Life blood, it’s no joke. Blood delivers nutrients to all the tissues and organs of the body, eliminates carbon dioxide and metabolic wastes, transmits hormonal signals throughout tissues, and mediates peripheral immune activity.
The vascular tree is made up of many types of blood vessels: Arteries and smaller arterioles that deliver oxygen and nutrients to the tissues, networks of microscopic blood vessels known as capillary beds that perform gas and nutrient exchange, and tiny venules and larger veins that drain blood away from the tissues. Each type of blood vessel serves a unique physiological function depending on its location in the vascular tree. Microvascular in particular (capillaries and postcapillary venules) have distinct properties that enable them to meet the unique requirements of the tissues and organs they vascularize.
The brain is no exception. The central nervous system (CNS), composed of the brain and spinal cord, has different needs than the rest of the body, and is protected by a persnickety boundary known as the blood-brain barrier (BBB).
The BBB creates a brain-friendly environment by strictly regulating the passage of ions, molecules, and cells between the blood and the brain, guarding neural tissue against exposure to toxins, pathogens, inflammation, and injury.
Dysfunction of the blood-brain barrier can result in ion dysregulation, altered signaling homeostasis, and infiltration of immune cells and molecules into the CNS. These processes are associated with neuronal dysfunction and degeneration. Indeed, loss of barrier function during neurological diseases such as stroke, multiple sclerosis, brain traumas, and neurodegenerative disorders, is often implicated in the pathology and progression of these diseases.
Blood-Brain Barrier: Structure and Function
The blood-brain barrier is a physical and biochemical boundary that consists of endothelial cells (ECs), astrocytes, mural cells, and vascular basement membranes. The protective properties of the BBB predominantly arise from the endothelial cells that make up the walls of the blood vessels, but are also induced and maintained by interactions with mural cells, immune cells, glial cells, and neural cells. Together these cells, along with extracellular matrix components, form the functional neurovascular unit (Daneman & Prat, 2015).
Blood-brain barrier microvasculature is composed of continuous non-fenestrated capillaries. “Continuous” means that the membranes of adjacent endothelial cells are joined together via tight junctions, which forms a virtually impermeable barrier that strongly limits paracellular flux (movement of molecules and ions between cells). Intercellular clefts (channels between cells) do allow some movement of ions across the blood vessel wall. Continuous capillaries are typically found in the nervous system, adipose (fat) tissue, and muscle tissue. “Non-fenestrated” refers to the absence of fenestrae (Latin for “window”) — small openings or pores in the vasculature. Fenestrated capillaries are typically found in tissues where extensive molecular exchange occurs, including the kidneys, endocrine glands, and small intestine. Conversely, non-fenestrated capillaries severely limit molecular exchange in regions like the CNS where such transmission is undesirable (Baxter, R., 2020).
Not only does the BBB limit movement of substances between cells, it prevents molecules from traveling through the endothelial cells themselves. ECs of the central nervous system demonstrate extremely low rates of transcytosis relative to ECs of the periphery. Transcytosis is a form of transcellular transport in which macromolecules are transported by vesicles (membrane-enclosed bubbles) across the interior of a cell. In this form of transport, macromolecules are enveloped in vesicles on one side of the cell, drawn across the cell, and discharged on the other side. Low rates of transcytosis in CNS ECs means there’s much less transmission of substances through the cells.
In addition to preventing substances from entering the CNS in the first place, CNS ECs are endowed with efflux transporters — proteinaceous pumps that remove lipophilic molecules which may have diffused across the blood-brain barrier.
Of course there are substances that the CNS requires, including nutrients. To accommodate this need, CNS ECS are equipped with highly specific influx transporters that deliver nutrients across the BBB into the brain. CNS ECs have more mitochondria than peripheral ECs in order to fuel efflux and influx transporters.
Blood vessels are enveloped and supported by basement membranes (BMs), one on the inside (vascular BM) and one on the outside (parenchymal BM). The vascular BM is made up of an extracellular matrix secreted by endothelial cells and pericytes, while the parenchymal BM is predominantly secreted by astrocytic processes that reach toward the blood vessels. These two basement membranes serve as an anchor for signaling processes in the vasculature, and act as an extra barrier molecules and cells must cross to access neural tissue. The blood-brain barrier may malfunction if the basement membranes are disrupted by enzymes that degrade extracellular matrix. BBB malfunction is often accompanied by leukocyte (white blood cell) infiltration, and is a factor in many neurological disorders (Daneman & Prat, 2015).
The BBB engages not only in cellular self-defence, but also serves as an active interface that controls the CNS microenvironment to promote normal neuronal functioning.
BBB cells communicate with CNS cells and adapt their behavior depending on the needs of the CNS (Bonferoni, et al., 2019).
Let’s take a look at the cell types that make this neurovascular coupling possible.
Astrocytes are star-shaped sub-types of glial cells in the CNS that provide the cellular link between blood vessels and neuronal circuitry. Astrocytes are involved in the provision of nutrients from blood vessels to neurons, and they supply neurotransmitters and support BBB integrity through the maintenance of tight junctions (Kubotera et al., 2019).
Mural cells — pericytes and vascular smooth muscles — are located adjacent to endothelial cells on their abluminal surface (the outward facing side of the blood vessel). Pericytes contain contractile proteins, and have the ability to control the diameter of the capillary. These cells are involved in the regulation of angiogenesis (the development of new blood vessels), deposition of extracellular matrix, wound healing, regulation of immune cell infiltration, regulation of blood flow in response to neural activity, and vascular clearance of toxic species out of the brain. They also possess stem cell-like properties.
Pericytes can modulate the BBB by releasing signaling factors that influence the number of tight junctions between endothelial cells. A drop in pericyte numbers can lead to loss of tight junctions, and thus an increase in BBB permeability. Pericytes act as the central mediator between brain parenchyma (functional tissues, as distinguished from supporting tissues) and the vascular system, ensuring that the blood supply meets the hefty metabolic demands of the brain. Pericytes are vulnerable to injury and stress, and their degradation is associated with multiple neurological diseases (Brown et al., 2019).
Therapeutic Relevance of the Blood-Brain Barrier
The blood-brain barrier performs an excellent service in keeping the central nervous system safe, but sometimes things go wrong. Systemic chronic inflammation and oxidative stress, which occurs in conditions like type 2 diabetes, leads to cerebral inflammation, which destabilizes the blood-brain barrier. This can result in premature cognitive decline; indeed, type-2 diabetes increases the risk of dementia 5-fold. Many treatment strategies for conditions like dementia thus investigate anti-inflammatory interventions to restore integrity and function of brain microvasculature.
The restrictive nature of the blood-brain barrier, which is typically protective of the CNS, is perversely the same factor that makes neurological disorders so difficult to treat. The BBB is a major obstacle for delivery of therapeutics to the central nervous system. Significant efforts are underway to develop methods to modulate or bypass the blood-brain barrier in order to administer treatments to target tissues (Brook et al., 2019).
Some estimates suggest that 98% of active substances of low molecular weight, and almost 100% of macromolecules, fail to permeate the BBB. This leads to paltry bioavailability of therapeutics in the CNS. Treatments can be administered directly to the brain via intracerebroventricular or intraparenchymal injections, intracranial delivery with mini-pumps, catheter infusions, focused ultrasound approaches, or external electromagnetic field-based methodologies, but these techniques are risky and invasive. Many are unsuitable for long-term treatment.
Other strategies are under investigation, including the development of nanoparticles and nanoemulsions to deliver therapeutics across the blood-brain barrier. Nose-to-brain drug delivery is also an emerging approach to bypassing the BBB. There are many advantages to using the olfactory system, including patient compliance, high safety, ease of administration, rapid onset of action, and minimal systemic exposure. Nasal administration allows therapeutics to skip hepatic first-pass metabolism, which means that nasal doses can be 2–10 times lower than oral doses.
Some researchers are developing curcumin-loaded nanoemulsions for intranasal delivery to the central nervous system. Curcumin is a constituent of turmeric (Curcuma longa) which is valued for its anti-inflammatory properties; studies have indicated that nano-delivery of curcumin may ameliorate some neurodegenerative diseases. The trick is to deliver curcumin across the BBB in sufficient quantities to elicit a therapeutic effect (Bonferoni et al., 2019).
Essential Oils and the Blood-Brain Barrier
A major obstacle in treating neurological disorders is that delivery of therapeutics to the central nervous system is limited by the blood-brain barrier. But what about essential oils? How do EOs and their constituents interact with this powerful physiological boundary?
Terpenes and terpenoids, which make up the majority of hydrocarbons in essential oils — are small, fat-soluble organic molecules. Many of these can traverse nasal mucosa when inhaled, and penetrate the skin when applied topically. Due to their small size and lipophilic properties, some terpenes can absorb into the bloodstream and cross the blood-brain barrier (Agatonovic-Kustrin et al., 2019).
There are two primary actions of essential oils and their constituents that are of interest for the present discussion:
- Some essential oil constituents, including terpenes and terpenoids, can pass through the BBB to elicit direct effects on the CNS
- Some essential oil constituents modulate the structure and function of the barrier itsef
Direct Effects of Terpenes in the Central Nervous System
ꞵ-elemene is a widely-researched sesquiterpene derived from the rhizome of Curcuma wenyujin, a plant in the Zingiberaceae family with an extensive history of use in Chinese medicine. One in vivo study investigated the tissue distribution of elemene, as well as its effects, on tumor-inoculated rodents. Researchers found that elemene passed through the blood-brain barrier, and exerted a therapeutic effect on cerebral malignancy (Wu et al., 2010).
A recent review article presented the findings that β-elemene exerted direct antitumor effects by inducing apoptosis, arresting the cell cycle, inhibiting angiogenesis and cell migration, enhancing the immunogenicity of tumor cells (the ability of a foreign substance to induce an immune response), promoting erythrocyte (red blood cell) immune function, and inhibiting cancer stem cell-like effects. β-elemene also reversed multidrug resistance and increased tumor cell chemosensitivity.
β-elemene was also found to regulate the NF-κB/STAT3 pathway, one that plays a major role in long-term inflammatory responses and cancer. The authors theorized that inhibition of the NF-κB signaling pathway is one of the top mechanisms by which β-elemene therapeutically alters the inflammatory environment and tumor microenvironment. Treatment with β-elemene regulated oxidative stress in vitro and in vivo, alleviated tissue damage, and prevented the development of the type of microenvironment that encourages tumor formation. No cytotoxicity or clinical side effects were observed (Xie et al., 2020).
In another in vivo rodent study, β-elemene was found to suppress the inflammatory responses in mice with experimentally-induced sepsis, and to attenuate the learning/memory deficit typically observed in septic mice. Researchers theorized that β-elemene may block cognitive impairment in septic mice by crossing the blood-brain barrier and directly suppressing microglia-mediated neuroinflammation. Indeed, β-elemene treatment was found to inhibit the RAC1/MLK3/p38 signaling pathway in microglia, and the authors considered the sesquiterpene to have potential as a treatment for sepsis-associated encephalopathy (Pan et al., 2019).
β-elemene isn’t the only sesquiterpene capable of crossing the BBB and exerting neural anti-inflammatory effects. Another in vitro study investigated the capacity of a sesquiterpenoid constituent of turmeric (Curcuma longa) known as aromatic (ar)-turmerone to reduce the inflammatory response to amyloid-beta (peptides that form plaques in the brains of those with Alzheimer’s) in mouse microglial cells. The researchers found that ar-turmerone exerted significant anti-inflammatory effects, as well as antioxidant and anti-tumor effects.
Neuroinflammatory responses of the central nervous system are well-established features of various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, HIV-associated dementia, stroke, and multiple sclerosis.
Activation of microglia, the resident immune cells of the central nervous system, play a significant role in neurodegenerative disease pathology. There are two routes of activation for microglial cells:
- As a response to neuronal cell death/damage induced by neuroinflammation
- Exposure to environmental toxins such as bacterial and viral pathogens
Microglia activation is typically adaptive, and plays an important role in host defense and CNS tissue repair. Chronic or dysregulation activation, however, can result in excessive neuroinflammation, leading to inflammation-mediated neuronal cell death and brain injury.
Ar-turmerone was found to impair the amyloid-beta-induced inflammatory response of microglial cells by inhibiting the NF-κB, JNK, and p38 MAPK signaling pathways, and also protected hippocampal HT-22 cells from indirect neuronal toxicity triggered by activated microglial cells (Park et al., 2012).
Essential Oil Constituents Alter Blood-Brain Barrier Permeability
Increased blood-brain barrier permeability has been associated with the development and progression of a number of CNS pathologies, including multiple sclerosis, Alzheimer’s disease, and HIV-associated dementia.
A meta-analysis investigated the effect of borneol (a terpene-derivative) on decreasing BBB permeability in an experimental model of ischemic stroke in rodents. The study found that treatment with borneol exerted a protective effect by decreasing BBB permeability. The authors propose that borneol improved BBB integrity by:
- Upregulating tight junction proteins
- Accelerating proliferation of endothelial cells
- Acting on cytokines to induce anti-inflammatory effects
- Reducing oxidative reactions
- Improving energy metabolism (Chen et al., 2019)
So what does this mean for you as a clinician or caregiver in your household? Probably not much, in practical terms. Despite the publication of myriad studies, there’s still so little we know about essential oils and the blood-brain barrier. As always, look to long-standing traditional usage for guidance. And take the science for what it is: an excessively granular, hopeful, incomplete portal into the curious interface between bodies, plants, and pathologies.
References
Agatonovic-Kustrin, S., Kustrin, E., & Morton, D. W. (2019). Essential oils and functional herbs for healthy aging. Neural Regeneration Research, 14(3), 441–445. https://doi.org/10.4103/1673-5374.245467
Baxter, R. (2020, October 29). Capillaries. Kenhub. https://www.kenhub.com/en/library/anatomy/capillaries
Bonferoni, M. C., Rossi, S., Sandri, G., Ferrari, F., Gavini, E., Rassu, G., & Giunchedi, P. (2019). Nanoemulsions for “nose-to-brain” drug delivery. Pharmaceutics, 11(2). https://doi.org/10.3390/pharmaceutics11020084
Brook, E., Mamo, J., Wong, R., Al-Salami, H., Falasca, M., Lam, V., & Takechi, R. (2019). Blood-brain barrier disturbances in diabetes-associated dementia: Therapeutic potential for cannabinoids. Pharmacological Research, 141, 291–297. https://doi.org/10.1016/j.phrs.2019.01.009
Brown, L. S., Foster, C. G., Courtney, J.-M., King, N. E., Howells, D. W., & Sutherland, B. A. (2019). Pericytes and neurovascular function in the healthy and diseased brain. Frontiers in Cellular Neuroscience, 13. https://doi.org/10.3389/fncel.2019.00282
Chen, Z., Xu, Q., Shan, C., Shi, Y., Wang, Y., Chang, R. C.-C., & Zheng, G. (2019). Borneol for regulating the permeability of the blood-brain barrier in experimental ischemic stroke: Preclinical evidence and possible mechanism. Oxidative Medicine and Cellular Longevity, 2019, 1–15. https://doi.org/10.1155/2019/2936737
Daneman, R., & Prat, A. (2015). The blood–brain barrier. Cold Spring Harbor Perspectives in Biology, 7(1). https://doi.org/10.1101/cshperspect.a020412
Kubotera, H., Ikeshima-Kataoka, H., Hatashita, Y., Allegra Mascaro, A. L., Pavone, F. S., & Inoue, T. (2019). Astrocytic endfeet re-cover blood vessels after removal by laser ablation. Scientific Reports, 9(1), 1263. https://doi.org/10.1038/s41598-018-37419-4
Pan, C., Si, Y., Meng, Q., Jing, L., Chen, L., Zhang, Y., & Bao, H. (2019). Suppression of the rac1/mlk3/p38 signaling pathway by β-elemene alleviates sepsis-associated encephalopathy in mice. Frontiers in Neuroscience, 13, 358. https://doi.org/10.3389/fnins.2019.00358
Park, S. Y., Jin, M. L., Kim, Y. H., Kim, Y., & Lee, S. J. (2012). Anti-inflammatory effects of aromatic-turmerone through blocking of NF-κB, JNK, and p38 MAPK signaling pathways in amyloid β-stimulated microglia. International Immunopharmacology, 14(1), 13–20. https://doi.org/10.1016/j.intimp.2012.06.003
Wu, X. S., Xie, T., Lin, J., Fan, H. Z., Huang-Fu, H. J., Ni, L. F., & Yan, H. F. (2010). An investigation of the ability of elemene to pass through the blood-brain barrier and its effect on brain carcinomas. Journal of Pharmacy and Pharmacology, 61(12), 1653–1656. https://doi.org/10.1211/jpp.61.12.0010
Xie, Q., Li, F., Fang, L., Liu, W., & Gu, C. (2020). The antitumor efficacy of β -elemene by changing tumor inflammatory environment and tumor microenvironment. BioMed Research International, 2020, 1–13. https://doi.org/10.1155/2020/6892961
