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Paclitaxel-Associated Mechanical Sensitivity and Neuroinflammation Are Sex-, Time-, and Site-Specific and Prevented through Cannabigerol Administration in C57Bl/6 Mice

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Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients. One identified mechanism underlying CIPN is neuroinflammation. Most of this research has been conducted in only male or female rodent models, making direct comparisons regarding the role of sex differences in the neuroimmune underpinnings of CIPN limited. Moreover, most measurements have focused on the dorsal root ganglia (DRG) and/or spinal cord, while relatively few studies have been aimed at characterizing neuroinflammation in the brain, for example the periaqueductal grey (PAG). The overall goals of the present study were to determine (1) paclitaxel-associated changes in markers of inflammation in the PAG and DRG in male and female C57Bl6 mice and (2) determine the effect of prophylactic administration of an anti- inflammatory cannabinoid, cannabigerol (CBG).

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Identification of Anti-Neuroinflammatory Bioactive Compounds in Essential Oils and Aqueous Distillation Residues Obtained from Commercial Varieties of Cannabis sativa L.

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Neuroinflammation, which is mainly triggered by microglia, is a key contributor to multiple neurodegenerative diseases. Natural products, and in particular Cannabis sativa L., due to its richness in phytochemical components, represent ideal candidates to counteract neuroinflammation. We previously characterized different C. sativa commercial varieties which showed significantly different chemical profiles. On these bases, the aim of this study was to evaluate essential oils and aqueous distillation residues from the inflorescences of three different hemp varieties for their anti-neuroinflammatory activity in BV-2 microglial cells. Cells were pretreated with aqueous residues or essential oils and then activated with LPS. Unlike essential oils, aqueous residues showed negligible effects in terms of anti-inflammatory activity. Among the essential oils, the one obtained from ‘Gorilla Glue’ was the most effective in inhibiting pro-inflammatory mediators and in upregulating anti-inflammatory ones through the modulation of the p38 MAPK/NF-κB pathway. Moreover, the sesquiterpenes (E)-caryophyllene, α-humulene, and caryophyllene oxide were identified as the main contributors to the essential oils’ anti-inflammatory activity. To our knowledge, the anti-neuroinflammatory activity of α-humulene has not been previously described. In conclusion, our work shows that C. sativa essential oils characterized by high levels of sesquiterpenes can be promising candidates in the prevention/counteraction of neuroinflammation.

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Neuroinflammation and status epilepticus: a narrative review unraveling a complex interplay

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Status epilepticus (SE) is a medical emergency resulting from the failure of the mechanisms involved in seizure termination or from the initiation of pathways involved in abnormally prolonged seizures, potentially leading to long-term consequences, including neuronal death and impaired neuronal networks. It can eventually evolve to refractory status epilepticus (RSE), in which the administration of a benzodiazepine and another anti-seizure medications (ASMs) had been ineffective, and super-refractory status epilepticus (SRSE), which persists for more than 24 h after the administration of general anesthesia. Objective of the present review is to highlight the link between inflammation and SE. Several preclinical and clinical studies have shown that neuroinflammation can contribute to seizure onset and recurrence by increasing neuronal excitability. Notably, microglia and astrocytes can promote neuroinflammation and seizure susceptibility. In fact, inflammatory mediators released by glial cells might enhance neuronal excitation and cause drug resistance and seizure recurrence. Understanding the molecular mechanisms of neuroinflammation could be crucial for improving SE treatment, wich is currently mainly addressed with benzodiazepines and eventually phenytoin, valproic acid, or levetiracetam.

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Neuroinflammation, Its Role in Alzheimer’s Disease and Therapeutic Strategies

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Neuroinflammation precedes the clinical onset of various neurodegenerative diseases, including Alzheimer’s disease (AD), by years or frequently even decades (1–3). In terms of the underlying physiology, there is a great need for understanding and controlling interactions between the central nervous system (CNS) and the immune system in an attempt to develop approaches to prevent or delay the disease’s progression. Nerve cells have limited motion capability, whereas immune cells can migrate freely via circulation. This difference raises a variety of questions in the context of senile plaque formation and phagocytosis. Broad-scale unbiased genomic studies bring several genetic variants such as sialic acid binding Ig-like lectin 3 (CD33), triggering receptor expressed on myeloid cells 2 (TREM2) or complement receptor type 1 (CR1) into the focus of researchers’ attention as potential risk factors for neuroinflammation. In addition, advanced proteomic analyses have been revealing links between these genetic contributors and complex, malfunctioning signaling pathways (including the upregulation of factors like tumor necrosis factor TNF-α, tumor growth factor TGF-β and interleukin IL-1α) that promote proinflammatory mechanisms via intracellular signaling and trafficking, synaptic function, and cell metabolism/proliferation.

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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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Under the umbrella of depression and Alzheimer’s disease physiopathology: can cannabinoids be a dual-pleiotropic therapy?

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Depression and Alzheimer´s disease (AD) are two disorders highly prevalent worldwide. Depression affects more than 300 million people worldwide while AD affects 60% to 80% of the 55 million cases of dementia. Both diseases are affected by aging with high prevalence in elderly and share not only the main brain affected areas but also several physiopathological mechanisms. Depression disease is already ascribed as a risk factor to the development of AD. Despite the wide diversity of pharmacological treatments currently available in clinical practice for depression management, they remain associated to a slow recovery process and to treatment-resistant depression. On the other hand, AD treatment is essentially based in symptomatology relieve. Thus, the need for new multi-target treatments arises.

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Under the umbrella of depression and Alzheimer’s disease physiopathology: can cannabinoids be a dual-pleiotropic therapy?

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Depression and Alzheimer´s disease (AD) are two disorders highly prevalent worldwide. Depression affects more than 300 million people worldwide while AD affects 60% to 80% of the 55 million cases of dementia. Both diseases are affected by aging with high prevalence in elderly and share not only the main brain affected areas but also several physiopathological mechanisms. Depression disease is already ascribed as a risk factor to the development of AD. Despite the wide diversity of pharmacological treatments currently available in clinical practice for depression management, they remain associated to a slow recovery process and to treatment-resistant depression. On the other hand, AD treatment is essentially based in symptomatology relieve. Thus, the need for new multi-target treatments arises.

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Cannabidiol in the acute phase of Febrile Infection-Related Epilepsy Syndrome (FIRES)

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Febrile infection-related epilepsy syndrome (FIRES) is a prolonged refractory status epilepticus (SE) that develops among healthy individuals after a febrile infection.

FIRES treatment is challenging due to its poor response to anti-seizure medications (ASMs) and anesthetic drugs. The use of cannabidiol (CBD) as an adjunctive treatment has been suggested, albeit data about its role in the acute phase is lacking. This report describes the use of purified CBD in the acute phase of two pediatric cases of FIRES and their long-term outcome.

Both children were treated with several ASMs, immunomodulators, anesthetics, and non-pharmacological treatment (ketogenic diet). CBD was administered, as an adjunctive treatment, through nasogastric tube about 30 days after onset. SE resolved within three days of reaching the target dose and both were seizure-free for one year after.

Although it is difficult to define the extent to which each previous therapy contributed to recovery, in both cases CBD therapy was a turning point, reinforcing its potential role as add-on treatment in the acute phase of FIRES.

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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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Mutual Links between the Endocannabinoidome and the Gut Microbiome, with Special Reference to Companion Animals: A Nutritional Viewpoint

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Dysbiosis, which is an imbalance of gut microbial composition and function, can be caused by several external as well as internal factors, contributing to the onset of human and animal disorders, not limited to the gastrointestinal tract. Accordingly, the mechanisms leading to disease development involve a crucial interaction between the gut microbiota, their metabolic products, and the host. The expanded endocannabinoid system, also known as the “endocannabinoidome”, includes endocannabinoids (e.g., anandamide) and endocannabinoid-like mediators (e.g., palmitoylethanolamide), their receptors and metabolic enzymes. Dysregulation of this newly recognized endogenous system is also involved in several diseases. It is becoming increasingly apparent that a link between the endocannabinoidome and the gut microbiome exists. Here, we review some of the latest discoveries related to the functional link between these two complex systems and the disorders emerging from the malfunctioning of such a mutual interaction: for example, idiopathic inflammation, chronic enteropathies, metabolic disease and certain neuroinflammatory disorders. It is expected that in the near future new nutritional tools will emerge based on the expanding knowledge in this cutting-edge field.

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Cannabidiol for neurodegenerative disorders: A comprehensive review

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This review briefly discusses the role of inflammation and oxidative stress in neurodegeneration and demonstrates the neuroprotective effect of cannabidiol, highlighting its general mechanism of action and disease-specific pathways in Parkinson’s disease (PD) and Alzheimer’s disease (AD). Furthermore, we have summarized the preclinical and clinical findings on the therapeutic promise of CBD in PD and AD, shed light on the importance of determining its therapeutic window, and provide insights into identifying promising new research directions.

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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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