Abstract:The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.Keywords: cannabinoid; endocannabinoid; receptor; signaling; central nervous system
GABA is the most common neurotransmitter in the central nervous system, found in high concentrations in the cortex and limbic system. GABA is inhibitory in nature and thus reduces the excitability of neurons. GABA produces a calming effect on the brain.2 The 3 GABA receptors are designated A, B, and C. This article focuses primarily on the GABA-A receptor, with which BZDs interact.
From a pharmacological perspective, BZDs are usually well absorbed by the gastrointestinal tract after oral administration. After intravenous administration, BZDs quickly distribute to the brain and central nervous system. BZD activity is terminated by redistribution similar to that of the lipid-soluble barbiturates. Following intramuscular injection, absorption of diazepam or chlordiazepoxide is slow and erratic, whereas absorption of intramuscular administration of lorazepam or midazolam appears to be rapid and complete. Lorazepam is well absorbed after sublingual administration, reaching peak levels in 60 minutes.2
BZDs and their metabolites are highly protein bound. They are widely distributed in the body and preferentially accumulate in lipid-rich areas such as the central nervous system and adipose tissue. As previously mentioned, the more lipophilic agents generally have the highest rates of absorption and fastest onset of clinical effects. Most BZDs are oxidatively metabolized by the cytochrome P450 enzymes (phase I), conjugated with glucuronide (phase II), and excreted almost entirely in the urine.
Development of central nervous system (CNS) is regulated by both intrinsic and peripheral signals. Previous studies have suggested that environmental factors affect neurological activities under both physiological and pathological conditions. Although there is anatomical separation, emerging evidence has indicated the existence of bidirectional interaction between gut microbiota, i.e., (diverse microorganisms colonizing human intestine), and brain. The cross-talk between gut microbiota and brain may have crucial impact during basic neurogenerative processes, in neurodegenerative disorders and tumors of CNS. In this review, we discuss the biological interplay between gut-brain axis, and further explore how this communication may be dysregulated in neurological diseases. Further, we highlight new insights in modification of gut microbiota composition, which may emerge as a promising therapeutic approach to treat CNS disorders.
NF-κB family of transcription factors contribute to both innate and adaptive immune responses and maintenance of immune system . Our previous study identified dynamic K63-linked ubiquitination of NLRC5 which regulates NF-κB signaling and dynamically shapes inflammatory responses [20, 43]. Alterations in gut microbiota composition contribute to various inflammatory diseases via regulation of innate immunity, especially via NF-κB signaling . Studies have shown that in ampicillin-treated mice, variations of succinate and butyrate leads to significant enhancement of NF-κB . Moreover, the invasion by Campylobacter jejuni due to dysbiosis of intestine microbiome also resulted in activation of NF-κB due to secretion of various cytokines which stimulate different immune cells . In contrast, another strain of microbiota, Lachospiraceae and its metabolites mediate protective function of NLRP12 in extreme inflammatory diseases by attenuating the activation of NF-κB/MAPK signaling and high fat diet-induced inflammasome activation . Additional studies have revealed that the interaction between microbiota and NF-κB signaling is also responsible for CNS inflammation. For instance, the disturbance of gut microbiota induced by antibiotic treatment leads to inhibition of BDNF expression (in hippocampus) and activation NF-κB, which leads to severe neuroinflammation and anxiety-like behavior in animal models. In contrast, administration of lactobacilli alleviates CNS inflammation and mitigates anxiety-related symptoms . Similarity, in a colitis model, elevated NF-κB is detected in intestines as well as hippocampal zone with cooperative expression of TNF-α, which leads to serious memory impairment. The restoration of unbalanced gut microbiota attenuated both colitis and amnesia .
During CNS development, the generation of neurons is affected by exposure to various environmental factors  while host microbiome also exhibits dynamic variation in its composition during brain maturation . Previous studies suggest that the permeability of maternal-fetal interface allows regulators from gut bacteria to activate TLR2, which promotes fetal neural development and has potential impact on cognitive function during adulthood [93, 94]. Previous studies also point to the role of gut microorganisms in modulating and directing developmental progress of neurogenesis in CNS, and that this complex interaction mainly occurs in hippocampus [95, 96]. Hippocampal formation involves the limbic system, which is known for memory, and increased neurogenesis in this area weakens established memory but facilitates the encoding of new conflicting information in mice . Critical role of microbiota in neurogenesis in hippocampus and its potential link with loss of memory comes from the studies conducted in GF mice. Proliferation of neurons at dorsal hippocampus is greater in GF mice than in conventional mice. However, post-weaning exposure of GF mice to microbial clones did not influence neurogenesis, suggesting that neuronal growth is stimulated by microbiota at an early stage . The connection between microbiota and hippocampal neuronal generation is further strengthened by the findings that deficient neurogenesis can be counteracted by a probiotic combination of specific bacterial strains [99, 100]. As mentioned earlier, NF-κB signaling participates in microbiota-neuron axis. Studies indicate that microbiota disturbance leads to increased NF-κB activation and TNF-α expression with induced memory impairment in animal models, and the restoration of microbiota composition alleviates neuroinflammation in hippocampus and ameliorates relevant symptoms . Additional studies are warranted to precisely define the specific pathways and microbial species that mediate neurogenesis and CNS health.
Vagus nerve (VN) is a component in parasympathetic nervous system and a key route of neural communication between CNS and gut microbiota [108, 109]. VN actively participates in the bidirectional interactions between gut microbiota-brain to maintain homeostasis in both cerebrum and intestine. For example, perturbations of the nerve may cause either CNS dysfunction, e.g., mood disorders or neurodegenerative diseases, or gastrointestinal pathologies, such as inflammatory bowel disease and irritable bowel syndrome [110,111,112]. Previous studies have indicated that vagal efferent fibers regulate the responses to environmental or pathophysiological conditions in gastrointestinal system via the release of neurotransmitters [113, 114]. A minor inappropriate activation of VN results in excessive activation and elevation of neurotransmitters, thereby impairing the digestive process and influencing gastric motility [112, 115]. Moreover, immune regulatory effects of VN on local immunity and intestinal permeability have also been observed. Studies have established that the activation of M1 macrophages and increased levels of proinflammatory cytokines induced by abdominal surgery are alleviated by electrical vagal stimulation, which might relieve inflammatory reactions after surgery and improve postoperative recovery . Furthermore, the stimulation of VN by electro acupuncture promotes the expression and proper localization of tight junction proteins, thus decreasing intestinal permeability and exerting protective effects in intestinal epithelium barrier [117, 118].
Neurological diseases are historically studied within CNS; however, recent studies have implicated that peripheral influences in the onset and progression of diseases impact the brain . Evidence from a study of α-synuclein overexpressing (ASO) mouse model of PD suggests a role of microbiota in the evolution of this disease . ASO mice under a germ-free environment or treated with antibiotics show increased inhibition of PD-associated neuropathology compared with the mice from regular housing condition, whereas depletion of gut microorganisms in young ASO mice inhibited the progression of PD in adulthood. Furthermore, the symptom-free state could