scholarly journals Cannabinoid Receptor 2 Alters Social Memory and Microglial Activity in an Age-Dependent Manner

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5984
Author(s):  
Joanna Agnieszka Komorowska-Müller ◽  
Tanushka Rana ◽  
Bolanle Fatimat Olabiyi ◽  
Andreas Zimmer ◽  
Anne-Caroline Schmöle
Keyword(s):  
Cannabinoid Receptor ◽  
Social Memory ◽  
Brain Aging ◽  
Endocannabinoid System ◽  
Immunohistochemical Analysis ◽  
Cellular Level ◽  
Spatial Learning And Memory ◽  
Dependent Manner ◽  
Cannabinoid Receptor 2 ◽  
Age Related

Physiological brain aging is characterized by gradual, substantial changes in cognitive ability, accompanied by chronic activation of the neural immune system. This form of inflammation, termed inflammaging, in the central nervous system is primarily enacted through microglia, the resident immune cells. The endocannabinoid system, and particularly the cannabinoid receptor 2 (CB2R), is a major regulator of the activity of microglia and is upregulated under inflammatory conditions. Here, we elucidated the role of the CB2R in physiological brain aging. We used CB2R−/− mice of progressive ages in a behavioral test battery to assess social and spatial learning and memory. This was followed by detailed immunohistochemical analysis of microglial activity and morphology, and of the expression of pro-inflammatory cytokines in the hippocampus. CB2R deletion decreased social memory in young mice, but did not affect spatial memory. In fact, old CB2R−/− mice had a slightly improved social memory, whereas in WT mice we detected an age-related cognitive decline. On a cellular level, CB2R deletion increased lipofuscin accumulation in microglia, but not in neurons. CB2R−/− microglia showed an increase of activity markers Iba1 and CD68, and minor upregulation in tnfa and il6 expression and downregulation of ccl2 with age. This was accompanied by a change in morphology as CB2R−/− microglia had smaller somas and lower polarity, with increased branching, cell volume, and tree length. We present that CB2Rs are involved in cognition and age-induced microglial activity, but may also be important for microglial activation itself.

scholarly journals Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Ting Zhao ◽  
Shengfan Ye ◽  
Zimu Tang ◽  
Liwei Guo ◽  
Zhipeng Ma ◽  
...  
Keyword(s):  
Replicative Senescence ◽  
Brain Aging ◽  
Ventricular Zone ◽  
Human Fibroblasts ◽  
Cell Lineage ◽  
Lineage Tracing ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Antioxidant Genes ◽  
Age Related

AbstractReactive oxygen species (ROS) stress has been demonstrated as potentially critical for induction and maintenance of cellular senescence, and been considered as a contributing factor in aging and in various neurological disorders including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). In response to low-level ROS stress, the expression of Δ133p53, a human p53 isoform, is upregulated to promote cell survival and protect cells from senescence by enhancing the expression of antioxidant genes. In normal conditions, the basal expression of Δ133p53 prevents human fibroblasts, T lymphocytes, and astrocytes from replicative senescence. It has been also found that brain tissues from AD and ALS patients showed decreased Δ133p53 expression. However, it is uncharacterized if Δ133p53 plays a role in brain aging. Here, we report that zebrafish Δ113p53, an ortholog of human Δ133p53, mainly expressed in some of the radial glial cells along the telencephalon ventricular zone in a full-length p53-dependent manner. EDU-labeling and cell lineage tracing showed that Δ113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Importantly, Δ113p53M/M mutant telencephalon possessed less proliferation cells and more senescent cells compared to wild-type (WT) zebrafish telencephalon since 9-months old, which was associated with decreased antioxidant genes expression and increased level of ROS in the mutant telencephalon. More interestingly, unlike the mutant fish at 5-months old with cognition ability, Δ113p53M/M zebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. The results demonstrate that Δ113p53 protects the brain from aging by its antioxidant function. Our finding provides evidence at the organism level to show that depletion of Δ113p53/Δ133p53 may result in long-term ROS stress, and finally lead to age-related diseases, such as AD and ALS in humans.

scholarly journals Expression of the endocannabinoid receptors in human fascial tissue

2016 ◽  
Author(s):  
C. Fede ◽  
G. Albertin ◽  
L. Petrelli ◽  
M.M. Sfriso ◽  
C. Biz ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Trigger Points ◽  
Small Samples ◽  
Myofascial Trigger Points ◽  
Cannabinoid Receptor 2 ◽  
Culture Cells ◽  
Cb1 Cannabinoid Receptor ◽  
A Cell

Cannabinoid receptors have been localized in the central and peripheral nervous system as well as on cells of the immune system, but recent studies on animal tissue gave evidence for the presence of cannabinoid receptors in different types of tissues. Their presence was supposed also in myofascial tissue, suggesting that the endocannabinoid system may help resolve myofascial trigger points and relieve symptoms of fibromyalgia. However, until now the expression of CB1 (cannabinoid receptor 1) and CB2 (cannabinoid receptor 2) in fasciae has not yet been established. Small samples of fascia were collected from volunteers patients during orthopedic surgery. For each sample were done a cell isolation, immunohistochemical investigation (CB1 and CB2 antibodies) and real time RT-PCR to detect the expression of CB1 and CB2. Both cannabinoid receptors are expressed in human fascia and in human fascial fibroblasts culture cells, although to a lesser extent than the control gene. We can assume that the expression of mRNA and protein of CB1 and CB2 receptors in fascial tissue are concentrated into the fibroblasts. This is the first demonstration that the fibroblasts of the muscular fasciae express CB1 and CB2. The presence of these receptors could help to provide a description of cannabinoid receptors distribution and to better explain the role of fasciae as pain generator and the efficacy of some fascial treatments. Indeed the endocannabinoid receptors of fascial fibroblasts can contribute to modulate the fascial fibrosis and inflammation.

scholarly journals A Double Histochemical/Immunohistochemical Staining for the Identification of Canine Mast Cells in Light Microscopy

2021 ◽  
Vol 8 (10) ◽  
pp. 229
Author(s):  
Francesca Gobbo ◽  
Giuseppe Sarli ◽  
Margherita De De Silva ◽  
Giorgia Galiazzo ◽  
Roberto Chiocchetti ◽  
...  
Keyword(s):  
Mast Cells ◽  
Cannabinoid Receptor ◽  
Immunohistochemical Analysis ◽  
Inflammatory Cells ◽  
Staining Technique ◽  
Cannabinoid Receptor 2 ◽  
Mast Cell Tumors ◽  
Immunohistochemical Markers ◽  
Poorly Differentiated ◽  
Cutaneous Mastocytosis

Immunohistochemistry (IHC) is a widely used technique in diagnostic pathology, but the simultaneous analysis of more than one antibody at a time with different chromogens is rather complex, time-consuming, and quite expensive. In order to facilitate the identification of mast cells (MCs) during immunohistochemical analysis of membrane and/or nuclear markers, we propose a new staining method that includes the association of IHC and toluidine blue as a counterstain. To achieve this goal, we tested c-kit, Ki67, and cannabinoid receptor 2 on several cases of cutaneous canine mast cell tumors (MCTs), cutaneous mastocytosis, and atopic dermatitis. The results obtained show how this double staining technique, although limited to non-cytoplasmic markers and of little use in poorly differentiated MCTs in which MC metachromasia is hard to see, can be used during the evaluation of nuclear and/or membranous immunohistochemical markers in all canine cutaneous disorders, especially if characterized by the presence of a low number of MCs. It can help to evaluate those MCTs in which neoplastic MCs must be clearly distinguished from inflammatory cells that can infiltrate the tumor itself, in facilitating the calculation of the Ki67 index. Moreover, it can be used to study the expression of new markers in both animal and human tissues containing MCs and in MC disorders.

scholarly journals THC-induced behavioral stereotypy in zebrafish as a model of psychosis-like behavior

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Amelia Dahlén ◽  
Mahdi Zarei ◽  
Adam Melgoza ◽  
Mahendra Wagle ◽  
Su Guo
Keyword(s):  
Nmda Receptor ◽  
Cannabinoid Receptor ◽  
Repetitive Behavior ◽  
Endocannabinoid System ◽  
Adult Zebrafish ◽  
Acute Effects ◽  
Cannabinoid Receptor 1 ◽  
Cannabinoid Receptor 2 ◽  
High Doses ◽  
Underlying Mechanisms

AbstractHigh doses of the Cannabis constituent Δ9-tetrahydrocannabinol (THC) increase the risk of psychosis in humans. Highly accessible animal models are needed to address underlying mechanisms. Using zebrafish with a conserved endocannabinoid system, this study investigates the acute effects of THC on adult zebrafish behavior and the mechanisms involved. A concentration-dependent THC-induced behavioral stereotypy akin to THC’s effect in rats and the psychotropics phencyclidine and ketamine in zebrafish was established. Distinctive circular swimming during THC-exposure was measured using a novel analytical method that we developed, which detected an elevated Repetition Index (RI) compared to vehicle controls. This was reduced upon co-administration of N-methyl-D-aspartate (NMDA) receptor agonist NMDA, suggesting that THC exerts its effects via biochemical or neurobiological mechanisms associated with NMDA receptor antagonism. Co-treatment of γ‐aminobutyric acid receptor antagonist pentylenetetrazol also showed signs of reducing the RI. Since THC-induced repetitive behavior remained in co-administrations with cannabinoid receptor 1 inverse agonist AM251, the phenotype may be cannabinoid receptor 1-independent. Conversely, the inverse cannabinoid receptor 2 agonist AM630 significantly reduced THC-induced behavioral stereotypy, indicating cannabinoid receptor 2 as a possible mediator. A significant reduction of the THC-RI was also observed by the antipsychotic sulpiride. Together, these findings highlight this model’s potential for elucidating the mechanistic relationship between Cannabis and psychosis.

scholarly journals Impaired Mitophagy in Neurons and Glial Cells during Aging and Age-Related Disorders

2021 ◽  
Vol 22 (19) ◽  
pp. 10251
Author(s):  
Vladimir Sukhorukov ◽  
Dmitry Voronkov ◽  
Tatiana Baranich ◽  
Natalia Mudzhiri ◽  
Alina Magnaeva ◽  
...  
Keyword(s):  
Glial Cells ◽  
Brain Aging ◽  
Cellular Level ◽  
Aging Brain ◽  
The Past ◽  
Age Related ◽  
Accumulation Of Damage ◽  
Quantity Control ◽  
The Brain

Aging is associated with a decline in cognitive function, which can partly be explained by the accumulation of damage to the brain cells over time. Neurons and glia undergo morphological and ultrastructure changes during aging. Over the past several years, it has become evident that at the cellular level, various hallmarks of an aging brain are closely related to mitophagy. The importance of mitochondria quality and quantity control through mitophagy is highlighted by the contribution that defects in mitochondria–autophagy crosstalk make to aging and age-related diseases. In this review, we analyze some of the more recent findings regarding the study of brain aging and neurodegeneration in the context of mitophagy. We discuss the data on the dynamics of selective autophagy in neurons and glial cells during aging and in the course of neurodegeneration, focusing on three mechanisms of mitophagy: non-receptor-mediated mitophagy, receptor-mediated mitophagy, and transcellular mitophagy. We review the role of mitophagy in neuronal/glial homeostasis and in the molecular pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and other disorders. Common mechanisms of aging and neurodegeneration that are related to different mitophagy pathways provide a number of promising targets for potential therapeutic agents.

scholarly journals Cnr2 Is Important for Ribbon Synapse Maturation and Function in Hair Cells and Photoreceptors

2021 ◽  
Vol 14 ◽  
Author(s):  
Luis Colón-Cruz ◽  
Roberto Rodriguez-Morales ◽  
Alexis Santana-Cruz ◽  
Juan Cantres-Velez ◽  
Aranza Torrado-Tapias ◽  
...  
Keyword(s):  
Hair Cells ◽  
Cannabinoid Receptor ◽  
Sensory Information ◽  
Endocannabinoid System ◽  
Cannabinoid Receptor 2 ◽  
Ribbon Synapses ◽  
Sensory Epithelia ◽  
Synapse Maturation ◽  
And Function

The role of the cannabinoid receptor 2 (CNR2) is still poorly described in sensory epithelia. We found strong cnr2 expression in hair cells (HCs) of the inner ear and the lateral line (LL), a superficial sensory structure in fish. Next, we demonstrated that sensory synapses in HCs were severely perturbed in larvae lacking cnr2. Appearance and distribution of presynaptic ribbons and calcium channels (Cav1.3) were profoundly altered in mutant animals. Clustering of membrane-associated guanylate kinase (MAGUK) in post-synaptic densities (PSDs) was also heavily affected, suggesting a role for cnr2 for maintaining the sensory synapse. Furthermore, vesicular trafficking in HCs was strongly perturbed suggesting a retrograde action of the endocannabinoid system (ECs) via cnr2 that was modulating HC mechanotransduction. We found similar perturbations in retinal ribbon synapses. Finally, we showed that larval swimming behaviors after sound and light stimulations were significantly different in mutant animals. Thus, we propose that cnr2 is critical for the processing of sensory information in the developing larva.

scholarly journals Sensitivity of the Fasciae to the Endocannabinoid System: Production of Hyaluronan-Rich Vesicles and Potential Peripheral Effects of Cannabinoids in Fascial Tissue

2020 ◽  
Vol 21 (8) ◽  
pp. 2936 ◽  
Author(s):  
Caterina Fede ◽  
Carmelo Pirri ◽  
Lucia Petrelli ◽  
Diego Guidolin ◽  
Chenglei Fan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Small Samples ◽  
In Vitro Production ◽  
Cannabinoid Receptor 2 ◽  
Transmission Electron ◽  
Peripheral Effect ◽  
Vitro Production

The demonstrated expression of endocannabinoid receptors in myofascial tissue suggested the role of fascia as a source and modulator of pain. Fibroblasts can modulate the production of the various components of the extracellular matrix, according to type of stimuli: physical, mechanical, hormonal, and pharmacological. In this work, fascial fibroblasts were isolated from small samples of human fascia lata of the thigh, collected from three volunteer patients (two men, one woman) during orthopedic surgery. This text demonstrates for the first time that the agonist of cannabinoid receptor 2, HU-308, can lead to in vitro production of hyaluronan-rich vesicles only 3–4 h after treatment, being rapidly released into the extracellular environment. We demonstrated that these vesicles are rich in hyaluronan after Alcian blue and Toluidine blue stainings, immunocytochemistry, and transmission electron microscopy. In addition, incubation with the antagonist AM630 blocked vesicles production by cells, confirming that release of hyaluronan is a cannabinoid-mediated effect. These results may show how fascial cells respond to the endocannabinoid system by regulating and remodeling the formation of the extracellular matrix. This is a first step in our understanding of how therapeutic applications of cannabinoids to treat pain may also have a peripheral effect, altering the biosynthesis of the extracellular matrix in fasciae and, consequently, remodeling the tissue and its properties.

scholarly journals Endocannabinoid Signaling for GABAergic-Microglia (Mis)Communication in the Brain Aging

2021 ◽  
Vol 14 ◽  
Author(s):  
Jorge Carrera ◽  
Jensen Tomberlin ◽  
John Kurtz ◽  
Eda Karakaya ◽  
Mehmet Bostanciklioglu ◽  
...  
Keyword(s):  
Communication System ◽  
Brain Aging ◽  
Neuronal Loss ◽  
Endocannabinoid System ◽  
Therapeutic Interventions ◽  
Aging Brain ◽  
Age Related ◽  
The Brain ◽  
Excessive Activation ◽  
By Products

The aging brain seems to be characterized by neuronal loss leading to cognitive decline and progressively worsening symptoms related to neurodegeneration. Also, pro-inflammatory states, if prolonged, may increase neuronal vulnerability via excessive activation of microglia and their pro-inflammatory by-products, which is seen as individuals increase in age. Consequently, microglial activity is tightly regulated by neuron-microglia communications. The endocannabinoid system (ECS) is emerging as a regulator of microglia and the neuronal-microglia communication system. Recently, it has been demonstrated that cannabinoid 1 (CB1) receptor signaling on GABAergic interneurons plays a crucial role in regulating microglial activity. Interestingly, if endocannabinoid signaling on GABAergic neurons are disturbed, the phenotypes mimic central nervous system insult models by activating microglia and leading to accelerated brain aging. Investigating the endocannabinoid receptors, ligands, and genetic deletions yields the potential to understand the communication system and mechanism by which the ECS regulates glial cells and aspects of aging. While there remains much to discover with the ECS, the information gathered and identified already could lead to the development of cell-specific therapeutic interventions that help in reducing the effects of age-related pro-inflammatory states and neurodegeneration.

scholarly journals PO-065 The Role and Mechanism of Endocannabinoid System in Exercise-induced Antinociception

2018 ◽  
Vol 1 (3) ◽  
Author(s):  
Guoqin Xu ◽  
Hong Zhao
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Exercise Intensity ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
The Body ◽  
Cannabinoid Receptor 1 ◽  
Cannabinoid Receptor 2 ◽  
The Central Nervous System ◽  
Exercise Induced

Objective As we all know, exercise can enhance the will, improve the mood, and counteract the bad feelings of the body, but the cause and mechanism of action have not been clear. The endocannabinoid system is an important regulatory system in the central nervous system that regulates cognition, mood and behavior. Endocannabinoids can exert physiological regulation through cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). Cannabinoid receptors are widely distributed in the body and participate in the regulation of anti-nociceptive signals at multiple levels. This study will explore the role and mechanism of the endocannabinoid system in exercise-induced antinociception by literature research methods. Methods Using endocannabinoid, exercise/sports and antinociception or emotion as keywords, using Pubmed, Medline, and Embase databases to search for nearly 15 years of research literature and the literatures from cross-references of journals, after excluding the literature that is not relevant to the research content, the 12 articles included were analyzed. Results Exercise can activate the endocannabinoid system, the degree of activation is related to exercise intensity, and high-intensity exercise significantly increases endocannabinoid levels in the human body. Cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) are widely distributed in the nervous system including the central nervous system and the peripheral nervous system. When exercise activates the endocannabinoid system, the increased endocannabinoid in the circulatory system activates CB1 and CB2 receptors, promotes hyperpolarization of the nervous system cells, reduces the rate of excitable cell release, and inhibits neurotransmitters, and reduce nociceptive impulses, thereby the body produces anti-nociception. Pretreatment with endocannabinoid metabolic enzyme inhibitors (MAFP, JZL184) and endocannabinoid reuptake inhibitors (VDM11) can be extended and enhanced the antinociceptive effect of exercise. Pretreatment with endocannabinoid receptor antagonists (AM251 and AM630) will inhibit the antinociception induced by aerobic exercise in mechanical and thermal nociceptive tests. Conclusions Exercise can enhance the level of circulating endocannabinoids, activate the endocannabinoid system through endocannabinoid receptors, and then induce the body to produce anti-nociceptive effects. The degree of activation is related to exercise intensity. Studying the role and mechanism of the endocannabinoid system in exercise-induced antinociception can provide a theoretical basis for exercise to improve depression, anxiety and other emotions, improve the sense of life and prevent mental disorders.

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