain after injury, suggesting a role in regeneration and self-repair. Targeting the purinergic system to develop new strategies for neurodevelopmental disorders and neurodegenerative diseases will be also discussed.
Article
Cannabichromene (CBC) is a major non-psychotropic phytocannabinoid that inhibits endocannabinoid inactivation and activates the transient receptor potential ankyrin-1 (TRPA1). Both endocannabinoids and TRPA1 may modulate gastrointestinal motility. Here, we investigated the effect of CBC on mouse intestinal motility in physiological and pathological states. Inflammation was induced in the mouse small intestine by croton oil. Endocannabinoid (anandamide and 2-arachidonoyl glycerol), palmitoylethanolamide and oleoylethanolamide levels were measured by liquid chromatography-mass spectrometry; TRPA1 and cannabinoid receptors were analysed by quantitative RT-PCR; upper gastrointestinal transit, colonic propulsion and whole gut transit were evaluated in vivo; contractility was evaluated in vitro by stimulating the isolated ileum, in an organ bath, with ACh or electrical field stimulation (EFS). Croton oil administration was associated with decreased levels of anandamide (but not 2-arachidonoyl glycerol) and palmitoylethanolamide, up-regulation of TRPA1 and CB₁ receptors and down-regulation of CB₂ receptors. Ex vivo CBC did not change endocannabinoid levels, but it altered the mRNA expression of TRPA1 and cannabinoid receptors. In vivo, CBC did not affect motility in control mice, but normalized croton oil-induced hypermotility. In vitro, CBC reduced preferentially EFS- versus ACh-induced contractions. Both in vitro and in vivo, the inhibitory effect of CBC was not modified by cannabinoid or TRPA1 receptor antagonists. CBC selectively reduces inflammation-induced hypermotility in vivo in a manner that is not dependent on cannabinoid receptors or TRPA1.
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Powerful software for statistical analysis is expensive. Here I present BrightStat, a statistical software running on the Internet which is free of charge. BrightStat's goals, its main capabilities and functionalities are outlined. Three different sample runs, a Friedman test, a chi-square test, and a step-wise multiple regression are presented. The results obtained by BrightStat are compared with results computed by SPSS, one of the global leader in providing statistical software, and VassarStats, a collection of scripts for data analysis running on the Internet. Elementary statistics is an inherent part of academic education and BrightStat is an alternative to commercial products.
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Adult neurogenesis, a process of generating functional neurons from adult neural precursors, occurs throughout life in restricted brain regions in mammals. The past decade has witnessed tremendous progress in addressing questions related to almost every aspect of adult neurogenesis in the mammalian brain. Here we review major advances in our understanding of adult mammalian neurogenesis in the dentate gyrus of the hippocampus and from the subventricular zone of the lateral ventricle, the rostral migratory stream to the olfactory bulb. We highlight emerging principles that have significant implications for stem cell biology, developmental neurobiology, neural plasticity, and disease mechanisms. We also discuss remaining questions related to adult neural stem cells and their niches, underlying regulatory mechanisms, and potential functions of newborn neurons in the adult brain. Building upon the recent progress and aided by new technologies, the adult neurogenesis field is poised to leap forward in the next decade.
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Astrocyte-like cells, which act as stem cells in the adult brain, reside in a few restricted stem cell niches. However, following brain injury, glia outside these niches acquire or reactivate stem cell potential as part of reactive gliosis. Recent studies have begun to uncover the molecular pathways involved in this process. A comparison of molecular pathways activated after injury with those involved in the normal neural stem cell niches highlights strategies that could overcome the inhibition of neurogenesis outside the stem cell niche and instruct parenchymal glia towards a neurogenic fate. This new view on reactive glia therefore suggests a widespread endogenous source of cells with stem cell potential, which might potentially be harnessed for local repair strategies.
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Cannabidiol (CBD) and Δ(9) -tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system. The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested. CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors. These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts.
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Anaphylatoxin C3a is a third complement component (C3)-derived peptide, the multiple functions of which range from stimulation of inflammation to neuroprotection. In a previous study, we have shown that signaling through C3a receptor positively regulates in vivo neurogenesis in adult mouse brain. Here, we studied the direct effects of C3a on adult mouse whole brain-derived neural progenitor cells (NPCs) in vitro. Our results demonstrate that NPCs bind C3a in a specific and reversible manner and that C3a stimulates neuronal differentiation of NPCs. Furthermore, C3a stimulated the migration of NPCs induced by low concentrations of stromal cell-derived factor (SDF)-1α, whereas it inhibited NPC migration at high concentration of SDF-1α. In the same manner, C3a modulated SDF-1α-induced extracellular-signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation in these cells. In addition, C3a had inhibitory effect on SDF-1α-induced neuronal differentiation of NPCs. These data show that C3a modulates SDF-1α-induced differentiation and migration of these cells, conceivably through the regulation of ERK1/2 phosphorylation. Our results provide the first evidence that C3a regulates neurogenesis by directly affecting the fate and properties of NPCs. Disclosure of potential conflicts of interest is found at the end of this article.
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Neural stem cells (NSCs) are in a complex niche in which cell-extrinsic cues and cell-intrinsic genetic mechanisms in chorus mediate their cellular processes such as self-renewal and differentiation. In this study, we found that inactivation of Erk1/2 with U0126 in NSCs significantly promoted neuronal differentiation and inhibited proliferation. Sustained Erk1/2 inactivity was required in this process. We also found that nerve growth factor (NGF) and collagen could promote the proliferation and inhibit neuronal differentiation by activating phosphorylation of Erk1/2. Cell-cycle regulators such as cyclin-dependent kinase 2 (Cdk2), Cyclin D1 and Hes1 mediated the effect of Erk on NSCs proliferation and differentiation. Our results showed that Erk1/2 played an important role in the interplay between cell-extrinsic cues and cell-intrinsic genetic mechanisms in neural stem cell biology.
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Until recently, the neuroscience community held the belief that glial cells such as astrocytes and oligodendrocytes functioned solely as "support" cells of the brain. In this role, glial cells simply provide physical support and housekeeping functions for the more important cells of the brain, the neurons. However, this view has changed radically in recent years with the discovery of previously unrecognized and surprising functions for this underappreciated cell type. In the past decade or so, emerging evidence has provided new insights into novel glial cell activities such as control of synapse formation and function, communication,cerebrovascular tone regulation, immune regulation and adult neurogenesis. Such advances in knowledge have effectively elevated the role of the astrocyte to one that is more important than previously realized. This review summarizes the past and present knowledge of glial cell functions that has evolved over the years, and has resulted in a new appreciation of astrocytes and their value in studying the neurobiology of human brain cells and their functions. In this review, we highlight recent advances in the role of glial cells in physiology, pathophysiology and, most importantly, in adult neurogenesis and "stemness", with special emphasis on astrocytes.
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It was not known if Cannabichromene (CBC), which is a major constituent of drug types of , has anti-inflammatory properties as do other cannabinoids. CBC was tested using the rat paw edema test and using the erythrocyte membrane stabilization assay. CBC was as effective as phenylbutazone (PBZ) at equivalent doses. Since CBC is less toxic than PBZ, larger doses may be given to produce a greater therapeutic effect.
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Adult neurogenesis from neural stem/progenitor cells occurs in discrete regions of the central nervous system of all mammals, but the mechanisms regulating endogenous neurogenesis are poorly understood. Advances in understanding the neurogenesis depend on knowing their intrinsic properties and responses to environmental signals that control their behavior. Before these issues can be addressed, it is necessary to know whether there are significant species-specific differences in the properties of the stem/progenitor cells derived from CNS of two commonly studied model systems, mouse and rat. We found major differences between rat and mouse stem/progenitor cell proliferation in response to various substrates, mitogenic growth factors and heparin and to the influence of differentiation factors on generation of neurons and glia. Thus, extrapolation of cell properties from one species to another based on studies of these cells should be made with caution.
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Neurospheres are clonal cellular aggregates of neural stem/precursor cells that grow in culture as free-floating clusters. Activation of CB1 cannabinoid receptors, which are expressed by these cells, promotes proliferation. In the present study we investigated the expression of CB2 cannabinoid receptors and the effect of exogenous cannabinoids on neural stem/precursor cell proliferation. Neurospheres containing nestin-positive and sn-1 diacylglycerol lipase alpha-positive cells expressed both CB1 and CB2 receptors, which were maintained through several passages. Application of the non-selective cannabinoid agonist (HU-210, 0.5 microM) stimulated bromodeoxyuridine incorporation and neurosphere formation. This action involved both CB1 and CB2 receptors as neurosphere formation was stimulated by either selective CB1 [arachidonyl-2'chloroethylamide/(all Z)-N-(2-cycloethyl)-5,8,11,14-eicosatetraenamide (ACEA), 200 nM and 1 microM] or CB2 (JWH-056, 0.5 microM) agonists. In addition, CB1 or CB2 antagonists (1 microM SR-141716A and SR-144528, respectively) blocked basal proliferation, suggesting that endogenous cannabinoids are implicated in neurosphere proliferation. In addition, cannabinoid agonist-stimulated proliferation was reduced by the Akt translocation inhibitor BML-257 (12.5 microM), suggesting a role for phosphoinositide-3 kinase signalling. Together, our results suggest that cannabinoids stimulate proliferation of neural stem/precursor cells acting on both CB1 and CB2 cannabinoid receptors through a phosphoinositide-3 kinase/Akt pathway.
Article
It is now widely accepted that neurogenesis occurs in two regions of the adult mammalian brain--the hippocampus and the olfactory bulb. There is evidence for adult neurogenesis in several additional areas, including the neocortex, striatum, amygdala and substantia nigra, but this has been difficult to replicate consistently other than in the damaged brain. The discrepancies may be due to variations in the sensitivity of the methods used to detect new neurons.
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Adenosine is an endogenous neuromodulator, acting on four distinctive G-protein-coupled receptors, the A1, A2A, A2B and A3 adenosine receptors. Increased neuronal activity and, hypoxia or ischemia, result in elevated levels of adenosine reflecting changes of the metabolic state. This increases activation of the adenosine receptors. It is well appreciated that adenosine has a neuroprotective role in brain injuries. Although adenosine effects have been explained mainly by actions on nerve cells, modulation of glial functions by adenosine is likely to be important as discussed in this minireview. Thus, in astrocytes adenosine receptors modulate inter alia glycogen metabolism, glutamate transporters, astrogliosis and astrocyte swelling. Microglial cells appear to be important in regulating adenosine formation from ATP and adenosine can affect many microglial signaling pathways. Adenosine receptors on oligodendrocytes regulate white matter development.
Complementderived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells in vitro
  • N Shinjyo
  • A Ståhlberg
  • M Dragonow
  • M Pekny
  • M Pekna
Shinjyo, N., Ståhlberg, A., Dragonow, M., Pekny, M., Pekna, M., 2009. Complementderived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells in vitro. Stem Cells 27, 2824-2832.