CB2R activation ameliorates late adolescent chronic alcohol exposure-induced anxiety-like behaviors during withdrawal by preventing morphological changes and suppressing NLRP3 inflammasome activation in prefrontal cortex microglia in mice

Brain Behavior and Immunity, Год журнала: 2023, Номер 110, С. 60 - 79

Опубликована: Фев. 6, 2023

Chronic alcohol exposure (CAE) during late adolescence increases the risk of anxiety development. Alcohol-induced prefrontal cortex (PFC) microglial activation, characterized by morphological changes and increased associations with neurons, plays a critical role in pathogenesis anxiety. Alcohol NLRP3 inflammasome expression, increasing cytokine secretion activated microglia. Cannabinoid type 2 receptor (CB2R), an essential endocannabinoid system, regulates activation neuroinflammatory reactions. We aimed to investigate CB2R ameliorating adolescent CAE-induced anxiety-like behaviors C57BL/6J mice.Six-week-old mice were acclimated for 7 days then administered gavage (4 g/kg, 25 % w/v) 28 days. The intraperitoneally injected specific agonist AM1241 1 h before treatment. Anxiety-like withdrawal assessed open field test elevated plus maze 24 after last administration. Microglial microglia-neuron interactions, inflammasome-related molecule expression PFC measured using immunofluorescence, immunohistochemical, qPCR, Western blotting assays. morphology was evaluated Sholl analysis cell body-to-total size index. Additionally, N9 microglia LPS vitro, effects on investigated.After CAE, exhibited severe withdrawal. CAE induced obvious associations, markers, CB2R, molecules PFC. Microglia also showed marked filament retraction reduction body enlargement CAE. treatment ameliorated model mice, it prevented changes, reduced marker suppressed proinflammatory LPS-induced increase molecules, IL-1β release, M1 phenotype markers (iNOS CD86) cell, which reversed antagonist treatment.CAE caused at least partly inducing these preventing suppressing

Язык: Английский

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A critical review of the relationship between dietary components, the gut microbeAkkermansia muciniphila, and human health

Critical Reviews in Food Science and Nutrition, Год журнала: 2019, Номер 60(13), С. 2265 - 2276

Опубликована: Июль 1, 2019

The human gut contains trillions of microorganisms with a great diversity that are associated various health benefits. Recent studies have reported an increasing correlation between diet, microbiota, and health, indicating rapid development in the field health. Diet is important factor determines microbiota composition. comprises diversities microbes involved immune modulation other functions. In particular, Akkermansia muciniphila mucin-degrading bacterium believed to several benefits humans. Several evaluated prebiotic effects dietary components on A. their association ailments, such as diabetes mellitus, atherosclerosis, cancer. Hence, this review aims provide plausible mechanistic basis for interactions components, therapeutic interaction illnesses.

Язык: Английский

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Molecular Pathophysiological Mechanisms in Huntington’s Disease

Biomedicines, Год журнала: 2022, Номер 10(6), С. 1432 - 1432

Опубликована: Июнь 17, 2022

Huntington's disease is an inherited neurodegenerative described 150 years ago by George Huntington. The genetic defect was identified in 1993 to be expanded CAG repeat on exon 1 of the huntingtin gene located chromosome 4. In following almost 30 years, a considerable amount research, using mainly animal models or vitro experiments, has tried unravel complex molecular cascades through which transcription mutant protein leads neuronal loss, especially medium spiny neurons striatum, and excitotoxicity, transcriptional dysregulation, mitochondrial dysfunction, oxidative stress, impaired proteostasis, altered axonal trafficking reduced availability trophic factors crucial contributors. This review discusses pathogenic literature demise. However, due ubiquitous presence huntingtin, astrocytes are also dysfunctional, neuroinflammation may additionally contribute pathology. quest for therapies delay onset reduce rate progression ongoing, but based findings from basic research.

Язык: Английский

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The Dynamic Role of Microglia and the Endocannabinoid System in Neuroinflammation

Frontiers in Pharmacology, Год журнала: 2022, Номер 12

Опубликована: Фев. 4, 2022

Microglia, the resident immune cells of brain, can take on a range pro- or anti-inflammatory phenotypes to maintain homeostasis. However, sustained activation pro-inflammatory microglia lead state chronic neuroinflammation characterized by high concentrations neurotoxic soluble factors throughout brain. In healthy brains, inflammatory processes cease and transition an phenotype, but failure halt is characteristic many neurological disorders. The endocannabinoid system has been identified as promising therapeutic target for there evidence that synthetic endogenously produced cannabinoids temper response may encourage switch phenotype. Activation cannabinoid type 2 (CB2) receptors proposed mechanism action responsible these effects. abundance components in also change dynamically several brain pathologies. This impact ability synthesize degrade endocannabinoids react endogenous exogenous cannabinoids. Cannabinoid participate formation receptor heteromers which influences their function specifically express both receptors, such microglia. creates opportunities drug-drug interactions between CB2 receptor-targeted therapies other classes drugs. this article, we review roles development resolution neuroinflammation. We discuss fluctuations observed examine potential context.

Язык: Английский

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

Antioxidants, Год журнала: 2022, Номер 11(10), С. 2049 - 2049

Опубликована: Окт. 18, 2022

In the last few decades, endocannabinoids, plant-derived cannabinoids and synthetic have received growing interest as treatment options in neurodegenerative conditions. various experimental settings, they displayed antioxidative, anti-inflammatory, antiapoptotic, immunomodulatory, neuroprotective effects. However, due to numerous targets downstream effectors of their action, cellular molecular mechanisms underlying these effects are rather complex still under discussion. Cannabinoids able neutralize free radicals modulate production reactive oxygen species activity antioxidative systems acting on CB1 CB2 cannabinoid receptors. The activation receptors stimulates signaling pathways involved defense survival (such phosphoinositide 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), Nrf2 pathways) regulates glutamatergic signaling, N-methyl-D-aspartate (NMDA) receptors, calcium influx, induction Ca2+-regulated cascades, whereas mediated by suppression microglial release prooxidative proinflammatory mediators. This review summarizes main new advances understanding cannabinoids. Because plethora possible pharmacological interventions related oxidative stress cannabinoid-mediated neuroprotection, future research should be directed towards a better interplay between activated signal transduction with aim improve efficacy targeting endocannabinoid system.

Язык: Английский

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CB2 receptor in the CNS: From immune and neuronal modulation to behavior

Neuroscience & Biobehavioral Reviews, Год журнала: 2023, Номер 150, С. 105226 - 105226

Опубликована: Май 8, 2023

Язык: Английский

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Scientific Validation of Cannabidiol for Management of Dog and Cat Diseases

Annual Review of Animal Biosciences, Год журнала: 2023, Номер 11(1), С. 227 - 246

Опубликована: Фев. 15, 2023

Cannabidiol (CBD) is a non-psychotropic phytocannabinoid of the plant Cannabis sativa L. CBD increasingly being explored as an alternative to conventional therapies treat health disorders in dogs and cats. Mechanisms action have been investigated mostly rodents vitro include modulation CB1, CB2, 5-HT, GPR, opioid receptors. In companion animals, appears good bioavailability safety profile with few side effects at physiological doses. Some dog studies found improve clinical signs associated osteoarthritis, pruritus, epilepsy. However, further are needed conclude therapeutic for each these conditions, well decreasing anxiety aggression Herein, we summarize available scientific evidence mechanisms CBD, including pharmacokinetics, safety, regulation, efficacy ameliorating various conditions

Язык: Английский

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Interplay among Oxidative Stress, Autophagy, and the Endocannabinoid System in Neurodegenerative Diseases: Role of the Nrf2- p62/SQSTM1 Pathway and Nutraceutical Activation

Current Issues in Molecular Biology, Год журнала: 2024, Номер 46(7), С. 6868 - 6884

Опубликована: Июль 2, 2024

The onset of neurodegenerative diseases involves a complex interplay pathological mechanisms, including protein aggregation, oxidative stress, and impaired autophagy. This review focuses on the intricate connection between stress autophagy in disorders, highlighting as pivotal disease pathogenesis. Reactive oxygen species (ROS) play dual roles cellular homeostasis regulation, with disruptions redox signaling contributing to neurodegeneration. activation Nrf2 pathway represents critical antioxidant mechanism, while maintains by degrading altered cell components. interaction among p62/SQSTM1, Nrf2, Keap1 forms regulatory essential for response, whose dysregulation leads aggregate accumulation. Targeting Nrf2-p62/SQSTM1 holds promise therapeutic intervention, mitigating preserving functions. Additionally, this explores potential synergy endocannabinoid system neuroprotection. Further research is needed elucidate involved molecular mechanisms develop effective strategies against

Язык: Английский

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Microglia and BDNF at the crossroads of stressor related disorders: Towards a unique trophic phenotype

Neuroscience & Biobehavioral Reviews, Год журнала: 2021, Номер 131, С. 135 - 163

Опубликована: Сен. 16, 2021

Stressors ranging from psychogenic/social to neurogenic/injury systemic/microbial can impact microglial inflammatory processes, but less is known regarding their effects on trophic properties of microglia. Recent studies do suggest that microglia modulate neuronal plasticity, possibly through brain derived neurotrophic factor (BDNF). This particularly important given the link between BDNF and neuropsychiatric neurodegenerative pathology. We posit certain activated states play a role in maintaining delicate balance release onto synapses. focused review will address how different "activators" influence expression question tropomyosin receptor kinase B (TrkB) then assess sex-based differences function expression, are involved stress response related disorders such as depression. Drawing research variety other disorders, we highlight challenges opportunities for modulators shift "trophic" phenotype with view potential therapeutics relevant stressor-related disorders.

Язык: Английский

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Cannabinoid CB2 Receptors Modulate Microglia Function and Amyloid Dynamics in a Mouse Model of Alzheimer’s Disease

Frontiers in Pharmacology, Год журнала: 2022, Номер 13

Опубликована: Апрель 27, 2022

The distribution and roles of the cannabinoid CB2 receptor in CNS are still a matter debate. Recent data suggest that, addition to its presence microglial cells, may be also expressed at low levels, yet biologically relevant, other cell types such as neurons. It is accepted that expression receptors under physiological conditions significantly elevated chronic neuroinflammatory states associated with neurodegenerative diseases Alzheimer's disease. By using novel mouse model (CB2EGFP/f/f), we studied 5xFAD disease (by generating 5xFAD/CB2EGFP/f/f mice) explored function. We used selective brain penetrant agonist (RO6866945) well mice lacking (5xFAD/CB2-/-) for these studies. found dystrophic neurite-associated microglia their modulation modifies number activity cells metabolism insoluble form amyloid peptide. These results support potential targets development amyloid-modulating therapies.

Язык: Английский

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