Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid.
Ewa Kozela, Ana Juknat, and Zvi Vogel
International Journal of Molecular Sciences, 2017, 18, 1669, 20 pp.
- PMID : 28788104 PMCID : PMC5578059
The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. Their precise regulation is still far from understood, although several candidate molecules/systems arise as promising targets for astrocyte-mediated neuroregulation and/or neuroprotection. The cannabinoid system and its ligands have been shown to interact and affect activities of astrocytes. Cannabidiol (CBD) is the main non-psychotomimetic cannabinoid derived from Cannabis. CBD is devoid of direct CB1 and CB2 receptor activity, but exerts a number of important effects in the brain. Here, we attempt to sum up the current findings on the effects of CBD on astrocyte activity, and in this way on central nervous system (CNS) functions, across various tested models and neuropathologies. The collected data shows that increased astrocyte activity is suppressed in the presence of CBD in models of ischemia, Alzheimer-like and Multiple-Sclerosis-like neurodegenerations, sciatic nerve injury, epilepsy, and schizophrenia. Moreover, CBD has been shown to decrease proinflammatory functions and signaling in astrocytes.
astrocyte; cannabidiol; cannabinoid; neurodegeneration; neuroinflammation
Astrocytes are the most numerous cells populating the central nervous system (CNS). Research during the last two decades has shown that they actively participate in brain development and activity, and maintain tissue homeostasis, far beyond their previously believed role of a sole “glue”-like support for neurons. In healthy brain, astrocytes regulate neuronal growth and synapse formation and pruning, support neuro-signaling (e.g., by forming the so called “tri-partite synapse”), regulate glutamate, potassium, and calcium release and uptake, and modulate synaptic potentiation and learning [1,2].
Astrocytes serve as the primary glycogen storage site in the CNS, and they perform metabolite cleansing. Together with endothelial cells, they form the blood brain barrier (BBB) providing selective protection to the brain. Astrocytes, together with microglia, are the primary mediators of “reactive gliosis”, defined as the reactive response of glial cells to various CNS insults such as infection, trauma, ischemia, and neurodegenerative diseases. Reactive gliosis involves phenotypic and molecular changes of astrocytes and of microglia, and frequently leads to scar formation, an indicator of many brain injuries and pathologies. Glial scars may have a protective function by limiting the spread of neurodegeneration and infection as well as of ischemia-induced cellular rearrangements. However, more severe threats, such as autoimmune neuroinflammation and T cell/monocytes infiltration, may lead to a higher degree of astrogliosis, thus changing the tissue structure and damaging neuronal connectivity Astrocytes are crucial regulators of innate and adaptive immune responses in the CNS. Astrocytes participate in antigen recognition. Following their activation, the astrocytes secrete chemokines, cytokines, neurotoxic factors, molecules affecting blood vessel diameter (thus modulating blood flow), such as nitric oxide and prostaglandins, and by this way affect BBB permeability
- 2. Astrocytes as Potential Therapeutic Target. Role of Cannabinoid System
Due to their crucial involvement in brain function, astrocytes have gained robust interest as a potential target for neurotherapies. Astrocyte activity has been shown to be involved in acute injury, neurodegeneration; to affect neuroplasticity, learning and memory; and to accompany neuropsychiatric disorders, drug addiction and dependence [3,4]. An accumulation of oxidative stress and chronic neuroinflammation as a result of inefficient astrocytic clearance of debris or misfolded proteins has been observed to significantly contribute to neuronal degeneration, progressing cognitive loss and motor disability. Thus, the pharmacological modulation of reactive astrocytes has been proposed as a tool to blunt neuronal damage and to slow the course of brain diseases [5,6].
- The precise regulation of astrocyte activity is still far from understood, although a few candidate molecules/systems arise as promising targets for astrocyte-mediated neuroprotection. The endocannabinoid system and its ligands provide such a possibility. Mounting evidence shows that many cannabinoids, including phytocannabinoids (constituents of the Cannabis plant), endocannabinoids, and synthetic ligands, can modulate the intensity of reactive gliosis, resulting in neuromodulatory, anti-inflammatory, and neuroprotective effects in both mature and immature brain [7–10].
- The cannabinoid system is comprised of two plasma membrane Gi/o-coupled cannabinoid receptors (CB1 and CB2) and a family of their endogenous ligands (N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG)) together with synthesis/degradation enzymatic machinery (the serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively). It has been shown that neurons express mostly CB1 cannabinoid receptors, while microglia express CB2. Interestingly, both types of the cannabinoid receptors were found to be present on astrocytes. Remarkably, CB2 expression was shown to be elevated in neuroinflammatory conditions in both microglia and astrocytes [11,12]. The expression of CB2 in neuroinflammatory conditions takes place in parallel with increased levels of endocannabinoids [13,14], further indicating the involvement of the cannabinoid system in the regulation of brain pathology and/or recovery.
- Cannabis plant preparations (marijuana, hashish) are a source of over 100 cannabinoid chemicals with diverse affinities towards CB1 and CB2 receptors. The psychoactive material, D9-Tetrahydrocannabinol (THC, a CB1 and CB2 ligand), and the non-psychoactive Cannabidiol (CBD, binding neither CB1 nor CB2) are the most abundant phytocannabinoids in Cannabis, and exert a variety of bioactivities, including neuroprotective and anti-neuroinflammatory effects. Indeed, THC was shown to be neuroprotective (via CB1 mediated mechanisms) and to protect glial cells from apoptosis [15,16]. However, justified concerns have arisen regarding a possible deleterious effect of CB1 activation resulting in psychoactivity and memory disruption, particularly in the immature brain . CB2 selective cannabinoids seem to serve as attractive therapeutics as they would presumably invoke minimal psychoactive responses. However, recent observations show heteromer CB1/CB2 functional interaction, suggesting that even CB2 ligands may induce some THC-like effects upon their activation [12,18]. Interestingly, cannabinoids devoid of both CB1 and CB2 activities (such as CBD) have also been shown to affect microglia and astrocyte functions (see below). CBD, a major non-psychoactive constituent of Cannabis, has been described as neuroprotective, anti-oxidant, and anti-inflammatory in various models of brain insults (reviewed by [19–23]). In addition, CBD has been shown to be cytotoxic in cancer cells, to reduce pain, spasticity, and seizures, to reduce peripheral and CNS inflammation, to modulate blood circulation and metabolism, and to be anxiolytic and reduce psychosis [22–24]. There is increasing evidence that such broad CBD beneficial effects in the CNS involves the modulation of astrocyte activity, although the data are still scarce and fragmentary. Therefore, our aim in this manuscript is to summarize the findings on the effects of CBD on astrocytes in various experimental models of brain insults and pathologies.