Endocannabinoid system and neuroprotection
The plant cannabis has the pharmacological effects of antiemetic, sedative, anti-inflammatory and analgesic. More than 80 kinds of cannabinoids were extracted from plants. In addition to natural cannabinoids, studies have found that there are substances that synthesize and secrete cannabinoids in the body, which is called endocannabinoid system. This scientific research has conducted extensive and in-depth research on endogenous cannabinoids. The main functions of endocannabinoid system- system in the central nervous system are closely related to neuroprotection, in addition to regulating emotional, memory, appetite, autonomic behavior and other neural activities.
Scholars have studied cannabinoid receptors in tissues and cells, which is helpful to better understand the role of endogenous cannabinoid system in some diseases. Cannabinoid receptor CB1 and cannabinoid receptor CB2 are a class of cell membrane receptors, belonging to G protein coupled receptors.
CB1 receptors mainly exist in the central and peripheral nervous system. CB1 is much higher in the central nervous system than in the surrounding. CB1 receptors in the basal ganglia nucleus are hippocampus, cerebellum and neocortex. At the cellular level, GABA in the terminals of presynaptic neurons in various brain regions is higher than that of glutamatergic neurons. CB1 receptors are also found in microglia and peripheral immune cells. CB1 receptors on microglia inhibit the release of nitric oxide and are used for anti-inflammatory effects. There are also CB1 receptors on astrocytes. It has been found that acute cannabinoid impairs working memory (short-term memory) through the long-term inhibition of hippocampus through the CB1 receptors on astrocytes.
Amino acids and C-terminus in CB2 receptors play a major role in ligand mediated receptor desensitization and receptor down-regulation. Different from CB1 receptor, CB2 receptor mainly exists in the peripheral immune system, including spleen and thymus, monocytes, T cells and B cells. Studies have found that CB2 receptor gene transcripts are also widespread in brain tissue. CB2 receptors in brain tissue are mainly located in inflammatory cells related to central immunity, such as microglia, dendritic cells and cerebrovascular endothelial cells. Activation of these receptors can attenuate the inflammatory response, inhibit the release of pro-inflammatory factors, reduce leukocyte chemotaxis and extravasation to the brain parenchyma.
Endogenous cannabinoids are found in brain tissues. There are five kinds of endogenous cannabinoids: anandamide (AEA), 2-AG, o-arachidonoyl ethanolamine, n-arachidonyldopamine (Nada) and 2-arachidonoyl glycerol ether. Although many endogenous cannabinoids have been found, AEA and 2-AG are the focus of attention.
AEA is the earliest endogenous cannabinoid substance found in brain tissue and periphery. The chemical structure of AEA is different from THC, but its pharmacological characteristics are similar. AEA levels were higher in hippocampus, thalamus, striatum and brainstem, but lower in cerebral cortex and cerebellum. AEA is a partial agonist of cannabinoid receptor. It has a strong ability to excite the CB1 receptor in the central nervous system and a weak ability to excite the CB2 receptor in peripheral tissues. 2-AG has been found in the brain and periphery. It is abundant in the hippocampus, striatum, brainstem and medulla of rats. The concentration of 2-AG in the brain is higher than that of AEA. 2-AG is a complete agonist of cannabinoid receptor. It has similar affinity for CB1 and CB2 receptors and is more effective than AEA. 2-AG is an endogenous ligand of CB2 and has greater stability than AEA.
Synthesis and release of endocannabinoids
Different from the traditional neurotransmitters, endocannabinoids synthesize a certain amount when they need to be released, and release them to the synaptic space immediately. The synthesis and degradation enzymes of endocannabinoids dynamically regulate the changes of endocannabinoids under normal and disease conditions, which has become a key research point for treatment. AEA and 2-AG are produced by the cleavage of plasma membrane phospholipids, and ca2+ is used as a membrane depolarization biosensor to induce synthesis.
AEA is synthesized from its precursors arachidonic acid and phosphatidylethanolamine through two intracellular enzymes, N-acyltransferase and phospholipase (NAPE-PLD). The ability of n-acylphosphodylethanolamines (napes) to cleave to produce AEA in the environment with low ca2+ concentration decreases and will not disappear completely. Nape cleaves to produce AEA through other pathways besides PLD, such as phospholipase A2 and phospholipase C. 2-AG is produced by hydrolysis of membrane derived diglycerides by diglyceride lipase (dagl), which is located on the membrane of dendritic spines of neurons and induced by activated astrocytes.
Once released into synaptic space, endocannabinoids are rapidly reabsorbed and inactivated. Fatty acid amide hydrolase (FAAH) is a membrane enzyme belonging to serine hydrolase family, which is mainly located in postsynaptic neurons and complementary to CB1 receptor. Reactive astrocytes (activated and proliferated from a resting state after central nervous system injury to form reactive astrocyte proliferation) increase FAAH. FAAH mainly decomposes AEA and a small amount of 2-AG. 2-AG is mainly decomposed by monoacylglycerol lipase (MAGL). The distribution of MAGL in rat brain is heterogeneous, and the expression level of MAGL is the highest in the regions where CB1 receptors are widely distributed, such as hippocampus, cortex and cerebellum.
MAGL is distributed in presynaptic nerve endings and plays a role in the reverse signal transduction of presynaptic neurons. AEA was degraded to arachidonic acid and ethanolamine in FAAH; 2-AG was degraded to arachidonic acid and glycerol by MAGL. FAAH and MAGL play an important role in regulating the signal intensity of endocannabinoids. Their inhibitors can produce different behavioral effects, some of which are overlapping. After nerve injury, it can activate the signal transmission of endogenous cannabinoids in the central nervous system, and indirectly activate the downstream signal pathway through drug inhibition of FAAH and MAGL, which can promote the maintenance and function maintenance of neurons. FAAH and MAGL have become the research directions of potential drugs for neuroprotection.
Endocannabinoid system and neuroprotection
The neuroprotective effect of cannabinoid system is a hot topic in many disciplines. Endogenous cannabinoid system can improve the prognosis of nerve injury and neurodegenerative diseases by regulating the nervous and immune system.
Endogenous cannabinoid system and ischemic brain injury
The prevention and treatment of cerebral ischemia injury and its mechanism are the focus of medical research. It has been found that cerebral ischemic preconditioning can induce cerebral ischemic tolerance. The experiment found that before cerebral ischemia, electroacupuncture was used to stimulate Baihui Point in rats to simulate the brain protective effect of ischemic preconditioning. It was found that electroacupuncture pretreatment increased the synthesis of endogenous cannabinoid ligands (2-AG and AEA) in brain tissue, up regulated the neuronal cannabinoid receptor CB1, and activated intracellular ERK ε PKC signaling pathway up regulates the ratio of bcl-2/bax, inhibits neuronal apoptosis, and induces rapid phase brain protection.
Neurons are the target cells of brain preconditioning. Glial cells account for 90% of the total number of cells in the central nervous system. A large number of glial cells are also indispensable for neuroprotection. CB2 receptors can not only regulate the proliferation, differentiation and migration of microglia, but also reduce their neurotoxic reactions, and play an important role in the activation of microglia; After cerebral ischemia, CB2 receptor of glial cells increases, which can better promote the protective effect of astrocytes on neurons. Animal experiments have found that CB2 receptor agonists can alleviate focal cerebral ischemia-reperfusion injury in mice, and activate CB2 receptor to regulate glial cell activation, which has a protective effect on cerebral ischemia-reperfusion injury.
Endocannabinoid system and Parkinson's disease
Parkinson's disease (PD) is characterized by myotonia, tremor and bradykinesia, high-level cognitive dysfunction and fine language problems. It usually occurs due to the lack of dopamine formation caused by the apoptosis of dopaminergic neurons in the substantia nigra. Endogenous cannabinoid system plays an important role in the dopaminergic system, and they regulate each other. For example, CB1 receptors and d1/d2 like receptors in striatal neurons show complex interaction signals. The level of endogenous cannabinoid AEA in cerebrospinal fluid of patients with Parkinson's disease increased.
Changes of cannabinoid receptors and endogenous cannabinoids in Parkinson's disease model. It was found that in the primates treated with MPTP (1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, used to make animal Parkinson's disease models) and in the rats treated with 6-OHDA (6-hydroxy-dopamine, a hydroxylated derivative of catecholamine, used to induce animal Parkinson's disease), the binding of cannabinoid CB1 receptor and the level of CB1 mRNA increased.
Future and Outlook
The research on the endocannabinoid system and its related two common central diseases and the protection of endocannabinoids in the central nervous system have great potential and prospect, and will be the focus and hotspot of future research. The role of cannabinoid system in the central nervous system is complex, and the specific role and mechanism of cannabinoid system in the central nervous system are still unclear. Cannabinoid receptors in different parts activated by different ligands may have different effects on different neurotransmitters. Due to the extensive pathological cell damage in these central diseases and the complex involvement of inflammatory environmental system, it is more difficult to study the specific mechanism of endocannabinoids in normal and disease states.
Endogenous cannabinoid system is involved in most of the pathogenesis of central system diseases, which has confirmed some pathogenesis. Central system diseases are a very complex process. The proposal of endogenous cannabinoid system has opened up a new way for the study of central system diseases. With the improvement of experimental technology and animal models, the components of the endocannabinoid system, such as ligands, receptors, synthetic and hydrolytic metabolic enzymes, will become the guidance and discovery to link clinical diseases and solve clinical problems. There is still a long way to go to clarify the mechanism of action and the research of endogenous cannabinoid related alternative drugs from animals to clinic.
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