What are the dangers of neurotoxic effects? Neurotoxins Action of neurotoxins.

What are neurotoxins?

Neurotoxins are substances that affect the nervous system of mammals. They are absorbed by nerve endings and transmitted through neurons into cells. Along the way, they destroy vital functions of nerve cells, such as axonal transmission of nutrients, mitochondrial respiration and the correct reading of DNA information. The body is constantly trying to eliminate neurotoxins in all available ways: through the liver, kidneys, skin and exhaled air. Detoxification mechanisms include acetylation, sulfation, glucuronidation, oxidation and others. Often, a body affected by microbes experiences a molecular malfunction that causes it to begin producing neurotoxins (destructive to its own tissues).

The liver plays the most significant role in the process of eliminating toxins. Here, most waste products are sent into the bile into the small intestine and must leave the body through the gastrointestinal tract. However, due to the lipophilic/neurotrophic nature of neurotoxins, most are reabsorbed by the numerous abdominal nervous system (VNS) nerve endings in the intestinal wall. The LBP has more neurons than the spinal cord.

Once reabsorbed, toxins can take one of the following four routes:

Here is a partial list of neurotoxins in order of importance:

I have found that mercury in its various chemical forms has a synergistic, reinforcing effect with all other neurotoxins. Once mercury is eliminated, the body begins to eliminate other neurotoxins more effectively.

What are the symptoms?

Any disease can be caused, provoked or enhanced by neurotoxins. Fatigue, depression, insomnia, memory loss, dullness of the senses are common early symptoms (see list of mercury-related symptoms on following pages).

How to make a diagnosis?

	History of contact with the source of infection (Have you had amalgam fillings? tick bites? etc.)
	Symptoms (short-term memory, numbness, strange sensations, etc.)
	Laboratory tests (for metals: hair, stool, blood, urine; for xenobiotics: biopsy of adipose tissue, urine; for fungus)
	Autonomic Response Testing by Dr. Detrich Klinghardt
5.	Bioenergy test (EAV, movement physiology, etc.)
6.	Response to Therapeutic Trial.
7.	Functional Acuity Contrast Test measures blood flow in the retina.

Treatment

Why do we even want to treat someone? Is this necessary? Can't the body get rid of these toxins on its own?

Here's a short list single risk factors, which can trigger the accumulation of metals in a healthy body or slow down the elimination processes in the body:

	genetic
	working with toxic materials
	previous diseases
	operations
	medicines or drugs
	emotional trauma, especially in childhood
	social status
	high carbohydrate intake with insufficient protein intake (especially in vegetarians)
	use of homeopathic mercury
	food intolerances
	electromagnetic exposure (when using a mobile phone, a house near high voltage lines, etc.)
	constipation
	amalgam fillings from the patient or his mother.

In this paper, we will only discuss elimination techniques that are natural, safe, and have also been shown to be effective (or more effective) than some of the available pharmaceutical techniques. Because these products cannot be patented and used for unethical personal gain, European and North American scientists have not paid much attention to them. Many of the best scientific studies on this topic come from Asian countries.

Main program:

1. High intake of proteins, minerals, fatty acids and fluids.

	Proteins are stored by progenitor cells for endogenous metal detoxification and shuttle agents such as glutathione, etc. The branched chain amino acids in bovine and goat whey have an important independent detoxification effect.
	Metals attach only in those locations that are programmed for metal ions to attach. Mineral deficiency allows toxic metals to attach to the free receptor. A healthy mineral base is a prerequisite when attempting detoxification (selenium, zinc, manganese, germanium, molybdenum, etc.). Replacement minerals can cleanse the body of toxins. Also important are electrolytes (sodium, potassium, calcium, magnesium), which help in transporting toxic waste through the extracellular space to the lymphatic and venous vessels.
	Lipids (derived from fatty acids) make up up to 60-80% of the central nervous system and must be constantly replenished. Their deficiency makes the nervous system vulnerable to fat-soluble metals, such as metallic mercury, which is constantly released as an odorless and invisible vapor from amalgam fillings.
	Without enough fluid, the kidneys can be poisoned by metals. The underlying membranes swell and the kidneys can no longer filter toxins effectively. Adding a small amount of a balanced solution of electrolytes to water helps restore intra- and extracellular fluid balance.

This kitchen seasoning can mobilize mercury, cadmium, lead and aluminum in both the bones and the central nervous system (see. “Removal and Preconcentration of inorganic and methyl mercury from aequeous media using a sorbent prepared from the plant Coriandrum Sativum”, J of Hazardous Materials B 118(2005) pp 133-139 D Karunasagar et al.). BioPure Cilantro is grown from special seeds from Brazil that are grown in conditions and soils that enhance its toxin-busting properties. It is perhaps the only effective substance for mobilizing mercury accumulated in the intracellular space (attaching to mitochondria, tubulin, liposomes, etc.) and in the cell nucleus (correcting damage caused to DNA by mercury).

Because cilantro mobilizes more toxins than it can eliminate from the body, it can overwhelm the connective tissue (where the nerves are located) with metals that were previously concentrated elsewhere. This process is called retoxification. This can easily be avoided by simultaneous consumption of substances that absorb toxins. Our preferred algal organism is Chlorella. Recent animal studies have shown faster skeletal clearance of aluminum compared to all other known detoxifying substances (Intnl J Acup and Electro-Therapeutics Res, 2003).

Dosage and the use of BioPure cilantro tincture: 10 drops dissolved in warm water before bed (many detoxification processes are activated during sleep) or 30 minutes after taking chlorella. Cilantro causes the gallbladder to send bile containing neurotoxins into the small intestine. Bile secretion occurs naturally during meals and is greatly enhanced by cilantro. If chlorella is not taken, most of the neurotoxins are reabsorbed on their way to the small intestine by the multiple nerve endings of the intestinal nervous system.

Gradually increase the dose to 10 drops 3 times a day for better effect. During the initial phase of detoxification, cilantro should be used for 5 days with a break of 2 days.

Most effective in combination with the Toxaway microcurrent foot bath.

Other methods of taking cilantro:

3. Chlorella

Both Chlorella pyreneidosa (better toxin absorption, but more difficult to digest) and Chlorella vulgaris (higher chlorella growth factor - see below, easily digestible, lower metal absorption capacity) are available. A list of expert reviews can be obtained from BioPure. Be careful: there is a huge difference in quality. We only recommend BioPure Chlorella.

Chlorella has many health effects:

	Antiviral(especially effective against the cell gigantism virus from the herpes family).
	Toxin binding(micropolysaccharide membrane) all known toxic metals, environmental toxins such as dioxin and others.
	Improves and activates features detoxification of the body:
	-	significantly increases the reduced level of intracellular glutathione;
	-	various peptides accumulate coeruloplasmin and metallothionein;
	-	lipids (12.4%) alpha and gamma linoleic acid help balance the increasing intake of omega 3s during our detoxification program and are necessary for many functions, including the formation of peroxisomes;
	-	Methyl-cobalamin is a food for the nervous system, revives damaged neurons and has its own detoxification effect;
	-	Chlorella growth factor helps the body detoxify itself in as yet unexplained ways. It turns out that over a million years, chlorella has developed detoxification proteins and peptides specific to each toxic metal;
	-	Porphyrins in chlorophyll have their own metal-scavenging effect. Chlorophyll also activates the PPAR receptor in the cell nucleus, which is responsible for DNA transcription and encoding peroxisome information (see fish oil), opening cell walls (an unknown mechanism), which is important for the detoxification process, normalizes insulin resistance and much more. Medicines that activate this receptor (such as pioglitazone) have shown positive results in the fight against breast and prostate cancer.
	Beneficial Nutrient: contains 50-60% amino acids, an ideal nutrient for vegetarians, methyl-cobalamin is the most easily digestible form of vitamins B 12, B 6, minerals, chlorophyll, beta carotene, etc.
	Strengthening the immune system.
	Improves intestinal flora.
	Helps with digestion.
	Alkalinizing agent (important for patients with malignant tumors).

Dosage: start with 1 gram (= 4 tablets) 3-4 times a day. This is the standard dose for adults for 6-24 months of active detoxification. During the more active phase of detoxification (every 2-4 weeks for 1 week), each time cilantro is taken, the dose can be increased to 3 grams 3-4 times a day (1 week of use, 2-4 weeks return to the main dose) . Take 30 minutes before meals and before bedtime. In this way, chlorella reaches precisely the part of the small intestine where bile is injected into the intestine at the beginning of a meal, carrying toxic metals and other toxic waste with it. They are retained by the walls of chlorella cells and are excreted through the gastrointestinal tract.

When removing amalgam fillings, a higher dose should be applied 2 days before and 2-5 days after the procedure (the more fillings removed, the higher the dose and for a longer time). Cilantro should not be consumed during a dental procedure. At this time, it is not a good idea to mobilize deeply buried metals in addition to the expected new effects. If you are taking vitamin C during a detox program, the time between taking the vitamin and chlorella should be as long as possible (preferably after a meal).

Side effects: Most side effects are related to the effects of mobilized metal toxins that are carried throughout the body. This problem can be avoided by significantly increasing the dose of chlorella, rather than decreasing it, which will only worsen the problem (small doses of chlorella mobilize more metals than are retained in the intestines, large doses retain more toxins than they mobilize). Some people have trouble digesting the chlorella cell membrane. The enzyme cellulase solves this problem. Cellulase can be found in many health food stores among the digestive enzyme products. Taking chlorella with food also helps in some cases, although it is less effective this way. Chlorella vulgaris has thinner cell walls and is better tolerated by people with digestive problems. Some manufacturers have created chlorella extracts without cell walls (NDF, PCA), which are very expensive, less effective, but easily absorbed.

This is a thermal extract of chlorella that concentrates certain peptides, proteins and other ingredients. Research on chlorella growth factor (GGF) shows that children have no dental problems, are less sick and grow faster, have a higher IQ and better social skills. There are reports of patients with significant tumor shrinkage after using large amounts of PRX. In addition, FHR makes the detoxification process easier, faster and more effective for patients.

4. Garlic(allium sativum) and wild garlic (allium ursinum)

Garlic protects white and red blood cells from destruction by oxidation caused by metals in the blood stream when cleansing the body; it also has its own detoxifying effect. Garlic contains many sulfur compounds, including those that oxidize mercury, cadmium and lead, and makes these metals soluble in water, making it easier for the body to eliminate these substances. Garlic also contains allicin, the most potent natural antiseptic.

Patients with metal toxin poisoning most often suffer from secondary infections, which are partly responsible for many of the symptoms. Garlic also contains the most important mineral that protects against mercury toxicity - bioactive selenium. Most selenium products are poorly soluble and cannot reach the parts of the body where they are needed. Garlic is the most advantageous natural biological source of selenium. Garlic also protects against heart disease and cancer.

The half-life of allicin (after crushing garlic) is less than 14 days. Most prepared garlic products do not contain active allicin. This distinguishes dry frozen garlic from other products. Garlic tincture is an excellent detoxifier, but it is not as effective as an antimicrobial agent.

Dosage: 1-3 capsules of dry frozen garlic after each meal. Start with 1 capsule per day after lunch, gradually increasing the dose. Sometimes a patient may have a negative reaction to dead pathogenic fungal or bacterial organisms. Use 5-10 drops of garlic tincture with food at least 3 times a day.

5. Fish oil

The fatty acids in fish oil make red and white blood cells more pliable, thus improving microcirculation in the brain, heart and other organs and tissues. The entire detoxification process depends on optimal oxygen supply and blood flow. Fish oil fatty acids protect the brain from viral infections and are needed for better mental development and vision. The most vital cellular organelle for detoxification is the peroxisome. These small structures are also responsible for the specific work of each cell: melatonin is produced in the pineal gland in peroxisomes, dopamine and norepinephrine are produced in neurons, etc. This is where mercury and other toxic metals take hold and interfere with normal cell function.

Other researchers are focusing on mitochondria and other cellular organelles, which we have noticed are damaged much later. Cells are constantly trying to produce new peroxisomes to replace damaged ones - for this they need a sufficient amount of fatty acids, especially EPA and DHA acids. Until recently, it was believed that our bodies were able to produce EPA/DHA acids themselves from other omega 3 fatty acids, such as fish oil. Today we know that this process is too slow and cannot cope with the increased lack of EPA/DHA acids in the body under the environmental conditions in which modern humans live. Fish oil is now considered an essential food product, even for vegetarians. Recent research has also shown that the transformation that occurred when great apes became intelligent and evolved into humans only occurred in coastal regions where the apes began to consume large quantities of fish. Why not take advantage of this knowledge and consume more fish oil?

The fatty acids in fish oil are very sensitive to electromagnetic radiation, temperatures, light and other processing techniques. Ideally, fish oil should be stored continuously at low temperatures until it is placed in the patient's refrigerator. The source of the fish must be free of mercury or contaminants, which is becoming more and more difficult. Fish oil should taste slightly like fish, but not too much. If the taste of the fish is absent, it means that over-processing has destroyed the vital energy of the fat. If the fishy taste is too strong, then oxidation products are present. I recommend the following products (group 1), during the production of which all conditions were carefully observed to give the product the desired qualities. The clinical results are amazing.

Dosage: 1 capsule of omega3 4 times a day in the active phase of treatment, 1 capsule 2 times a day to maintain the effect. Best used simultaneously with chlorella.

VegiPearls products contain half EPA/DHA acids. Vegetarian capsules eliminate even the slightest possibility of containing a prion and make the idea of ​​\u200b\u200btaking fish oil more acceptable for vegetarians. Recently, fatty acid receptors have been discovered on the tongue, along with other taste buds. If the capsules are chewed, the stomach and pancreas begin to prepare the gastrointestinal tract in such a way as to ensure maximum absorption. Children love chewing VegiPearls.

To treat bipolar disorder and other mental illnesses, 2000 mg of EPA acid per day is needed (David Horrobin). For malignant tumors - 120 mg 4 times a day. It is easy to calculate the required dose using the information on the package insert.

Molds

Many fungi produce toxic metabolites called mycotoxins, many of which are neurotoxins. More than 100 species cause infections in humans.

Three classifications of infections:

For example:

Stachybotrys Candida Aspergillus Mucor Cladosporium (most commonly found genus of fungus in outdoor air in temperate climates, in refrigerators and damp window frames, faded paint, textiles and paper, in soil or waterlogged houseplants; sporulates profusely, along with lternaria causing hay fever and asthma) Rhizopus Cryptococcus Fusarium graminaerum: in water-damaged carpets, often found in schools, also in cereals. 3. Skin fungus (hair, skin and nails). Usually transmitted through direct contact through shared toiletries, showers, towels). Also transmitted through soil.

Mycotoxins:

	aspergillus and penicillum species produce:
		aflatoxin
		sterigmatocytin
		ochratoxin
	species stachybotrys and fusarium produce (the worst are probably stachybotrys chartarum - a greenish-black fungus that grows on fiberboard, plaster, dust and lint, wallpaper, insulating material, wet wood. The spores are not destroyed by fire. The spores settle on the floor: even detection of 1 spore often indicates that “the case is lost”):
		satraoxins
		tricothecine (very powerful). Some subtypes: stachybotryolactone, verrucarin J, roridin E, satratoxin F, G&H, sporidesmin G, trichoverrols and trichoverrins, 9-phenylspirodrimanes (cyclosporins & spirolactams)
		T-2 toxin
		vomitoxin
		fumonisin
		zearalenone

There are many other mycotoxins produced by these and other fungi, the health effects of which remain unknown.

Symptoms of mycotoxin exposure:

	acute effect:
		sudden memory loss
		fistula problem
		flu-like symptoms
		body pain
		pharyngitis
		diarrhea
		general malaise
		headaches
		nosebleed

in biochemistry

Mechanism of action of snake venom neurotoxins

Introduction

chemistry snake venom

Snake venoms are a unique group of biologically active compounds in their chemical composition and physiological effects. Their toxic and medicinal properties have been known to mankind since ancient times. For a long time, interest in the study of these poisonous products was limited to the needs of medical practice. Most of the work was devoted to describing the clinical picture of poisoning, finding methods of specific and nonspecific therapy, as well as the use of snake venoms and their preparations as therapeutic agents. The rational use of snake venoms in medicine is impossible without experimental study and theoretical justification of the essence of the reactions that develop in the body in response to the introduction of a particular poison. The study of individual mechanisms of action of snake venoms on the body is necessary to create scientifically based treatment methods.

Insufficient knowledge about the mechanisms of the toxic action of snake venoms often does not allow doctors to quickly and effectively alleviate the condition of the victim. In some cases, only the external picture of poisoning is taken into account, and clinical care is limited to symptomatic means without taking into account the specific effects of the poison on the vital systems of the body.

It should be noted that snake venoms have a strong toxic effect only in lethal and sublethal doses. Small doses do not cause any clinical manifestations of poisoning and have long been used in practical medicine. However, therapeutic application is often carried out empirically without sufficient theoretical justification, which entails errors. There is no need to prove that the effective use of snake venoms in the clinic should be based on deep knowledge of their composition and properties and, first of all, on experimental studies that should reveal the physiological nature and mechanisms of action of these poisonous substances and help doctors scientifically use venoms for therapeutic purposes. In research laboratories, interest in zootoxins, and in particular in snake venoms, has sharply increased, in connection with obtaining from them in pure form a number of components that have highly specific effects and certain biological structures.

The purpose of this work is to highlight the current state of experimental study of snake venoms, to reveal the mechanisms of pathophysiological effects on the most important functional systems of the body.

State of the chemistry of snake venoms.

Preparation of poisons and its physicochemical properties.

The simplest way to obtain poisonous secretions from snakes is mechanical massage of the poisonous glands. Nowadays, electric current stimulation is often used instead of mechanical massage.

Electrical stimulation is not only a more gentle method of collecting poison, but also allows you to obtain a larger amount of it. The amount of poison obtained from one individual depends on the size of the snake’s body, its physiological state, the number of repeated doses of poison, as well as on a number of environmental conditions. It should be noted that keeping snakes in captivity affects not only the amount of poison obtained, but also its toxicity. Thus, in cobra venom, a decrease in toxicity is observed after six months of captivity. The poison of the viper changes its toxicity only after 2 years of keeping in the nursery. As for small snakes (viper, copperhead, eph), keeping them in serpentariums throughout the year does not affect the properties of the poisons. Freshly extracted snake venom is a slightly opalescent, viscous, fairly transparent liquid; the color of the venom varies from light yellow to lemon.

The active reaction of poisons is usually acidic. Aqueous solutions of them are unstable and lose toxicity after a few days. They become much more resistant to environmental factors after drying over calcium chloride or lyophilization. The poisons are quite thermostable and can withstand heating up to 120 degrees Celsius in an acidic environment without loss of activity. Chemical reagents have a destructive effect on poisons: KMnO 4, ether, chloroform, ethanol methylene blue. Physical factors also influence: UV irradiation, X-rays. Chemical analysis shows the presence of both organic and inorganic substances in snake venoms. According to modern concepts, the toxic activity and biological properties of snake venoms are associated with their protein components.

The main stages of studying the chemical composition and structure of toxic polypeptides of snake venoms. Questions about the chemical nature and mechanisms of action of snake venoms have attracted the attention of researchers. In early studies, the toxic effect was associated with the activity of enzymes present in poisons. Currently, the generally accepted point of view is that the main toxic properties are determined by non-enzymatic polypeptides, along with which poisons contain powerful enzyme systems, the nature and specificity of the action of which in most cases determines the uniqueness of the integral picture of poisoning. Achievements and successes in the field of studying the chemical composition of poisons are closely related to the development and improvement of methods for fractionation and purification of complex mixtures of high molecular weight compounds. Until the 1960s, the study of poisons mainly used dialysis through semipermeable membranes and electrophoretic separation. The development of methods of gel filtration, ion exchange chromatography, ultracentrifugation, as well as the development and automation of methods for analyzing the primary structure of macromolecules made it possible to decipher the sequence of amino acid residues of toxic polypeptides of most snakes in a relatively short time.

1.Terminology and classification of toxic polypeptides

chemistry snake venom

Until recently, there were terminological difficulties when attempting a comparative analysis of the functional and structural features of various non-enzymatic toxic polypeptides of snake venoms. This mainly concerns polypeptides isolated from the venom of snakes of the Elapidae family. At the first stages of studying the chemical composition of poisons, such difficulties were inevitable and were explained by the insufficient degree of purification of individual polypeptides, which in most cases made it difficult to determine the specific nature of their action. As a result, different authors gave different names to polypeptides that turned out to be extremely close, and sometimes identical, in their chemical structure and pharmacological effects. In particular, a group of cardiotoxins was designated as a factor that depolarizes skeletal muscles; toxin Y; direct lytic factor - PLF; cobramines A and B; cytotoxins 1 and 2.

Some authors, when choosing a name, were based on pathophysiological effects (cardiotoxin, PLP, cytotoxin), others emphasized some chemical properties of the polypeptide, for example, its basic character (cobramin), while others assigned a numerical or letter designation to the fraction. Only in recent years has a close similarity in the chemical structure of these polypeptides been established. Evidence has been obtained that hemolytic, cytotoxic, cardiotoxic and other types of activity are inherent in most of these toxins. Therefore, a group of basic polypeptides that do not have specific neurotoxic activity, but effectively act on biological membranes, were called membrane-active polypeptides (MAP).

Based on a comparative analysis of the primary structure and physiological action, which showed the great similarity of neurotoxic polypeptides to each other, they were united under the common term - neurotoxin. Thus, all toxic polypeptides, which do not have enzymatic properties and according to their mechanism of action, have been isolated so far from the venom of snakes of the family Elapidae and are divided into three groups. The first group includes polypeptides that selectively and specifically block cholinergic receptors of the subsynaptic membrane of the neuromuscular junction - postsynaptic neurotoxins (post-NT). The second group is represented by polypeptides that act selectively on the presynaptic endings of myoneural synapses and disrupt the process of acetylcholine release - presynaptic neurotoxins (pre-NTs).

The third group includes polypeptides that actively affect the membrane structures of cells, including excitable ones, causing their depolarization - membrane-active polypeptides (MAP).

2. Chemistry of postsynaptic neurotoxins

Despite the fact that post-NTs isolated from cobra venom are similar in their pharmacological properties, from the point of view of chemical structure they can be divided into two types.

Type 1 includes post-HT, which is a simple polypeptide chain consisting of 60-62 amino acid residues having 4 disulfide bridges (Fig. 1. A) and having basic properties, a molecular weight of about 7000 (post-HT-1).

Type 2 includes post-NT, consisting of 71-74 amino acid residues, having 5 disulfide bridges (Fig. 1, B), molecular weight of about 8000 (post-NT-2).

Fig 1. Primary structure of neurotoxin II (A) and neurotoxin I (B) from the venom of the Central Asian cobra

Post - NT-1 are built from 15 common amino acid residues; as a rule, Ala, Met and Phen are absent in their composition. On the contrary, post-HT-2 alanine occurs. An interesting feature of the Central Asian cobra venom is the presence of both types of neurotoxins in it. Moreover, in the neurotoxin containing 73 amino acid residues, Arg or Lys 51, characteristic of all post-HT-2, are replaced by Glu.

The saturation of post-HT 1 and 2 disulfide bonds suggests their important functional significance in maintaining the biologically active conformation of the molecule. Reduction of disulfide bonds leads to a loss of 92% of the activity of post - NT-1 and 50% of post - NT-2. re-oxidation restores the original activity of the neurotoxins. Apparently, the greater resistance of post-NT-2 to chemical influences is due to the presence of a fifth disulfide bond, stabilizing a portion of the polypeptide chain. At the same time, in post-NT-1 this same section of the molecule is the most elongated and lacks disulfide bridges. The presence of bridges determines the resistance of post-LT to thermal effects. Thus, in an acidic environment, post-NT can withstand heating to 100°C for 30 minutes without noticeable loss of activity or treatment with 8M urea for 24 hours, but is inactivated by alkalis.

Deciphering the primary structure of neurotoxic polypeptides made it possible to raise the question of the localization and structure of the active center of the molecule that interacts with the choline receptor. The study of the structure of these polypeptides indicates the presence of both α and β structures in the neurotoxin molecules. The central part of the post-HT -1 molecule, free of disulfide bonds, may have greater α-helicality. In addition, the hydrophilic nature of most of the side chains of amino acid residues that make up the sequence from positions 24-25 to positions 39-40 may cause the projection of this loop to the outer side of the molecule, so it is possible that the active center is localized in this region.

Analysis of the location and chemical modification of invariant amino acids found in homologous neurotoxins in the same regions is important. These amino acids, preserved during evolution in identical parts of the polypeptide chain, can participate in the organization of the active center or ensure the maintenance of the active conformation of the molecule. The presence of constant amino acids requires the presence of an invariant triplet gene code in the DNA molecule necessary for the synthesis of a given amino acid sequence.

Since the target for post-HT, as well as for acetylcholine, is the cholinergic receptor, the apparently active sites of neurotoxins should be similar to the quaternary ammonium and carbonyl groups of acetylcholine. It was found that free amino groups, including N-terminal ones, are not obligate to provide toxic activity. Acytylation of 6 amino groups in the neurotoxin from the venom of the Thai cobra led to the loss of 1/3 of the activity.

It could be assumed that the carbonyl groups of the peptide composition, always present in the post-HT molecule, may be important in ensuring toxicity. However, they are inaccessible in the reaction of interaction with the receptor. To a greater extent, the side groups of the side chains of invariant aspartic acid and asparagine meet this requirement. Modification of aspartic acid with glycine methyl ester results in a loss of activity of 75% of the original value.

Irreversible binding between post-NT and the cholinergic receptor cannot be explained solely by the interaction of guanidine and carbonyl groups of post-NT with the corresponding regions of the receptor. Their interaction should be mainly electrostatic in nature, however, the receptor-toxin complex does not dissociate in concentrated saline solutions. Probably these two functional groups serve as “recognition sites” during the initial contact of the post-NT and the receptor. The final irreversible binding is determined by protein-protein interaction, which already includes other areas of the post-HT and cholinergic receptor.

3. Chemistry of presynaptic neurotoxins

The second group of neurotoxins, presynaptic neurotoxins (pre-NTs), are rarely found in snake venoms. Only some of them have been isolated in purified form and studied. In the family Elapidae, presynaptic NTs are found in the venom of the Australian taipan - typoxin, of the Australian tiger snake - notexin, and in the venom of the krait - β-bungarotoxin. Crotoxin, a neurotoxin from rattlesnake venom, has a predominant presynaptic effect on neuromuscular junctions in amphibians and a postsynaptic effect in mammals. In contrast to post-HT, group 2 neurotoxins are built from a larger number of amino acid residues and, accordingly, have a greater molecular weight. In addition, some of them are complexes consisting of subunits.

One of the first pre-NTs obtained using zone electrophoresis on a starch gel and subsequently purified by chromatography on KM-Sephadex with repeated rechromatography was β-bungarotoxin. β-bungarotoxin is built from approximately 179 amino acid residues, among which aspartic acid (22 residues), glycine (16), lysine (13), arginine (14), tyrosine (13) predominate. The presence of 20 cystine residues indicates that the β-bungarotoxin molecule is stabilized by at least 10 sulfide bonds. The molecular weight of the neurotoxin is 28500.

It was assumed that β-bungarotoxin lacks enzymatic properties and is homogeneous. However, it was established that β-bungarotoxin consists of two subunits with molecular weights of 8800 and 12400, and by studying the effects of β-bungarotoxin on oxidative phosphorylation in the mitochondria of nerve endings, they came to the conclusion that the toxin has phospholipase activity.

Notexin was obtained by ion exchange chromatography in an ammonium acetate gradient. The main neurotoxic component of notexin, constituting 6% of the crude, unrefined venom, was isolated in the form of a preparation containing 27% notexin by repeated chromatography.

4. The effect of poisons on neuromuscular transmission

The mechanism of disruption of the transmission of excitation in the myoneural synapse under the influence of snake venoms has been most studied. Already the first observations of the picture of the death of a poisoned animal, which was dominated by symptoms of paralysis of the skeletal and respiratory muscles, necessitated the study of this phenomenon under strict laboratory conditions. Numerous experiments on isolated neuromuscular preparations have shown that snake venoms block the transmission of excitation from nerve to muscle, reduce excitability to direct and indirect stimulation and cause depolarization of nerve and muscle membranes.

Inhibition of neuromuscular transmission under the influence of poison can be realized through two mechanisms. One of them is associated with the blocking effect of the poison on the end plate. The second is based on a depolarizing effect on excitable membranes. However, when using whole venom, it is difficult to differentiate these two mechanisms, since its depolarizing effect leads to blocking of propagating excitation in nerve fibers, and in high concentrations the venom causes muscle contracture. The venom prevents the depolarizing effect of acetylcholine on isolated muscles, while acetylcholinesterase compounds reduce its blocking effect.

In experiments, crotoxin blocked muscle contraction due to indirect stimulation and had no effect on membrane potential. However, studies of the effect of poisons of two varieties (with and without crotamine) reported a practically irreversible blocking effect on neuromuscular transmission in cats and rats of poison without crotamine, both on muscle membranes and on specific receptors of the postsynaptic membrane. Neuromuscular block under the influence of poison containing crotamine was achieved by depolarization of muscle membranes. Viper venom is also capable of disrupting neuromuscular transmission, causing peripheral paralysis due to irreversible blockade of specific acetylcholine receptors. It also inhibits the electrical activity of muscle fibers. Immunochemical analysis showed the presence in the venom of a protein fraction similar to the postsynaptic α- toxin from the venom of the black-necked cobra.

At the Institute of Bioorganic Chemistry named after. Academicians M.M. Shemyakina<#"justify">5. Postsynaptic neurotoxins (post-NT)

Unlike whole cobra venom, post-NTs selectively block the transmission of excitation in the neuromuscular junction without affecting the electrical properties of the nerve and muscle. Incubation of isolated neuromuscular preparations for an hour in a solution containing post-NT at a concentration of about 1 μg/ml leads to a progressive decrease in the amplitude of the end plate potential (EPP). The inhibitory effect increases with increasing stimulation frequency; at the same time, the amplitude of EPPs decreases without significant changes in their frequency. Even at high concentrations, post-NT had no effect on the resting potentials of both muscle and motor terminals.

The cholinergic receptor membranes of the skeletal muscles of vertebrates are most sensitive to the effects of post-NT. At the same time, the somatic muscles of marine mollusks and the heart of the lamprey are resistant to the action of cobra neurotoxins. Species differences in the sensitivity of cholinergic receptors in various representatives of vertebrates (frogs, chickens, kittens, rats). It has been suggested that post-NTs are not direct competitors of acetylcholine for the active site of the cholinergic receptor.

6. Presynaptic neurotoxins (pre-NT)

Neurotoxins with a presynaptic nature of action selectively affect the mechanism of acetylcholine release without affecting the sensitivity to the mediator of postsynaptic structures. Processing of isolated neuromuscular preparation β- bungarotoxin after an initial period of increasing frequency leads to complete elimination of PEP. The rate of onset of the inhibitory effect depends on both the concentration of pre-NT and the frequency of stimulation. The dependence of the time of onset of neuromuscular transmission block on ambient temperature was also established. Thus, typoxin (1 µg/ml) at a temperature of 37 °C caused inhibition of the drug for an hour; when the temperature decreased to 28 °C, conductivity remained until 4 hours of incubation. Pre-NTs do not reduce the response of isolated muscles to exogenous acetylcholine and do not affect the conduction of excitation along nerve terminals. Other evidence of selective presynaptic action β- bungarotoxin were obtained on a nerve-deprived tissue culture obtained from myoblasts of 10-day-old chicken embryos. Pre-incubation α- bungarotoxin completely eliminated the depolarization caused by the subsequent introduction of acetylcholine into the medium. Under these conditions β- bungarotoxin was not effective. In the later stages of action β- bungarotoxin, destruction of vesicles with acetylcholine is observed until their complete disappearance. Vacuolization of mitochondria of motor nerve terminals is also noted.

Action β- bungarotoxin is similar to the action of botulinum toxin, which also affects the mechanism for the release of acetylcholine from nerve endings. However, there are differences: botulinum toxin does not cause an initial increase in PEP; unlike botulism toxin β- bungarotoxin interacts only with cholinergic endings; No changes in the presynaptic area were observed under the action of botulinum toxin.

The ability was revealed on synaptosomes from the rat brain β- bungarotoxin reduces the accumulation of GABA, serotonin, norepinephrine and choline. Because β- bungarotoxin mainly displaces already accumulated neurotransmitters; it can be assumed that its action is associated with damage to the storage process, and not the transport of mediators.

Conclusion

The mechanism of action of snake venoms has not yet been fully deciphered by scientists. But a transparent drop of poison, once in the blood, spreads throughout the body and, in a certain dose, has a beneficial effect on the patient’s body. It has been established that small amounts of cobra venom have an analgesic effect and can even be used as a morphine substitute in patients suffering from malignant neoplasms. Moreover, unlike morphine, snake venom acts longer and, most importantly, is not addictive. In addition, drugs based on cobra venom have been created that improve the general condition of patients suffering from bronchial asthma, epilepsy, and angina pectoris.

The need for snake venom is increasing from year to year, and snake nurseries established in a number of regions of our country cannot yet satisfy this need. Therefore, there is a need to protect venomous snakes in natural conditions, as well as to ensure their reproduction in captivity.

It should be remembered that in the hands of inexperienced people, snake venom becomes not an ally in the fight to maintain health, but a dangerous enemy and can cause severe poisoning. Theophrastus Paracelsus spoke about the need to correctly select the dose of a medicinal substance, arguing that “...everything is poison, nothing is devoid of poisonousness, and everything is medicine. The dose alone makes a substance a poison or a medicine.” This saying of the famous scientist has not lost its meaning even today, and when using snake venoms, patients are obliged to strictly follow the instructions of the attending physician.

Snake venoms are known to be dangerous to many species of mammals. But among lower organized animals, especially among insects, species are known that are not susceptible to the action of snake venom, which allows them to be used as antidotes.

Summing up the consideration of a range of issues covering the features of the chemical structure and mechanisms of action of poisons, it is impossible not to mention that Nature - this most skillful experimenter - has given researchers unique tools for studying fundamental issues of the structure and functioning of a living cell.

Zootoxins are excellent models for molecular biology, allowing one to address questions of structure-function relationships in biomolecules.

References

1. Orlov B.N. “Poisonous animals and plants of the USSR.” M.: Higher School, 1990. - 272 s.

G.I. Oxendendler “Poisons and Antidotes” L.: Nauka, 1982. - 192 p.

E. Dunaev, I. Kaurov “Reptiles. Amphibians." M.: Astrel, 2010. - 180s.

B.S. Tuniev, N.L. Orlov "Snakes of the Caucasus". M.: Partnership of Scientific Publications KMK, 2009. - 223 p.

www.floranimal.ru

http://www.ncbi.nlm.nih.gov/pubmed

Research shows that autism and other nervous disorders are being diagnosed more and more often today. The reason for this may be not only hereditary genetic diseases, but also dangerous chemicals. In particular, organophosphates alone, used in agriculture, seriously affect the state of the central nervous system.

And recently, experts identified 10 chemicals, so-called neurotoxins, found both in the environment and in household items, furniture and clothing. According to scientists, these substances are the cause of the development of diseases that affect the nervous system. Most of them are already severely limited in use, but some of them still pose a great danger.

Chlorpyrifos

A common chemical in the past, part of the group of organophosphate pesticides, used to kill pests. Currently, chlorpyrifos is classified as a highly toxic compound, hazardous to birds and freshwater fish, and moderately toxic to mammals. Despite this, it is still widely used in non-food crops and for processing wood products.

Methylmercury

Methylmercury is a dangerous neurotoxin that affects the mechanisms of heredity in humans. It causes abnormal mitoses (K-mitoses) in cells and also damages chromosomes, and its effect is 1000 times greater than that of colchicine. Scientists believe it is possible that methylmercury can cause birth defects and mental defects.

Polychlorinated biphenyls

Or PCBs, are part of a group of chemicals defined as persistent organic pollutants. They enter the body through the lungs, gastrointestinal tract with food or skin, and are deposited in fats. PCBs are classified as a probable human carcinogen. In addition, they cause liver disease, disrupt reproductive function and destroy the endocrine system.

Ethanol

As it turns out, ethanol is not an environmentally friendly alternative to gasoline. Judging by data from scientists from Stanford University, cars using a mixture of ethanol and gasoline contribute to an increase in the level of two carcinogens in the atmosphere - formaldehyde and acetaldehyde. In addition, when using ethanol as fuel, the level of atmospheric ozone will increase, which, even at low concentrations, leads to all kinds of lung diseases.

Lead

Penetrating into the body, lead enters the bloodstream, and is partially excreted naturally, and partially deposited in various systems of the body. With a significant degree of intoxication, disturbances in the functional state of the kidneys, brain, and nervous system develop. Poisoning with organic lead compounds leads to nervous disorders - insomnia and hysteria.

Arsenic

Industrially, arsenic is used to make fertilizers, chemically treat wood, and make semiconductors. Arsenic enters the human body in the form of dust and through the gastrointestinal tract. With prolonged contact with arsenic, malignant tumors can form, in addition, metabolism and the functions of the central and peripheral nervous system are disrupted.

Manganese

First of all, manganese enters the human body through the respiratory tract. Large particles rejected by the respiratory tract can be swallowed along with saliva. Excessive amounts of manganese accumulate in the liver, kidneys, endocrine glands and bones. Intoxication over several years leads to disruption of the central nervous system and the development of Parkinson's disease. In addition, excess manganese leads to bone diseases and increases the risk of fractures.

Fluorine

Although fluoride is widely used in oral hygiene to combat bacterial dental diseases, it can cause many negative effects. Consumption of water containing fluoride at a concentration of one part per million causes changes in brain tissue similar to Alzheimer's disease. The most paradoxical thing is that an excess of fluoride has a destructive effect on the teeth themselves, causing fluorosis.

Tetrachlorethylene

Or perchlorethylene is an excellent solvent and is used in the textile industry and for degreasing metals. On contact with open flames and heated surfaces, it decomposes producing toxic fumes. With prolonged contact, tetrachlorethylene has a toxic effect on the central nervous system, liver and kidneys. A number of acute poisonings leading to death are known.

Toluene

In the chemical industry it is used for the production of benzene, benzoic acid and is part of many solvents. Toluene vapors penetrate the human body through the respiratory tract and skin. Intoxication causes disturbances in the development of the body, reduces learning abilities, affects the nervous system and reduces immunity.

Some substances can have extremely negative effects on human health. Natural or synthetic poisons affect the kidneys, liver, heart, damage blood vessels, causing bleeding, or act at the cellular level. Neurotoxins are substances that damage nerve fibers and the brain, and the results of such toxins are called neurotoxic disorders. The impact of this kind of poisons can be either delayed or cause acute conditions.

What are neurotoxins and where are toxic substances used?

Neurotoxins can be chemicals, drugs that cause anesthesia, antiseptics, metal fumes, aggressive detergents, pesticides and insecticides. Some living organisms are capable of producing neurotoxins in response to a threat to the immune system, and numerous toxic substances are present in the environment.

According to scientific research data summarized in the publication of the authoritative weekly medical journal “The Lancet,” about two hundred toxins can damage the human nervous system. Later (after studying data from the National Institute of Occupational Safety), it became necessary to add to the published list the same number of toxic substances that in one way or another have a negative effect on the central nervous system.

In the latter case, damage to nerve fibers was combined with damage to associated organs and systems, and symptoms of a neurotoxic disorder appeared when permissible exposure limits were exceeded.

Thus, the list of chemicals that can be classified as neurotoxins expands depending on what criteria a particular publication or author adheres to.

You can get neurotoxin poisoning by inhaling toxic fumes, increasing the permissible concentration in the blood, or eating foods saturated with large amounts of toxic substances. Many toxic substances are present in the environment, consumer goods, and household chemicals. Neurotoxins are used in cosmetology, medicine and industry.

What is the neurotoxic effect on the body?

The neurotoxic effect extends primarily to the brain and nerve fibers. Neutralization of the work of cells in the nervous system can lead to muscle paralysis, the occurrence of an acute allergic reaction, and affects the general mental state of a person. In severe cases, poisoning can cause coma and be fatal.

Toxic substances of this kind are absorbed into nerve endings, transmitted to cells and disrupt vital functions. The body's natural detoxification mechanisms are practically powerless against neurotoxins: in the liver, for example, the main functional feature of which is the elimination of harmful substances, most neurotoxins, due to their specific nature, are reabsorbed by nerve fibers.

Neurotoxic poison can complicate the course of any disease, making definitive diagnosis and timely treatment difficult.

Establishing an accurate diagnosis necessarily includes determining the suspected source of infection, studying the history of contact with a potential poison, identifying the full clinical picture and conducting laboratory tests.

Classification of the most famous representatives of neurotoxins

Medical sources classify neurotoxins into channel inhibitors, nerve agents, and neurotoxic drugs. Based on their origin, toxic substances are divided into those obtained from the external environment (exogenous) and those produced by the body (endogenous).

The classification of neurotoxins, poisoning from which is likely to occur at work and at home, includes three groups of the most common substances:

1. Heavy metals. Mercury, cadmium, lead, antimony, bismuth, copper and other substances are quickly absorbed into the digestive tract, spread through the bloodstream to all vital organs and settle in them.
2. Biotoxins. Biotoxins include potent poisons that are produced, in particular, by marine life and spiders. Substances can penetrate mechanically (by a bite or injection) or by eating poisonous animals. In addition, botulism bacteria are biotoxins.
3. Xenobiotics. A distinctive feature of this group of neurotoxins is their prolonged effect on the human body: the half-life of dioxin, for example, ranges from 7 to 11 years.

Symptoms of neurotoxin damage

Neurotoxic disorders caused by toxic substances are characterized by a number of symptoms typical of poisoning in principle, and specific signs that occur during intoxication with a particular compound.

Heavy metal intoxication

Thus, patients experience the following signs of heavy metal intoxication:

• abdominal discomfort;
• bloating, diarrhea or constipation;
• nausea and occasional vomiting.

At the same time, poisoning with a specific metal has its own distinctive characteristics. Thus, with mercury intoxication, a metallic taste is felt in the mouth, characterized by increased salivation and swelling of the lymph nodes, and is characterized by a strong cough (sometimes with blood), lacrimation, and irritation of the mucous membranes of the respiratory tract.

A severe case is: anemia develops, the skin becomes bluish, and the functioning of the liver and kidneys is quickly disrupted.

Biotoxin poisoning

In case of poisoning with biotoxins, the first signs of intoxication may include:

• increased salivation, numbness of the tongue, loss of sensation in the legs and arms (typical of poisoning with tetrodotoxin contained in puffer fish);
• increasing abdominal pain, nausea and vomiting, bowel irregularities, spots before the eyes and respiratory failure (botulinum toxin intoxication);
• severe pain in the heart, hypoxia, paralysis of internal muscles (a condition similar to a heart attack occurs when poisoned with batrachotoxin contained in the glands of some species of frogs).

Intoxication with xenobiotics

A neurotoxic poison of anthropogenic origin is dangerous because symptoms of intoxication can appear over a long period of time, which leads to chronic poisoning.

Damage from formaldehyde or dioxins - by-products of the production of pesticides, paper, plastics, etc. - is accompanied by the following symptoms:

• loss of strength, fatigue, insomnia;
• abdominal pain, loss of appetite and exhaustion;
• irritation of the mucous membranes of the mouth, eyes and respiratory tract;
• nausea, vomiting blood, diarrhea;
• impaired coordination of movements;
• anxiety, delirium, feeling of fear.

Features of neurotoxin poisoning

A distinctive feature of neurotoxins is damage to the human nervous system.

Thus, the patient’s condition is characterized by:

• impaired coordination of movements;
• slowing brain activity;
• disturbances of consciousness, memory loss;
• throbbing headache;
• darkening of the eyes.

As a rule, the general symptoms include symptoms of poisoning from the respiratory, digestive and cardiovascular systems. The specific clinical picture depends on the source of intoxication.

Prevention of intoxication at work and at home

Prevention of poisoning largely depends on the nature of the potential threat. So, in order to avoid intoxication with biotoxins, food should be thoroughly cooked, avoid eating expired or low-quality products, and prevent contact with potentially poisonous animals and plants. Heavy metal poisoning can be prevented by using products made from these materials strictly for their intended purpose, observing safety measures when working in hazardous industries and sanitary rules.

>>>> What are the dangers of neurotoxic effects?

What are the dangers of neurotoxic effects?

A number of substances can have a detrimental effect on nerve fibers, and such substances are called neurotoxins, and the results of their action are called neurotoxic disorders. Neurotoxins can cause acute reactions or delayed action, turning the toxic effect into a chronic process.

Chemical reagents, anesthetics, antiseptics, detergents, pesticides, insecticides, metal fumes, and drugs with neurotoxic side effects can act as neurotoxins. Neurotoxic effects can begin when the components of these substances accidentally enter the respiratory system, into the blood, and when their permissible concentration in the blood is exceeded.

Neurotoxic effects substances on the body manifests itself in a number of signs:

• Headaches,
• dizziness,
• Feeling faint
• Weakness of the muscles of the limbs,
• Balance disorders
• Feeling of tissue numbness
• Tissue sensitivity disorders
• Slow or impaired reflexes
• Cardiac disturbances (arrhythmias, tachycardia),
• Visual impairment,
• Breathing disorders
• Pain similar to radicular syndrome,
• Movement disorders
• Urinary retention or urinary incontinence,
• Confusion.

Neurotoxic disorders may be reversible and disappear when the action of the neurotoxin ceases, but they can also lead to irreversible damage in the body.

You can be exposed to neurotoxic effects:

• in the production of chemicals, being in a harmful atmosphere for a long time,
• when working with fertilizers and insecticides in agriculture and on private summer cottages,
• when carrying out disinfection of premises, being in an atmosphere filled with vapors of a concentrated disinfectant,
• during repair and construction work with paints and varnishes, adhesives, solvents in poorly ventilated areas,
• being near a combustion zone with a high concentration of carbon monoxide,
• Being in the zone of a chemical man-made disaster (emergency releases).

Neurotoxic disorders can over time transform into diseases of the nervous system and musculoskeletal system: myopathies, Parkinson's disease, decreased or loss of vision, dysfunction of the vestibular apparatus, mental degradation, tics, tremor.

Treatment of neurotoxic disorders is based on detoxification measures to remove toxic substances from the body and reduce their concentration in tissues, restore water and electrolyte balance, and cleanse the blood of toxins through hemosorption. In case of neurotoxicosis, symptomatic therapy is carried out (anticonvulsants, muscle relaxants, anti-inflammatory drugs, antiallergic drugs) to eliminate disorders that appear as a result of toxic effects. The priority direction in the treatment of neurotoxic disorders is the restoration of respiratory activity, hemodynamics, and the prevention of cerebral edema. Next, the affected organs are monitored, appropriate treatment is prescribed and motor activity is restored.