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Cannabinoids and endocannabinoids as therapeutics for nervous system disorders: preclinical models and clinical studies

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Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body. They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases. Some of these include central nervous system (CNS) diseases and dysfunctions such as forms of epilepsy, multiple sclerosis, Parkinson’s disease, pain and neuropsychiatric disorders. In addition, the endogenously produced cannabinoid lipids, endocannabinoids, are critical for normal CNS function, and if controlled or modified, may represent an additional therapeutic avenue for CNS diseases. This review discusses in vitro cellular, ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies. In addition, the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases. Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.

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Targeting Trauma-Induced Endocannabinoid System Dysfunction: A Novel Neuroprotective Approach For Traumatic Brain Injury

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Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. The primary injury results in neuronal damage and initiates secondary injuries like neuroinflammation, excitotoxicity, oxidative stress and blood-brain barrier disruption. This results in long-term cognitive, behavioral and motor deficits. Existing therapeutic options for TBI focus on symptomatic management rather than directly addressing the cellular processes that drive secondary damage. Novel neuroprotective therapies are urgently needed. The endocannabinoid system (ECS) is a promising therapeutic target for TBI. The ECS comprises the endocannabinoids anandamide and 2-AG, cannabinoid receptors CB1 and CB2, and metabolic enzymes like fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). It is involved in synaptic function, neuroinflammation, excitotoxicity, blood-brain barrier disruption, oxidative stress and neuronal loss. Modulation the ECS through receptor agonists/antagonists, inhibitors of endocannabinoid catabolism, or combination approaches represents a novel neuroprotective strategy in TBI.

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Hippocampal differential expression underlying the neuroprotective effect of delta-9-tetrahydrocannabinol microdose on old mice

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Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound of the cannabis plant and an exogenous ligand of the endocannabinoid system. In previous studies, we demonstrated that a single microdose of THC (0.002 mg/kg, 3–4 orders of magnitude lower than the standard dose for rodents) exerts distinct, long-term neuroprotection in model mice subjected to acute neurological insults. When administered to old, healthy mice, the THC microdose induced remarkable long-lasting (weeks) improvement in a wide range of cognitive functions, including significant morphological and biochemical brain alterations. To elucidate the mechanisms underlying these effects, we analyzed the gene expression of hippocampal samples from the model mice. Samples taken 5 days after THC treatment showed significant differential expression of genes associated with neurogenesis and brain development. In samples taken 5 weeks after treatment, the transcriptional signature was shifted to that of neuronal differentiation and survival. This study demonstrated the use of hippocampal transcriptome profiling in uncovering the molecular basis of the atypical, anti-aging effects of THC microdose treatment in old mice.

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Hippocampal differential expression underlying the neuroprotective effect of delta-9-tetrahydrocannabinol microdose on old mice

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Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound of the cannabis plant and an exogenous ligand of the endocannabinoid system. In previous studies, we demonstrated that a single microdose of THC (0.002 mg/kg, 3–4 orders of magnitude lower than the standard dose for rodents) exerts distinct, long-term neuroprotection in model mice subjected to acute neurological insults. When administered to old, healthy mice, the THC microdose induced remarkable long-lasting (weeks) improvement in a wide range of cognitive functions, including significant morphological and biochemical brain alterations. To elucidate the mechanisms underlying these effects, we analyzed the gene expression of hippocampal samples from the model mice. Samples taken 5 days after THC treatment showed significant differential expression of genes associated with neurogenesis and brain development. In samples taken 5 weeks after treatment, the transcriptional signature was shifted to that of neuronal differentiation and survival. This study demonstrated the use of hippocampal transcriptome profiling in uncovering the molecular basis of the atypical, anti-aging effects of THC microdose treatment in old mice.

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Hippocampal differential expression underlying the neuroprotective effect of delta-9-tetrahydrocannabinol microdose on old mice

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Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound of the cannabis plant and an exogenous ligand of the endocannabinoid system. In previous studies, we demonstrated that a single microdose of THC (0.002 mg/kg, 3–4 orders of magnitude lower than the standard dose for rodents) exerts distinct, long-term neuroprotection in model mice subjected to acute neurological insults. When administered to old, healthy mice, the THC microdose induced remarkable long-lasting (weeks) improvement in a wide range of cognitive functions, including significant morphological and biochemical brain alterations. To elucidate the mechanisms underlying these effects, we analyzed the gene expression of hippocampal samples from the model mice. Samples taken 5 days after THC treatment showed significant differential expression of genes associated with neurogenesis and brain development. In samples taken 5 weeks after treatment, the transcriptional signature was shifted to that of neuronal differentiation and survival. This study demonstrated the use of hippocampal transcriptome profiling in uncovering the molecular basis of the atypical, anti-aging effects of THC microdose treatment in old mice.

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Cannabidiol’s neuroprotective properties and potential treatment of traumatic brain injuries

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Cannabidiol (CBD) has numerous pharmacological targets that initiate anti-inflammatory, antioxidative, and antiepileptic properties. These neuroprotective benefits have generated interest in CBD’s therapeutic potential against the secondary injury cascade from traumatic brain injury (TBI). There are currently no effective broad treatment strategies for combating the damaging mechanisms that follow the primary injury and lead to lasting neurological consequences or death. However, CBD’s effects on different neurotransmitter systems, the blood brain barrier, oxidative stress mechanisms, and the inflammatory response provides mechanistic support for CBD’s clinical utility in TBI. This review describes the cascades of damage caused by TBI and CBD’s neuroprotective mechanisms to counter them. We also present challenges in the clinical treatment of TBI and discuss important future clinical research directions for integrating CBD in treatment protocols. The mechanistic evidence provided by pre-clinical research shows great potential for CBD as a much-needed improvement in the clinical treatment of TBI. Upcoming clinical trials sponsored by major professional sport leagues are the first attempts to test the efficacy of CBD in head injury treatment protocols and highlight the need for further clinical research.

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Cannabis sativa and Cannabidiol: A Therapeutic Strategy for the Treatment of Neurodegenerative Diseases?

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This work is a literature review, presenting the current state of the use of cannabinoids on neurodegenerative diseases. The emphasis is on Parkinson’s (PD) and Alzheimer’s (AD) diseases, the two most prevalent neurological diseases. The review goes from Cannabis sativa and its hundreds of bioactive compounds to Δ9-tetrahydrocannabinol (THC) and mainly cannabidiol (CBD) and their interactions with the endocannabinoid receptors (CB1 and CB2).

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Pharmacological management of cancer pain: Novel therapeutics

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Patients diagnosed with cancer often experience pain during their treatment course, making it difficult to care for themselves and continue with their activities of daily living. When cancer is found at later stages, the pain can become severe and constant; reducing their quality of life and significantly affecting mental and physical well-being. Despite opioids being known to provide adequate analgesia for higher pain levels, they are often the reason for under-dosing because of their adverse effects and concern for addiction. There are also patients who do not respond well to opioids because of genetic anomalies or personal preference. Therefore, there is a need for novel non-opioid cancer pain treatments. There are many new cancer pain treatments that are emerging. This manuscript discusses cancer pain, risk factors, epidemiology, guidelines for the treatment of cancer pain, personalization of cancer pain therapy, breakthrough pain, cancer-induced peripheral neuropathy, established cancer pain treatment options, and novel emerging cancer pain treatment options.

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Intracellular Molecular Targets and Signaling Pathways Involved in Antioxidative and Neuroprotective Effects of Cannabinoids in Neurodegenerative Conditions

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In the last few decades, endocannabinoids, plant-derived cannabinoids and synthetic can- nabinoids have received growing interest as treatment options in neurodegenerative conditions. In various experimental settings, they have displayed antioxidative, anti-inflammatory, antiapoptotic, immunomodulatory, and neuroprotective effects. However, due to numerous targets and down- stream effectors of their action, the cellular and molecular mechanisms underlying these effects are rather complex and still under discussion.

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Cannflavins – From plant to patient: A scoping review

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Authors: Simon Erridge, Nagina Mangal, Oliver Salazar, Barbara Pacchetti, Mikael H.Sodergren Published in Fitoterapia October 2020 Abstract Introduction Cannflavins are a group of prenylflavonoids derived from Cannabis sativa L.. Cannflavin…

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Cannabis Therapeutics and the Future of Neurology

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Author: Ethan B. Russo Published in: Frontiers in Integrative Neuroscience  October 2018 Abstract Introduction: Cannabis burst across the Western medicine horizon after its introduction by William O’Shaughnessy in 1838 (O’Shaughnessy, 1838–1840;…

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The Endocannabinoid System as a Therapeutic Target in Glaucoma

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Author: Elizabeth A. Cairns,1 William H. Baldridge,2,3 and Melanie E. M. Kelly Published in Hindawi January 2016 Abstract Glaucoma is an irreversible blinding eye disease which produces progressive retinal ganglion cell…

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