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Author: Sylvia Marinova, PhD student in in the "Genomic Stability" lab at BAS

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Researchers from the University of Florida have discovered a new mechanism of signal transmission between the nerve cells in the brain and the intestinal microbiome. In their study, they also showed how this mechanism can be modulated from a compound, called fenchol, that is abundant in basil and some other plants and can reduce neurotoxicity in Alzheimer's disease&nbsp; <a href="https://www.frontiersin.org/articles/10.3389/fnagi.2021.735933/full" target="_blank" rel="noopener"> [ref.1]</a>.&nbsp;&nbsp;

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In this article we will first look at what causes Alzheimer's disease, what causes it and then we will look in detail at whether basil can help fight the disease.

What-is-Alzheimer's-disease?

What is Alzheimer's disease?

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Alzheimer's disease is a neurodegenerative disease that is associated with memory loss (dementia). Usually it begins with a slight degree of forgetfulness, but over time it can progress to the inability to maintain conversation and cope with daily activities and needs. The disease is more characteristic of the elderly, although it is known that pathological changes in the brain begin long before the appearance of the first symptoms.

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Science still cannot give a full explanation of the causes of the onset of the disease, but usually patients experience increased deposition of the so-called amyloid-beta plaques in the brain. <a href="https://www.bioseek.eu/en/eng/research/pubmed/Neuronal_heparan_sulfates_promote_amyloid_pathology_by_modulating_brain_amyloid_clearance_and_aggregation_in_Alzheimer_s_disease_27030596" target="_blank" rel="noopener">[ref.2]</a>. This process leads to pathological changes, which include neurotoxicity and the dying of nerve cells, as a result of which dementia appearsas well as a decrease in the ability to communicate.&nbsp;

Is-there-a-link-between-Alzheimer's-and-our-gut-microbiome?

Is there a link between Alzheimer's and our gut microbiome?

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There is already data in the literature that show that patients suffering from Alzheimer's disease have a different composition of their intestinal microbiome. What does it mean?

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The human microbiome is a complex ecosystem containing over 100 trillion micro-organisms, which is proving crucial to our existence. In addition, many nerve cells that form a direct connection to our brain, called the gut-brain axis, can also be found in our guts. This two-way communication with the central nervous system also takes place through our immune system, the vagus nerve and various metabolites, which are a product of the metabolism of microorganisms living in the intestine. An important group of such substances are short-chain fatty acids. Recent studies suggest that this may be directly related to the development of pathological conditions such as Alzheimer's disease<a href="https://www.bioseek.eu/en/eng/research/pubmed/the_impact_of_the_microbiota_gut_brain_axis_on_alzheimer_s_disease_pathophysiology_33246175" target="_blank" rel="noopener">&nbsp;[ref.3]</a>. Indeed, the amount of short-chain fatty acids (SCFA)&nbsp;found in Alzheimer's patients is much less than in healthy patients with a well-balanced microflora.

How-does-our-brain-sense-the-presence-of-SCFAs?

How does our brain sense the presence of SCFAs?

How-does-our-brain-sense-the-presence-of-SCFAs?_2_0

This is a very logical question that science has an answer to. The nerve cells of our central nervous system have a sensor (receptor) on its surface that is called&nbsp;free fatty acid receptor . It is also found in many other tissues of the human body and its functions generally include regulation of energy metabolism and the&nbsp;immune system.&nbsp;In addition, researchers at the University of Florida, whose study is the subject of this article, show that the activity of these receptors may play a positive role in protecting brain cells from the accumulation of amyloid-beta plaques in Alzheimer's disease.

The-role-of-basil

The role of basil

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A mong144,000 compounds in search of natural products that can have a stimulating effect on free fatty acid receptors in the brain, the researchers came across a substance called fenchol.&nbsp;&nbsp;

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Fenchol is found in abundance in basil leaves and gives them the specific aroma that we all know. It has the ability to bind specifically to fatty acid receptors in the brain and activate them. This in turn reduces the accumulation of amyloid-beta plaques and their neurotoxicity on cells, as scientists have shown in living cells and in model animals.

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Continuing the study, they managed to get into greater depth of the exact cellular processes that are affected by fennel. They identify two processes that help reduce neurotoxicity.

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One is related to the breakdown of unnecessary proteins in the cell by the so-called proteasome. It seems that fenchol manages to stimulate it and thus break down the amyloid-beta plaques, which are of a protein nature.&nbsp;

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The other mechanism concerns the aging of nerve cells. Fenchol treatment reduces this process and this allows the cells to regenerate faster and not accumulate malfunctioning cells in the tissue, called zombie cells - cells that accumulate in diseased tissues and cause inflammation in them.

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"Fenhall affects two interconnected mechanisms - aging and proteolysis", says Yadav, project leader, "It reduces the formation of semi-dead zombie nerve cells and also increases the breakdown of pathological amyloid-beta plaques so that they clear faster than the brain"<a href="https://www.genengnews.com/news/alzheimers-disease-pathology-curbed-using-aromatic-compound-in-basil/?utm_medium=newsletter&amp;utm_source=GEN+News+Highlights+of+the+Week&amp;utm_content=01&amp;utm_campaign=GEN+News+Highlights+of+the+Week_20211009&amp;oly_enc_id=3770G6149945C3X" target="_blank" rel="noopener"> [ref.4]</a>.

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In the future, researchers will focus on the treatment and prevention options of Alzheimer's with fenchol. Their idea is to compare the effectiveness of taking fenchol directly as a drug or taking basil.

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&nbsp;

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Activation of Microbiota Sensing – Free Fatty Acid Receptor 2 Signaling Ameliorates Amyloid-β Induced Neurotoxicity by Modulating Proteolysis-Senescence Axis, 2021, Front. Aging Neurosci

<a href="https://www.bioseek.eu/en/eng/research/pubmed/Neuronal_heparan_sulfates_promote_amyloid_pathology_by_modulating_brain_amyloid_clearance_and_aggregation_in_Alzheimer_s_disease_27030596" target="_blank" rel="noopener">Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-β clearance and aggregation in Alzheimer's disease</a>, 2016, Science Translational Medicine

The impact of the microbiota-gut-brain axis on Alzheimer's disease pathophysiology, 2020, Pharmacological Research

Alzheimer's Disease Pathology Curbed Using Aromatic Compound in Basil, 2021, Genetic Engineering and Biotechnology News

What are the most famous natural sweeteners, what they are and from which plants are extracted. The answers to these questions can be found in the following article.

Sweetness From Nature Or How To Replace Sugar With Natural Sweeteners

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In this article you will find useful information about the healing properties of the broadleaf plantain according to the Iranian traditional medicine and modern science.

The Broadleaf Plantain: A Modest Plant with Great Healing Potential

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In the season of the ramson find out what health properties it possesses, how it has been used in the past and how to prepare delicious pesto from wild garlic.

Wild Garlic - The Healing Properties of Ramson. Bonus: Recipe for Delicious Wild Garlic Pesto

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In this article you will find information about the beneficial effects of nettle and learn whether it has the potential to help treat oncological diseases.

Healing Properties of Stinging Nettle and Its Potential in Cancer Treatment

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Tea is the second most common drink after water. Tea, which is prepared from the leaves of the Camellia sinensis plant is 3 types: green, oolong and black - depending on the degree of oxidation of the leaves. The most oxidized are the leaves of black tea, not so much of the oolong tea and the leafs of green tea are not oxidized at all.

9 unexpected health benefits of green tea and how to prepare it

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Chillies owe their effect to a compound called capsaicin, which can help control inflammation and other harmful processes in the body associated with the accumulation of fatty plaques in the arteries (atherosclerosis), for example.

Are chili peppers healthy - find out what science has to say

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Studies have suggested that ginseng reduces physical, chemical and biological stress, while increasing overall vitality and immune function, including physical and mental capacity.

8 reasons why the Chinese call ginseng The King of Herbs

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Over the past few decades, Ttribulus terrestris has been the subject of extensive research. It has been found that the herb has the following effects or at least potential for them, some of which we will discuss in the article.

Tribulus terrestris - what is the scientific evidence behind it's effects on your health

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Basil in the fight against Alzheimer's disease

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 Basil in the fight against Alzheimer's disease

Силвия Маринова

<h4>Author: Ivelina Yankova, Bachelor of Biomedical Sciences</h4>

What-is-marijuana?

What is marijuana?

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Marijuana is derived from the Cannabis sativa plant, which was originally found in India and Central Asia. It has characteristic shaped leaves, gives flowering, which also has a characteristic appearance and can grow over three meters. Marijuana is the dried leaves, flowers, twigs and seeds of the plant. Cannabis contains over 120 active substances called cannabinoids or phytocannabinoids, the most famous of which are cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC).&nbsp;

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How-is-marijuana-used?

How is marijuana used?

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<h4>People most often smoke marijuana in paper in the form of a cigarette (joint), as well as in a pipe or water pipe (bong). Rolling it into a paper made of tobacco (blunt) is also a known method for use of the plant.</h4>

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<h4>To avoid smoke inhalation, there are devices called vaporizers, which can also use liquid marijuana extract. They withdraw the active substances from the plant by decarboxylation (removing a carboxylic group from the compound, in which carbon dioxide is released – most often by heating) and storing their fumes in a specific part of the device.&nbsp; When smoking from the evaporator, these fumes are inhaled, which gives the same effect as when inhaling the smoke.</h4>

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<h4>Also, the active substances can be extracted and mixed with various food products to prepare meals.</h4>

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<h4>Lately, smoking or eating THC-rich marijuana extracts has become more common; these may be in a different form - oil, wax or solid.</h4>

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Marijuana-before-and-today

Marijuana before and today

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Marijuana use is believed to have started as early as 2900 BC. In the beginning, it was used for healing and there is evidence that the ancient Egyptians used it to treat glaucoma and inflammation of the body. In the original Jewish version of "Mass Exodus" (the second part of the Bible, which in Bulgaria we call the "New Testament") there are writings about sacred oil for anointing, in which content there was also marijuana. In 2900 BC, Chinese Emperor declared cannabis a popular drug and many other medicinal properties of this plant have since been discovered (ref.8).

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The following records found were from 1000 BC, when Indians created a drink containing marijuana, which to this day is used as an anti-phlegmatic and anesthetic in India. Indians also believed that cannabis helps against dysentery and leprosy, a disease known in antiquity that was once considered incurable. Marijuana is known for its spiritual significance for the Indians. The notes of the ancient collection "The Vedas" claimed that cannabis was born from a drop of heavenly nectar that fell to the ground. This religiosity had spread cannabis use even further (ref.9).

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Other ancient civilizations, such as the Greek, Roman, Arabic and English, have also used cannabis to treat various types of infections and diseases (arthritis, gout, syphilis, migraine, insomnia, etc.), and some had used it only for recreational purposes (ref.9). After the year 800, along with the spread of Islam, recreational cannabis use was on the rise because there was no specific ban on marijuana in the Koran.

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As people's skills progress and due to the rapid growth and easy cultivation of marijuana, it begins to be used as a resource for making clothes, paper, ropes and sails for ships. Later, cannabis began to be used and grown by American colonies and by Spain during military missions.

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By the mid-19th century, cannabis was already recommended by doctors and sold in pharmacies without the need for prescription (ref.10), and was even added to the American Pharmacopoeia, temporarily (ref.8). It wasn't until the early 20th century that marijuana began to be used for recreational use in America when it was imported by Mexican immigrants into the country. This happened during the Mexican Revolution and the Great Depression in America, when there was mass unemployment. People are believed to have started hating Mexican immigrants and the marijuana they imported. The great misunderstandings led to the introduction of the "Marijuana Taxes Act" in 1937 – to be used only for specific industrial and medical purposes, only when paying excise duty (ref. 11).

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Meanwhile, societies that opposed the ongoing change were growing. This continued until the late 1950s, when cannabis stopped being used entirely, and in 1970 President Richard Nixon repealed the Marijuana Tax Act and listed marijuana in the Controlled Substances Act as a first-degree drug, along with LSD, heroin and ecstasy. This law states marijuana as a drug with great potential for abuse and which has no medicinal properties that can be applied in medicine. This prohibition made it difficult to conduct any scientific research with the plant (ref.12).

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Years later, despite the law's attempts to impose strict measures against marijuana, some states began to decriminalize its use for medical reasons, and by 2019, eleven states in America and other countries around the world legalize marijuana for both medical and recreational purposes.

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The-first-research-on-the-effects-of-marijuana

The first research on the effects of marijuana

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Nowadays, there are many studies done on the benefits and side effects of marijuana use. Moreover, we also know much more about the substances that are responsible for the properties of marijuana, medicinal or not.

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The first published study on the healing properties of marijuana is from the year 1840 (ref.13). Dr. O'Shaughnessy first examined the effects of marijuana extract intake in animals, where he did not see any negative effects. Then he began clinical trials in people with different types of diseases – rheumatism, hydrophobia, cholera, dysentery, tetanus. In most patients, there were no noticeable improvements, but in the patients with tetanus, the doctor noticed significant improvements. Tetanus is a disease of the nervous system caused by the bacterium Clostridium tetani, which produces a toxin that affects the nervous system, causing painful muscle contractions all over the body. Dr. O'Shaughnessy believed that marijuana helped patients to cope with tetanus because it helps relax the muscles, which has led to a decrease in symptoms in these patients (ref.13). Subsequent studies have mentioned similar benefits of marijuana extract in diseases such as tuberculosis, rheumatism, tetanus, with the main and most notable effect being the relief of body aches that patients experience during diseases.

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The cannabis plant produces 8 cannabinoid acids, from which the phytocannabinoids CBG, THC, CBD, CBC, CBGV, THCV, CBDV and CBCV are synthesized. These are the phytocannabinoids in marijuana that resound the plant with its interesting influences on our organism. Due to the rich information about the effects of these substances, here we will concentrate only on THC and CBD.

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The two substances with the highest concentration in cannabis are Δ 9-tetrahydrocannabinol (THC) and cannabidiol (CBD). For the first time they were isolated from the plant in the 1940s, and their chemical structures were discovered in 1964 by Rafael Mekulam, who, a few years later, created the first synthetic cannabinoids (ref. 14), which to this day are used for scientific studies.&nbsp;

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Phytocannabinoids express their properties mainly by binding to endogenous cannabinoid receptors. Such a receptor was first detected in 1988 (ref. 15), when phytocannabinoids were shown to bind to a specific substance in the membrane of cells and thus induce their specific actions in the body. To date, only two endocannabinoid receptors have been detected – CB1 and CB2.

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Endocannabinoid-system

Endocannabinoid system

Endocannabinoid-system_4_0

Endocannabinoid receptors are part of a very important system for us called the endocannabinoid system (ECS).&nbsp; Its existence was discovered in the 1990s thanks to the inquisitiveness of scientists Allyn Howlett and Bill Devon and the new methods at the time in molecular science (ref.20). Not much is known about this system yet, but scientific studies have proven that it is important for the course of many processes that are essential for the normal function of the body. Some scientists believe that the role of ECS is to maintain homeostasis in the body.

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In addition to the endocannabinoid receptors, a part of the ECS are endocannabinoids (two previously detected - anandamide (AEA) and 2-arachidonoylglycerol (2-AG)) and enzymes (amidy hydrolase of fatty acids and monoacylglycelic acid linase) whose role is to break down AEA and 2-AG when they are no longer needed.

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The majority of CB1 receptors are localized on the surface of nerve cells in the brain and more precisely in the anatomical parts, which are associated with cognitive impairment, memory, feelings of satisfaction, anxiety and pain, motor coordination and endocrine function. Also, a small part of CB1 receptors are located in areas of the peripheral nervous system - the spleen, white blood cells, endocrine glands, as well as in some parts of the reproductive, gastrointestinal and urinary system.

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Unlike CB1, CB2 receptors are located mainly on the surface of cells in the peripheral nervous system – white blood cells, spleen and tonsils, and recently their presence was noticed in the central nervous system, but in a smaller concentration (ref.6).

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How-phytocannabinoids-affect-their-actions

How phytocannabinoids affect their actions

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Phytocannabinoids are not part of the endocannabinoid system, but it has been found that their properties overlap to some extent with the properties of AEA and 2-AG.

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CBD is one of the most studied phytocannabinoids due to its healing potential. Its effect on the body differs from that of THC, but it is believed that they may have a cumulative effect reinforcing the analgesic action of medical cannabis extract (ref. 17). CBD has a weak affinity (attraction) to CB1 and CB2 receptors, but in the presence of THC it may act as a CB1 antagonist (blocks the action of THC on CB1) and and a negative allosteric modulator of THC and AEA on the CB1 receptor (ref. 18, 19). This means that when CBD binds to CB1, THC's and AEA's affinity for that receptor is reduced, therefore reducing their effect in the body. It is believed that this property of CBD is key to its anti-inflammatory action, because when CB1 receptors are activated, the production of free radicals (these are oxygen-containing, highly reactive molecules that can cause chain chemical reactions in the body) and the pro-inflammatory substance TNF-alfa increase. Therefore, CBD's mechanism as a negative allosteric modulator reduces the activation of CB1 receptor (ref.31).

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It is not yet known what the target of CBD is in the endocannabinoid system; some scientists believe that the receptor with which CBD binds has not yet been discovered. However, other CBD functions that are diverse in nature and most likely also play a role in the manifestation of CBD's healing properties have been found outside the ECS. One of its mechanisms of action is the binding to specific cation channels (TRP), leading to a decrease in the release of glutamate, which has the potential to lead to neural death if its levels are higher than normal (ref. 43). The antioxidant properties of CBD are exhibited in its ability to capture free radicals, interrupt the chain chemical reactions caused by them, and to model the action and levels of both antioxidants and oxidants (ref. 32).

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THC is an analogue of the endocannabinoid AEA (ref.16) and gives the euphoric effect when using marijuana. THC has been shown to be a mixed agonist/antagonist of CB1 and CB2 receptors - it exhibits properties of both an antagonist and an agonist (the same as an antagonist, but instead of blocking, it mimics the properties of the substance it replaces) depending on the type of cell it binds to, the amount of receptors and whether there are endocannabionoids - complete agonists, that would replace THC (ref.7). Nevertheless, THC exhibits a strong affinity for the CB1 receptor, which is believed to be the cause of its psychoactive properties, as well as its potential proinflammatory properties.

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In addition, THC can bind nonspecifically to other receptors in the body outside the ECS, as a result of which many of its known physiological properties are manifested. For example, it has been documented that THC affects the metabolism of certain proteins and nucleic acids (DNA and RNA) (ref.3), as well as of hormonal secretion and various neurotransmitters (ref. 4,5). Due to the wide variety of effects that THC has, no specific mechanism of action can be determined. THC exhibits analgesic, anti-inflammatory, antioxidant, antipruritic, bronchodilator, antispasmodic and muscle-relaxing properties. Also, it can also induce the production of free radicals (ref. 31, 35).

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Diseases-and-symptoms-in-which-positive-effects-have-been-observed

Diseases and symptoms in which positive effects have been observed

Multiple-sclerosis

Multiple sclerosis

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MS – multiple sclerosis – is one of the most commonly discussed diseases when talking about medicinal properties of cannabis. This is an autoimmune disease in which a person's own immune system begins to attack nerve cells. This causes typical symptoms - numbness of the palms and feet, loss of muscle tone and problems with balance, orientation and walking, fatigue and chronic pain in the body. In some studies, the effect of cannabis on some of the symptoms of MS has been proven, and it seems to improve them significantly. As early as 1987, in a clinical trial of MS patients an improvement in muscle tone (spasticity) was observed, which is often painful, after taking THC (ref. 28). In another study, two years later, similar results in spasticity and tremors in the muscles of MS patients were documented (ref. 29). In studies of animal models of MS, the muscle-relaxing and anti-inflammatory action of THC and CBD is observed. Unfortunately, the intake of a combination of THC and CBD by MS patients does not show as good a change as in animals, but compared to pre-existing MS drugs, the effect is similar (ref.30). In some countries, smoking medical marijuana, as well as use of synthetic cannabis drugs, is approved for MS patients as a cure for spasticity and pain that they experience (ref. 33).

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Pain

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We have all experienced the feeling of pain at some point in our lives - when falling from the bike or when touching the hot pan unintentionally. Unfortunately, there are people who experience it on a daily basis for one reason or another. This painful feeling is caused by nerve signals sent to the brain where they are registered, processed and finally perceived as a feeling of pain. Nerve cells that transmit this information to the brain have many cannabinoid receptors. Due to the effects that cannabinoids exhibit on these receptors, cannabis intake may block the registration of this information. For example, in a study on the effect of THC on patients with chronic and acute, non-chronic pain, a significant decrease in chronic pain was observed. Acute pain is not affected until a combination of THC and CBD is administered. This may be due to a combination of the effect as a negative allosteric modulator , which CBD exhibits to THC, along with the healing effects of CBD itself (ref.25, 26). In another study, it was seen that CB1 receptor levels are rising in patients with chronic pain, which may explain the analgesic action of THC in these patients (ref.27). In contrast to what we discussed until now, there are also studies that have shown the opposite effect - pain intensification, from taking marijuana, but only in acute non-chronic pain (ref.39).&nbsp;

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Cancer

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The most encouraging discovery about the effect of cannabinoids is on the effect they exhibit in cancer patients who are subjected to body aches all day. Cannabinoids have been shown to have a calming effect on this chronic pain in patients. In addition, in all patients in this study, and in many others, there was also a decrease in nausea and an improvement in appetite in these patients (ref.40). Due to mass monitoring of these effects, the Food and Drug Administration (FDA) approves THC (Dronabinol (Marinol®)) to treat nausea and vomiting, and to improve appetite in patients in chemotherapy (ref.41).

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The same medicine is also approved in AIDS patients who experience similar symptoms.

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There are scientific studies that show inhinition of tumor growth in patients in advanced stages (ref. 42), but more research in this direction is needed to prove this effect.

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Epilepsy

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Epilepsy is a common condition that affects the brain and causes frequent seizures. About a third of people with epilepsy are resistant to existing drugs (ref. 34). Various studies have shown a positive effect, specifically from taking CBD, for the treatment of seizures (ref. 37). Also, interesting is the cumulative effect of CBD with other antiepileptic drugs, as it seems that CBD increases their concentration, which in turn can improve results in these patients. This property is most likely the result of the inhibiting effect that CBD has on the P450 system (a large system of proteins that underpins drug interactions) (ref. 38). On June 25, 2018, the FDA approved a synthetic CBD drug (EPIDIOLEX) for the treatment of adults and children over 2 years of age (ref. 36). Although the permit is only for two specific epileptic syndromes, this is a great advance in the history of marijuana, as well as in the treatment of this disease.

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Glaucoma

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One of the leading causes of blindness in the world is glaucoma. Glaucoma is a chronic disease in which the optic nerve that connects the eye to the brain is damaged. It is usually caused by a build-up of fluid in the front of the eye, which increases the pressure in the eye. There have been reports that smoking cannabis reduces eye pressure since 1970 (ref. 39). In subsequent years, this effect of cannabinoids has been demonstrated several times (ref. 44, 45). In addition, THC is considered a neuroprotective agent that can increase blood supply to the retina, aiding the survival of the eye nerve. Unfortunately, there are not enough studies on this issue to prove that phytocannabinoids are a good remedy for glaucoma.

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Marijuana's-benefits-on-other-conditions

Marijuana's benefits on other conditions

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Cannabis intake seems to improve connections between different parts of the brain, but it also reduces the volume of this part in the brain associated with decision-making (ref 46).

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There are many other benefits of cannabis use, such as constipation, skin problems, anxiety, etc.

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Side-Effects-of-Marijuana

Side Effects of Marijuana

Cognitive-problems

Cognitive problems

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The harmful effects of taking marijuana are most often caused by long-term use, especially in teenage years. A series of studies have proven that chronic cannabis use leads to cognitive brain damage – it becomes difficult for the abuser to concentrate, remember and learn new things, as well as to make simple decisions (ref.46, 47). Over the years, persistent memory and attention disorders increase (ref. 48); and the difference between long-term and shorter cannabis use in these indicators is significant (ref. 49). These cognitive changes in the brain may resume after a long period of abstinence (ref. 51).

Chance-of-psychosis

Chance of psychosis

Chance-of-psychosis_7_0

Numerous studies have analysed the possibility of psychosis in people using cannabis and in most, if not all, a link between the two occurences has been proven (ref. 50). One reason for the onset of psychosis in people using cannabis may be that THC causes neuronal noise - random neural activity in the brain.

The topic of marijuana is controversial - people have different opinions on whether its use is beneficial or harmful. In this article are summarized the most important things you need to know about marijuana in a scientific context. It is a fact that it has been used since ancient times for medical purpose, and rightly so - to date many positive effects of the active ingredients in cannabis have been found. At the same time, however, there are also negative effects, especially in chronic use. Despite the progress we see in science for marijuana use, new, well designed studies are necessary to further understand the mechanisms which phytocannabionoids use and hence the way they affect us.

Herbs and bioactive substances