Neuroprotective And Immunomodulatory Action Of The Endocannabinoid System Under Neuroinflammation

For more information:ali.ma@wecistanche.com

Abstract: Endocannabinoids (CBs)are lipid-based retrograde messengers with a relatively short half-life that are produced endogenously and, upon binding to the primary cannabinoid receptors CB1/2, mediate multiple mechanisms of intercellular communication within the body. Endocannabinoid signaling is implicated in brain development, memory formation, learning, mood, anxiety, depression, feeding behavior, analgesia, and drug addiction. It is now recognized that the endocannabinoid system mediates not only neuronal communications but also governs the crosstalk between neurons, glia, and immune cells, and thus represents an important player within the neuroimmune interface. Generation of primary endocannabinoids is accompanied by the production of their congeners, the N-acylethanolamines(NAEs), which together with N-acvlneurotransmitters, lipoamino acids, and primary fatty acid amides comprise expanded endocannabinoid/end vanilloid signaling systems. Most of these compounds do not bind CB,2, but signal via several other pathways involving the transient receptor potential cation channel subfamily V member 1 (TRPV1), peroxisome proliferator-activated receptor(PPAR)-α and non-cannabinoid G-protein coupled receptors(GPRs)to mediate anti-inflammatory, immunomodulatory and neuroprotective activities. In vivo generation of the cannabinoid compounds is triggered by physiological and pathological stimuli and, specifically in the brain, mediates fine regulation of synaptic strength, neuroprotection, and resolution of neuroinflammation. Here, we review the role of the endocannabinoid system in intrinsic neuroprotective mechanisms and its therapeutic potential for the treatment of neuroinflammation and associated synaptopathy.

Keywords: endocannabinoids; N-acylethanolamines; neuroinflammation; glutamate-mediated excitotoxicity; neurodegenerative diseases; synaptic plasticity

Highlights

•Retrograde endocannabinoid signaling provides a mechanism by which neurons can

rapidly regulate the strength of their synaptic inputs.

•Stimulation of postsynaptic neurotransmitter receptors and sustained Ca2+ influx is a potent trigger for the production of endocannabinoids (eCBs) and their congeners.

•Neuroinflflammation and alterations in endocannabinoid signaling are implicated in multiple neurological disorders.

•The activity-dependent fellow of glutamate and eCBs from synapses controls microglial attraction, secretion of pro-inflammatory and pro-survival factors, and defifines synapse stability under inflflammation and excitotoxicity.

•The pharmacological inhibition of eCB degradation exerts a primary effect in injured sites, where these mediators are actively produced de novo.

•The endocannabinoid system mediates communication within the tripartite synapse during the development and resolution of neuroinflammation. 

Introduction 

Neuroinflammation is widely regarded as inflammation of the central nervous system (CNS) comprising the brain and spinal cord. The inflammatory process is driven by the release of pro-inflammatory mediators such as cytokines, prostaglandins, and reactive oxygen and nitrogen species by activated endothelial and glial cells with subsequent infiltration of peripheral inflammatory cells into the CNS. As a consequence, neuroinflammation can lead to edema, tissue damage, and loss of neuronal functions as well as accelerate and cause cognitive impairment and neurodegenerative diseases. Common triggers of chronic neuroinflammation include toxic metabolites, harmful self-proteins during autoimmunity, aging, bacterial and viral infections, as well as traumatic brain, and spinal cord injury. The endocannabinoid system (ECS), consisting of the cannabinoid receptors CB1 and CB2, their major endogenous ligands 2-arachidonylglycerol (2-AG) and arachidonoylethanolamide (AEA or anandamide), and their synthesizing and degrading enzymes, plays a crucial role in the intrinsic response to neuroinflammation, brain injury, and neurodegenerative diseases [1–3]. 

Click to cistanche deserticola ma for neuroprotection

This system is now being expanded with ligands that do not show affifinity for CB1/2 but display cannabimimetic activity and can modulate the actions of true eCBs. N-acylethanolamine's generated as AEA congeners together with lipoaminoacids and acyl conjugates of neurotransmitters exert their biological activities through different receptors such as peroxisome proliferator-activated receptor (PPAR)-α [4], transient receptor potential cation channel subfamily V member 1 (TRPV1) and non-cannabinoid G-protein coupled receptors (GPRs). These compounds as well as true eCBs, their molecular targets, overall interplay, and metabolism comprise the endocannabinoidome having a profound role in homeostatic response to noxious endogenous and exogenous stimuli. The existence of multiple targets and routes for ligand synthesis and degradation within the endocannabinoidome enables complex scanning of cellular states and allows a tightly regulated response to relevant changes. Of particular interest is the involvement of this system in inherent protective responses against inflammatory and neurodegenerative processes in the brain as targeted manipulation of this system has high therapeutic potential. In this review, we provide an overview of the immune-regulatory and neuroprotective potential of the endocannabinoidome during neuroinflammation. 

Conclusions 

Neuroinflammation is caused and/or accompanied by the infiltration of immune cells through the BBB and secretion of a range of pro-inflammatory cytokines and other molecules with neurotoxic potential. These changes together with glutamate receptor-mediated neurotoxicity and neurodegenerative processes underlie the pathogenesis of several neuropathologies, among them, are Alzheimer’s disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, and Parkinson’s disease. Bacterial and viral infection, traumatic injury, and autoimmune disease compromise the integrity of BBB and favor the transition of systemic inflammation to neuroinflammation. Maintenance or restoration of the selective permeability of the blood-brain barrier is one of the therapeutic strategies under systemic inflammation to prevent systemic inflammation from spreading to the CNS. 

The interplay of true ECB and ligands that now belong to expanded ECS allows taking into consideration all relevant molecular targets for therapy of neuroinflammation-associated neuropathologies. The interference of PCB congeners with enzymatic degradation or endocannabinoid signaling suggests their role in tuning the activity of primary eCBs. The ‘entourage effect’ of the produced non-cannabinoid 2-acylglycerols, NAEs, and N-acylneurotransmitters may serve as an additional fine regulator of cannabinoid activity. Resident microglia and astrocytes are tightly coupled to functions of active synaptic contacts and are highly involved in inflammatory progression, pro-survival changes, and resolution of neuroinflammation. These cells promote neuronal survival, synaptogenesis, spine induction, and illumination and protect neurons from toxic metabolites. 

The contri-Int. J. Mol. Sci. 2021, 22, 5431 23 of 35 buttons of eCB signaling into the functional coupling of neurons, astrocytes, and microglia, suggests that in line with the conception of tripartite synapses, microglial cells are equal participants in such communication. Being activated during the immune response, microglial cells contribute to the resolution of neuroinflammation; however, chronic activation of microglia is detrimental to neurons and contributes to the development of synaptopathy in various neurodegenerative diseases. Components of ECS play an active role in the reactivity of these cells during inflflammation, attenuate the production of pro-inflammatory cytokines, and mediate neuroprotection against glutamate-receptor mediated excitotoxicity, ischemia, and oxidative stress. Normal synaptic activity as well as pathological overstimulation of postsynaptic neurotransmitter receptors is a potent trigger for the production of eCBs and non-cannabinoid NAEs. Glutamate-induced endocannabinoids [78] fellow from active synapses and injured sites might attract resident microglial cells [76,79]. 

Tight structural and functional cooperation of synaptic contacts, astrocytes, and microglia enables a highly dynamic response to synaptic events. Retrograde endocannabinoid signaling is implicated in several forms of short- and long-term synaptic plasticity. These lipid mediators reach the presynaptic sites of the same or other synaptic contacts and by binding to CB1/2 inhibit the synaptic vesicle fusion and neurotransmitter release. This is how synaptic contacts dynamically tune their strength and can potentiate/depress the response depending on present inputs. Released eCBs have a restricted area of action due to short half-lives and differences in CB receptor expression on cells in close vicinity. 

Thus, the concentration gradient of eCBs is formed on the site of their synthesis. This makes the pharmacological inhibition of eCB degradation primarily effective in injured sites, where they are actively produced. The novel, highly selective inhibitors of FAAH and MAGL with a good safety profile may become prospective agents with anti-nociceptive, anxiolytic, and anti-inflammatory activity and targeted action. The overall interplay and metabolism of endogenous ligands of CB1/2, TRPV1, GPR55, and GPR18 is now integrated into the “endocannabinoidome”, which is actively involved in the intrinsic response to inflflammation and neuroinflammation. The polymodality of this system provides a wide field for the development of highly efficient neuroprotective agents for the therapy of inflflammation-associated synaptopathy.