Cannabinoids protective effect goes beyond the BBB and also extends to the BSCB. Pretreatment by JHW-015, a CB2 receptor agonist prevents down regulation of occludin and ZO-1 induced by spinal cord ischemia reperfusion injury (SCII) in murine in vivo model. Moreover, JWH-015 pretreatment reduces BBB leakage (measured by Evans blue) compared to SCII only group 23 .
Cannabis potential ability to protect BBB integrity is of possible great importance, not only in autoimmune neurologic disorders, but in a vast verity of neurological fields as in Alzheimer’s disease and ischemia injury.
Cannabis and the Blood-Brain-Barrier
The tale of Cannabis sativa is as old as time. Through its first days as an herbal remedy, ranging back to 4000 BC and to Emperor Shen Nung’s Rule (2700 BC), to cannabis low point of being banned internationally at 1925 to its recent re-emergence by prof. Mechoulam isolation of the Tetrahydrocannabinol (THC, 1963), Cannabis is slowly gaining its place in medicine 1,2 .
Table 3: Perfusion analysis from 1H-NMR in 12-month-old female mdx mice. Reperfusion mean has been calculated during the first 25 minutes after release of ischemia. Wild-type mice, n=6; mdx mice, n=7. **p < 0.01. (a)The set-up of the tourniquet was sufficient to induce an absence of perfusion in both groups. After release of tourniquet, a rapid and important increase of perfusion was detected and the reperfusion of mdx mice was greater than wild-type mice. A single peak of reperfusion was however observed in mdxmice, when a first rapid and strong peak followed by a second attenuated peak of reperfusion was observed in wild-type animals.
Because the release of ischemia induced movements of the leg, images affected by these movement artifacts, at the moment of ischemia release, were removed from analysis of muscle perfusion. (b) In the first 5 minutes after ischemic stress release, below a threshold of 250 mL/100 g reperfusion (concerning mostly wt mice), PCr resynthesis rate was dependent on perfusion, an increase in reperfusion leading to a decrease of τPCr. In contrast, above the threshold of 250 mL/100 g reperfusion (concerning mostly mdx mice), PCr resynthesis rate was poorly affected by the increase of post-ischemia reperfusion. a: Perfusion analysis was performed through from 1H-NMR as described in the Material and Methods section; b: Correlation between reperfusion and PCr resynthesis rate (from 31P-spectroscopy analysis) during the first 300 seconds (5 minutes) after ischemia; n = 6 (wt, a, b); n = 7 (mdx, a, b); τPCr: time of creatine rephosphorylation.
Cannabis and Autoimmune Demyelinating Disease
Another aspect of the endocannabinoid system effect on microglial cell is the attenuation of the immune response induced by LPS (Lipopolysaccharide) stimulation, AEA attenuates the immediate release of IL-6 and NO by microglial cell by induction of MPK-1 11 .
CBG is an AEA reuptake inhibitor which, when combined with CBD, has anti-inflammatory activity as it reduces the expression of tumour necrosis factor (TNF) and up-regulates interleukin (IL)-10 and IL-37 levels. 44 CBC is also an agonist of CB receptor 2, 45 and CBN inhibits COX, LOX, and P450 cytochrome enzymes.
Cannabis is one of the oldest of cultivated plants, and has been used as a raw material, food and medicinal drug for thousands of years. 1–4 It contains 538 chemical compounds, of which just 100 are natural phytocannabinoids (PCs), 5 which are usually divided into the 10 subclasses of delta 9-tetrahydrocannabinol (THC), D8THC, cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), cannabinodiol, cannabielsoin, cannabicyclol, cannabinol (CBN), cannabitriol, and miscellaneous. The CBD and D9THC subclasses have so far received the most scientific attention: Gaoni and Mechoulam were the first to isolate THC and CBD in order to determine their structure and stereochemistry, and they subsequently synthesised them in the 1960s. 6 PCs are mainly secreted by the trichomes of female plants (the glandular protuberances found on the leaves and stems) in the form of a resin whose wealth of PCs (mainly THC) and terpenoids (eg, pinene, limonene, caryophyllene) give the plants their characteristic smell.
THC binds to PPARγ receptors, GPR55, GPR18, TRPA1 (or capsaicin receptors, which are predominantly expressed in the nociceptive neurons of the peripheral nervous system but are also found in the central nervous system), TRPV2, TRPV3, TRPV4, several glutamate receptors, glycine receptors, and adenosine receptors, and acts as an antagonist of 5-hydroxytryptamine (HT)3 receptors and TRPM8. It has recently been discovered that GPR55, which is coupled to a G-alpha protein and was once considered an orphan receptor, is activated not only by THC but also by CBD, certain synthetic cannabinoids, AEA and 2-AG, and its activation increases intracellular calcium levels. 17
Medical cannabis (MC) refers to the plant or an extract (usually with a specific relative amount of THC and CBD) used for medical purposes. The preparations may be administered by means of vaporisation and inhalation, ingestion, or topical applications; the use of vaginal, rectal or sublingual administrations is less frequent. 7 Oral cannabis formulations take effect 30–90 minutes after ingestion, and their effect peaks after 2–4 hours; and the approximate half-life of THC is eight days in fat, 8 , 9 since PCs are highly lipophilic. 10 Furthermore, it seems that the bio-distribution of orally ingested CBD and THC is greater in the lymphoid tissues of the intestinal lymphatic system than in the larger lymphatic tissue of the central compartment, 11 which may be particularly useful when treating chronic intestinal conditions. Conversely, its delivery to the lungs aids rapid absorption and leads to an early onset of action (after only one minute) that peaks after 30 minutes at most. This suggests that this route of administration is best in the case of more acute conditions, such as multiple sclerosis-associated spasticity. The drawback is that the faster THC reaches the brain, the more likely the occurrence of side effects. 12 Mild, dose-dependent, acute adverse events are well documented: the most frequent are drowsiness, dry mouth, dizziness, vertigo, and nausea, but others include blurred vision, tachycardia, gastrointestinal disturbances (diarrhea/stipsis, lost/increased appetite, dyspepsia), and muscle spasms. 13–16 THC-related side effects (fatigue, tachycardia and dizziness) can be avoided by very slow dose titration, which also promotes tolerance to its psychoactive side effects. 16
Pharmacodynamics and the Endocannabinoid System
CB1 receptors are mainly present in the central nervous system (CNS), but also found peripherally in hepatic, intestinal and adipose tissue, 27 the eye, cardiovascular system, pancreas, immune system, bone, skin, and skeletal muscle, thus suggesting a potentially enormous periphery/brain network of connections. 28 CB2 receptors are often called peripheral not only because they are mainly found in the immune system, 29 but also because their activation is largely devoid of psychotropic effects. 30 They are also present in microglial cells, 31 and on chondrocytes, osteocytes, and fibroblasts – all cells that take part in the inflammation of the autoimmune diseases discussed in this article. Within the immune system, CB2 expression is higher in lymph nodes and spleen than in peripheral blood cells, and varies in different cell sub-populations (B cells > NK cells > monocytes > neutrophils > CD8+ T cells > CD4+ T cells). 32 , 33
The activities of the large number of compounds contained in whole cannabis plants is extremely complex because the compounds themselves not only bind to a plethora of different receptors but also interact with each other both synergistically and otherwise: 42 for example, pinene is an acetylcholinesterase inhibitor that may decrease the short-term memory impairment induced by THC. 16 What follows is a brief summary of the activity of other PCs and terpenes (which have been more extensively reviewed elsewhere). 43
Much of CBD biological activity is independent of CB receptors, as has been demonstrated by its suppression of cytokine production in CB1 and CB2 receptor knock-out mice. 34 Some data suggest that CBD can indirectly activate CB1 and CB2 by increasing AEA and 2-AG levels. 35 Indirect targeting of the CB system is actually a well-known pharmacological technique: the most widely used analgesic drug is the decades-old paracetamol, which acts by producing AM404 and thus interfering with the reuptake of anandamide. 36
Terpenes are very promising compounds as they have a variety of positive (analgesic, anti-depressant, anti-oxidant, and anti-bacterial) functions, 42 but the possible contribution of adding terpenoids to cannabinoids is uncertain. 43 It has been reported that caryophyllenes are anti-microbial, anti-proliferative, anti-fungal, anti-oxidant and anti-inflammatory acetylcholinesterase inhibitors; 46 D-limonene may be anti-inflammatory as it mediates the inhibition of pro-inflammatory mediators, leukocyte migration, and vascular permeability. 47 Gamma-terpinene has an effect on the pro- and anti-inflammatory macrophage production of cytokines, particularly through the IL-10 axis. 48
Medical cannabis (MC) describes the usually inhaled or ingested use of a cannabis plant or cannabis extract for medicinal purposes. The action of whole cannabis plants is extremely complex because their large number of active compounds not only bind to a plethora of different receptors but also interact with each other both synergistically and otherwise. Renewed interest in the medicinal properties of cannabis has led to increasing research into the practical uses of cannabis derivatives, and it has been found that the endocannabinoid system (particularly CB2 receptor activation) is a possible target for the treatment of inflammatory and the autoimmune diseases related to immune cell activation. However, in vivo findings still lack, creating difficulties in applying translational cannabinoid research to human immune functions. In this review, we summarized the main mechanisms of action of medical cannabis plant especially regarding the immune system and the endocannabinoid system, looking at preliminary clinical data in three most important autoimmune diseases of three different specialities: rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease.