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Evolved To Defend: Cannabinoid Protection Of Barrier Tissues In Plants And Humans
Evolved To Defend: Cannabinoid Protection Of Barrier Tissues In
Plants And Humans
Andrea L. Small-Howard, Ph.D.1
1GBSciences, Inc., Las Vegas, NV.
Abstract

The skin is the human body’s largest organ and its barrier, immunological and sensory functions are essential to human health. Emerging scientific studies suggest that the homeostasis of the skin, and its return to health after damage, can both be attributed to the body's own endo-cannabinoid system. The skin is rich in classical and non-classical cannabinoid receptors, located in structural cells, sensory nerve endings and cells of the immune system. This enrichment of cannabinoid receptors provides the opportunity for therapeutic application of exogenous cannabinoids to regulate and preserve skin functionality. The chemical ecology of cannabinoids in plants suggests that these molecules are ancient protectants, providing anti-microbial, anti-desiccation and anti-UVB properties. Leveraging these evolutionarily preserved functions and our contemporary understanding of the skin endo-cannabinoid system presents new options for cannabinoid enhancement of skin health.

Keywords: Cannabis sativa, Cannabinoids, Skin, Dermatoses
Chemical Ecology Of Cannabinoid Compounds And Their Protective roles In Plants
Since the earliest days of life on Earth, organisms have needed to protect themselves from environmental stressors in order to survive. Ancient protective mechanisms have been evolved that address a multitude of physical, chemical and biological threats to the integrity of an organism. In plants, the stationary nature of the organism carries an inherent inability to use avoidance as a countermeasure to threats. Plants have therefore evolved complex physical and chemical protection mechanisms to preserve the integrity of their barriers and protect themselves against diverse threats including:

  • Physical threats
  • Temperature fluctuations
  • UV radiation
  • Desiccation
  • Chemical threats
  • Environmental toxins, pollutants
  • Biological threats
  • Pathogenic micro-organisms (bacteria, fungi, viruses)
  • Insects and larger predators
As with any defensive system, there are necessary compromises between the plant’s needs to feed, breed and grow, yet need to defend themselves while doing so. For example, while some microorganisms are pathogenic, others live in necessary symbiosis within the plant rhizosphere providing essential functions to the plant in terms of nutrient fixing and production of secondary metabolites. Similarly, while UV can be inherently damaging to all cellular systems (initiating DNA damage and lipid peroxidation within the cellular membrane), plants absolutely need photosynthetically active radiation (PAR) to reach their chloroplasts in order to survive. A third example is the balance between allowing insect pollinators free access to the plant while protecting leaves and other aerial parts against insect attack and damage. These trade-offs require the development of a complex defense system in which physical, chemical and biological elements work in concert to effect protection.

The plant cannabinoid system has been suggested to contribute to multiple aspects of plant defense. First, it is noticeable that cannabinoid production has been described in the cells that comprise all of the aerial components of the plant. Thus the plant cannabinoid system is positioned in the correct locations to participate in environmental defense. The cannabinoids are produced in specialized glandular structures (the
trichomes) that localize to the epidermal barrier of the plant (the interface between organism and environment). These trichomes are multicellular, may be pedestalized (exude from the epidermal surface) and encase a resin-secreting gland in a sheath of cutical proteins and polysaccharides. Resin builds up within the sheath, and lytic rupture of the sheath results in
extrusion. The distribution of the trichomes and glands are strain-specific, tissue-specific (e.g. anthers and stamens are highly enriched), and influenced by plant developmental stage and environmental factors. The latter is exemplified by the fact that environmental stressors such as desiccation apparently lead to proliferation of glandular number.
Figure 1. Trichome structure. The trichome is a specialized structure that secretes a resinous, cannabinoid and terpene-containing substance onto the plant cuticle. This resin is protective – its production increases under conditions of wounding and elevated levels of UV damage.
How Do Cannabinoids Contribute To Plant Defense?
Cannabinoids make multi-faceted contributions that can be categorized into two major categories: Cell extrinsic functions are those achieved by cannabinoids that have been extruded from the trichomes, while cell intrinsic functions are those that are carried out intracellularly by endogenous cannabinoids within multiple plant tissues.
Figure 2. The complex macroscopic surface structures of cannabis leaves include (on females) pistils, calyx and cola. At the microscopic level, trichomes decorate the leaves, secreting a surface resin on cannabinoid buds that protest the plant from environmental damage. Image credit: shutterstock.com
Cell extrinsic functions
(a) Anti-desiccant activity. The viscous, oily nature of extruded cannabis oils (as well as the terpenes and alkanes that accompany them) provides a hydrophobic layer that reduces surface evaporation and may somewhat insulate from temperature increases.

(b) Anti-microbial activity. Cannabinoids have been shown to be anti-bacterial, and anti-fungal, blocking micro-organism proliferation at a number of doses in
various in vitro assays. Anti-biotic properties have been shown for isolated and synthetic cannabinoids, as well as complex oils. The anti-fungal effects are also interesting, especially when we note that some successful plant fungal pathogens appear to have evolved the ability to catabolize cannabinoids, perhaps specifically to counteract these anti-fungal measures deployed by the plant.

(c) Anti-predation. The sticky and viscous barrier provided by extruded cannabinoids may provide some protection against insect attack, as does the complex surface topology engendered by the densely placed trichomes. The role of the highly aromatic terpenes and other compounds in the cannabinoid entourage may be to chemically repel predators (although conversely, some may be chemo-attractants for pollinators). Limonene, pinene and other terpenes are highly volatile, and form major constituents of the immediate air barrier around the plant (contributing of course to its odor). These compounds also act as insect repellants and some limited studies suggest the cannabis exudate may even be actively toxic to some insects.

(d) Wound healing. Plant wounding can occur in response to environmental events (wind, mechanical disturbance) or predation. When wounded, Cannabis plants increase resin exudation, suggesting that the exudate plays a role in immediate wound stasis and in longer term wound resolution. This enhanced exudation may also protect the plant against moisture loss associated with wounding.
Cell intrinsic functions
(a) Anti-oxidant and UV protection. Many environmental stressors converge at the molecular level upon pathways that generate oxidation and free radicals. Within cells, these radicalized molecules and oxidizing conditions are generally cytotoxic. Proteins and DNA molecules cannot function properly under oxidizing conditions, leading to widespread degeneration in cellular processes. The lipid membrane that separates the cytoplasm from the environment is prone to peroxidation and its integrity if compromised under oxidizing conditions and by high levels of free radicals. Cannabinoids have anti-oxidant capacity: this is one of the reasons they have been promoted as potential therapies in neurodegenerative
and inflammatory diseases where cellular oxidation and free radical generation are key. In this functionality of cannabinoids, it is important to note that we are looking at both receptor-dependent and receptor-independent mechanisms of action. Via CB1 and CB2, cannabinoids may initiate protective pathways that oppose the generation of free radicals or act to limit the effects of inflammatory damage. Absent receptor binding, however, cannabinoids themselves have the capacity to act as anti-oxidant (electron donors). If present in sufficient amounts, they may simply ‘defuse’ the oxidizing cellular environment, an ability conferred by the juxtaposition of their phenolic hydroxyl groups with alkyl side chains. Natural cannabinoids that contain this structural elements (e.g. L-THC, cannabidiol, cannabinol) are attractive candidates for use as therapeutic, nutraceutical or cosmeceutical anti-oxidants. An explicit demonstration of the anti-oxidant properties of cannabidiol and other cannabinoids was made by Hampson, et al in 1998. Here, cyclic voltammetry was used, a technique that measures the ability of a compound to donate or receive electrons. A recognized anti-oxidant (NHT) and anandamide, a
cannabinoid receptor ligand without cannabinoid structural features were used as positive and negative controls, respectively. The ability of cannabidiol and cannabinol to reduce oxidation of a compound called dihydrorhodamine were also studied. Figure 3 shows that cannabidiol and THC both exceeded the ability even of BHT to act as electron donors (left panel) or rescue the oxidation of dihydrorhodamine.

Protection against UV is a further aspect of the anti-oxidant properties of cannabinoids, and may again be viewed as both receptor dependent and independent. UV damage (especially UV-B) is a major generator of free radicals and oxidative cellular damage. The anti-oxidant properties of cannabinoids can thus translate to protection against UV damage. CB1 ligands have been shown in a study by Megina et al to protect directly against UV-B induced melanogenesis (darkening) of skin. UV levels affect plant production of THC and cannabidiol, suggesting that in response to UV threat the plant defends itself by over-producing the protective compounds. THC is a strong absorber of UV-B in the 280 -315 nm wavelength range.
Figure 3. Anti-oxidant potential of cannabinoids (Hampson et al 1998). Reproduced according to copyright permissions from http://intl.pnas.org/site/aboutpnas/rightperm.xhtml. Researchers have demonstrated that plant-derived cannabinoids have oxidation potentials similar to that of the known anti-oxidant butylated hydroxytoluene (BHT). In contrast, the human cannabinoid receptor ligand, anadamide, does not have these anti-oxidant properties and a different chemical structure.
Parallelization Of Function In Barrier Defense Between The Cannabinoid Systems In Plants And Humans
We have established above that cannabinoids and their entourage are evolutionarily ancient defense compounds that protect plants against desiccation microbes, insect damage, wounding and UV-B. Parallel needs exist in the human barrier against the environment, the skin. There is an opportunity to exploit these natural defense mechanisms to support skin health, remediate dermatological problems and repair damage. Each of these plant defense functions has a correlate in human skin and a cosmeceutical indication:
The medical dermatology and cosmeceutical communities have overlapping priorities for the promotion of human skin health. The constant assailing of skin by environmental threats, coupled with preventive measures for melanoma and the effects of aging, leads to an increasing trend for everyday skin treatments to be supplemented with bioactive ingredients. These ingredients are often plant-derived, reflecting the potential for barrier compounds in plants extend their protective effects to human skin. Table 1 presents an analysis of the most common desirable properties of the bioactive ingredients included in cosmeceuticals. Many of these properties are potently represented in the biological activity of cannabinoids.
Skin Physiology And The Skin Endo-Cannabinoid System
Humans have approximately 20 square feet of skin. This soft barrier both protects us from the environment and allows us to communicate and receive inputs from it. At the gross level skin has three major layers (depicted in Figure 4), the dermis (a highly impermeable layer of dead cells and extracellular matrix proteins), the epidermis (connective tissue, muscle and adipose), and the hypodermis (fat and connective tissue).
Blood capillaries supply oxygen and nutrients, the lymphatic system circulates plasma, and sensory neurons innervate. This gross view underestimates the complexity of the skin, for example the epidermis alone is divided into 5 specialized layers. Specialized layers arise from the presence and differentiation of multiple cell types (keratinocytes, fibroblasts, basal cells, Langerhans cells, skin-resident immune cells, adipocytes, neurons and melanocytes). Hair follicles, sebaceous glands and apocrine glands play important roles in sensation, thermoregulation, and maintaining the skin’s barrier function.

The centrality of skin function to human health has meant that evolution endowed skin with complex biochemical networks of receptors and small molecules that continually survey and respond to inputs, and modify the reactions of resident cells to react to incoming information. One such network is the skin endocannabinoid system (SkECS), where endogenous and exogenous cannabinoids can act at numerous receptor sites to promote skin health. Both metabotropic and ionotropic cannabinoid receptors (CB1, CB2, TRPV1, TRPA1 and TRPV4) are present on multiple cell types in the human skin (fibroblasts, keratinocytes, immune cells, neurons, subcutaneous fat cells and muscle layers). Figure 5 illustrates the location of these receptors in the multiple skin layers. Clearly they are positioned to control or contribute to many aspects of skin function.
Figure 3. Anti-oxidant potential of cannabinoids (Hampson et al 1998). Reproduced according to copyright permissions from http://intl.pnas.org/site/aboutpnas/rightperm.xhtml. Researchers have demonstrated that plant-derived cannabinoids have oxidation potentials similar to that of the known anti-oxidant butylated hydroxytoluene (BHT). In contrast, the human cannabinoid receptor ligand, anadamide, does not have these anti-oxidant properties and a different chemical structure.
How do cannabinoids promote skin health? A summary of the properties of cannabinoids that contribute to skin health are shown in Table 2.
Table 2. Documented properties of cannabinoids (blue boxes) that address skin problems shown in the first row of the table.
The presence of the SkECS is a clear indicator that cannabinoids may be central to skin health. It also presents the intriguing possibility that exogenously applied cannabinoids could augment, initiate or supplement the roles that endocannabinoids play in the skin to therapeutic benefit. Cannabinoids and their diverse receptors have been implicated in the proliferation of skins cells, in the differentiation processes that give rise to the multicellular complexity of skin, in hormone and mediator secretion that maintain skin tone, and in the activity of hair follicle cells and the sebaceous glands. The SkECS maintains skin homeostasis, and loss of this homeostasis leads to disorders such as acne, dermatitis, itch, pain, psoriasis, sclerosis and excessive or unwanted hair growth.

Targets for cannabinoid support of skin health are summarized as follows:

Epidermis

Synthetic and phytocannabinoids inhibit keratinocyte proliferation, decrease keratinization and suppress cornified envelop formation; promote epidermal differentiation; inhibit proliferation of transformed (tumorigenic) keratinocytes.
Sebaceous glands – CB2 ligands stimulate lipid and sebum production and apoptosis of glandular cells.

Hair follicles – Anandamide and THC inhibit hair shaft elongation and proliferation, promote intraepithelial apoptosis and catagen regression.

Dermatitis (acute/chronic) – Cannabinoid receptors suppress inflammation (receptor deficient mice display exacerbated inflammation).

Dermatitis (contact) – Cannabinoid receptors suppress inflammation (receptor deficient mice display exacerbated inflammation).

Dermal fibrosis – Cannabinoid receptors suppress fibrosis (receptor deficient mice display exacerbated inflammation).

UV-B induced skin tumors and skin inflammation –
Cannabinoid receptors suppress UV-B induced skin tumors and skin inflammation (receptor deficient mice display exacerbated UV-B induced skin tumors and skin inflammation).
Indications For Cannabinoid Enhancement Of Skin Health
Several recent publications have captured the excitement that surround potential indications for cannabinoids in skin (Table 3). This sense of a new frontier in skin health is heightened by the facts that (1) non-psychoactive cannabinoids are readily sourced from natural plant sources, and (2) that cannabinoids are attractive topical agents due to their lipophilicity and skin-penetrating properties. The latter is particularly important if the benefits of cannabinoids for skin health are to be disseminated to the widest possible population through easily accessible skincare formulations. Transdermal delivery of cannabidiol via ethosomes (synthetic vesicles designed for tissue penetration) produced significant accumulation in the skin that persisted for at least 72 h (Lodski et al). The prior work of Stinchcomb et al provides strong evidence that THC, cannabidiol and cannabinoid are highly skin permeant, even without an ethosomal component.
Figure 6. Word cloud (frequency analysis) of the desirable properties associated with >100 bioactive, naturally-derived cosmeceutical ingredients. Data analysed from GCS at
www.gscos.com/cosmeceuticals/ingredients-glossary
Table 3. The potential of topical cannabinoids in promotion of skin health. Reproduced with modification from Biro (2009). Trends in Pharmacological Sciences.
Cannabinoids are ancient defensive chemicals, evolved to protect plants from diverse environmental threats. In humans, our skin leverages this defensive capability through the presence of the skin endocannabinoid system (SkECS). The SkECS can be augmented, activated or supplemented by the therapeutic topical application of plant-derived cannabinoids, providing both general support of skin health and targeted actions to address specific skin health problems.
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