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This review focuses on the role of the
endocannabinoid system in ocular and systemic circulation. By studying
different analytic approaches, all of which had been previously proposed in the
literature, we explore the importance of the endocannabinoid system on ocular
vascularization and its interaction with other anti-inflammatory medication. We
focus on the cannabinoids effects on ocular circulation, as well as their
implications in visual function. We aim to provide a comprehensive assessment
of the endocannabinoid system as a complex neuromodulatory entity that could
play an important role in the visual system. Most importantly, modulating the
activity of the cannabinoid receptors seems to be very promising from the
therapeutic point of view for a wide range of pathological conditions, from
anxiety disorders and metabolic syndrome to autoimmune diseases and retina or
optic nerve pathology.
Keywords: Cannabinoids,
Endocannabinoid system, Ocular vascularization, Visual system
THE ENDOCANNABINOID SYSTEM
Introduction
The endocannabinoid
system comprises the cannabinoid receptors, the endogenous cannabinoids (endocannabinoids)
and their synthesis/degradation enzymes [1].
The multiple roles
of the endocannabinoid system in human physiology have been proven to be very
interesting for researchers worldwide, in order to find new perspectives on the
use of endocannabinoids as therapeutic goals for new drug development.
Anandamide
was the first identified endocannabinoid; the second one was 2-arachidonoyl
glycerol. These two cannabinoids belong to a wide spectrum of related bioactive
acylethanolamides, being also known as the two major agonists of the CB1 and
CB2 receptors. Nonetheless, only 2-arachidonoyl glycerol (2-AG) is considered a
full agonist for CB1 and CB2, mediating retrograde signals at the synaptic
levels, firmly suggesting 2-AG to be physiologically more valuable than
arachidonoyl ethanolamide (anandamide) [1-3].
A
particularity of endocannabinoids, comparing with other neuromodulators, is
that their precursors are synthetized “on demand”, meaning that they exist in
the cell membranes and can be cleaved by specific enzymes [3]. The transport of
endocannabinoids at the cellular level is facilitated by a specific uptake
system and their degradation is managed by the fatty acide amide hydrolase
(FAAH) and the monoacylglycerol lipase (MAGL). Fatty acid amide hydrolase is
implicated in degradation of anandamide into free arachidonic acid and
ethanolamine, while monoacylglycerol lipase manages the degradation of 2-AG
into arachidonic acid and glycerol. Oxidation of anandamide and 2-AG may
implicate cyclooxygenase-2 and different lipoxygenases [3,4].
CANNABINOID RECEPTORS LOCALIZATION AND VASCULAR
IMPLICATIONS
According
to International Union of Basic and Clinical Pharmacology classification
(IUPHAR), the endocannabinoid system consists of cannabinoid receptors CB1 and
CB2, activated by endogenous ligands such as Anandamide and
2-arachidonoylglycerol and inactivated by G-protein coupled receptors. CB1
receptors seem to have a predisposition towards central and peripheral neuronal
cells localization, whereas CB type 2 receptors are mainly expressed in immune
tissues, presenting a possible immuno-
Anandamide
and 2-arachidonoylglycerol - the two major endocannabinoids - can be found in
the adult human retina and also in the retina of adult bovines and rodents. The
majority of the studies comparing anandamide with 2-AG expression in the retina
pointed out significantly higher levels of 2-arachidonoylglycerol. In humans,
2-AG is mainly produced at the level of the retina, while anandamide is mainly
expressed in the iris [6].
In
vascular territory, anandamide acts through multiple mechanisms, CB1 dependent
and CB1 independent, inducing vasorelaxation. Also, direct activation of
vascular CB type 1 receptors has a profound coronary and cerebral vasodilator
effect. The hemodynamic profile differences of distinct cannabinoids might be
related to quantitative differences in CB type 1 receptor expression in various
tissues and the possible involvement of as-yet-unidentified receptors [3].
Another
interesting effect of anandamide is the promotion of vasodilation through an
indirect mechanism related to arachidonic acid production and secondary
cyclooxygenase (COX)-induced metabolism [3]. Relatively recent studies have
been shown a rising of cannabinoids levels after non-opioid drug therapy; this
effect could be explained by various mechanisms like inhibition of FAAH by some
non-opioids (Indomethacin and Ibuprofen included) followed by the inhibition of
cannabinoids metabolism or inhibition of cannabinoids metabolism by COX-2.
We
might consider though the fact that there are some differences between
vasorelaxant effect of anandamide and they are related to tissues and species
[3].
CANNABINOID-LIKE
RECEPTORS
Recent
studies suggested that G-protein coupled receptor 55 (GPR55) acts as a
cannabinoid receptor because of its interaction with anandamide and
Δ9-tetrahydrocannabinol (THC). Another example of cannabinoid-like receptor
presented in the retina is the transient receptor potential vanilloid 1
(TRPV1), which binds anandamide and N-arachidonoyl dopamine. There is also new
evidence pointing out the intracellular peroxisome proliferator-activated
receptors (PPARs) as targets of cannabinoid ligands [6].
CONCLUSION
Endocannabinoid system represents the newest neuromodulatory system that can
regulate inhibitory and excitatory synapses transmission in a short or
long-lasting manner. Endocannabinoids are widely spread in neural and
non-neural tissues throughout the body, their presence providing a broad
spectrum of possibilities for new therapeutic approaches.
Further
research is needed, especially because the mechanism of action of the
endocannabinoids in the human eye is incompletely known and understood. Yet,
considering the neuroprotective properties of the cannabinoids in the retina,
we can support additional studies regarding their use in the treatment and
prevention of retinal and optic nerve disorders.
1.
Mackie
K (2008) Cannabinoid receptors: Where they are and what they do? J
Neuroendocrinol 1: 10-14.
2.
Tsuboi
K (2018) Endocannabinoids and related N-acylethanolamines: Biological
activities and metabolism. Inflamm Regener 38: 28.
3.
Iancu
R, Coman IC, Barac C, Hammoud MA, Cherecheanu AP (2018) Endocannabinoid system
and ocular vascularization. Nepal J Ophthalmol 10: 168-175.
4.
Zou S
(2018) Cannabinoid receptors and the endocannabinoid system: Signaling and
function in the central nervous system. Int J Mol Sci 19: 833.
5.
Turcotte
C (2016) The CB2 receptor and its role as a regulator of inflammation. Cell Mol
Life Sci 73: 4449-4470.
6.
Bouchard
JF (2016) Expression and function of the endocannabinoid system in the retina
and the visual brain. Neural Plasticity 9247057: 14.
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