Rahul G. KadamPhD Scholar

Roll No. P-1661

PATHOLOGY & PATHOGENESIS OF TOXINS & POISONS AFFECTING THE NERVOUS SYSTEM,

OTHER THAN TERATOGENIC

DIVISION OF VETERINARY PATHOLOGY

Major Credit Seminar

On

Outline

Overlook on anatomy physiology nervous system Mechanism of neurotoxicity Compounds associated with neurotoxicity Bacterial toxins Mycotoxins Plant toxins Zootoxins Conclusion References

Overlook on anatomy and physiology nervous system

Mechanism of Neurotoxicity

Neuronopathies

Axonopathies

Myelinopathies

Neurotransmission-associated

Dendrite

Soma

Nucleus

AxonMyelin

Schwann cell

Nodes of Ranvier

Axon terminal

Compounds Associated with Neurotoxicity

NEUROTOXICANT NEUROLOGIC FINDINGS

Carbon monoxide Encephalopathy

Cyanide Coma, convulsions, rapid death

Common Salt Edema

Mercury, inorganic Emotional disturbances, tremor, fatigue

Lead Encephalopathy (acute), neuropathy with demyelination (rats)

Mercury, inorganic Emotional disturbances, tremor, fatigue

Arsenic Encephalopathy (acute), peripheral neuropathy (chronic)

Organochlorine Neurotransmission

Organophosphate Neurotransmission

Neuronal NecrosisGreater degrees of anoxia is sufficient to kill astroglia as well as neurons, result in softening

InhalationBurning coal and charcoal, combustible

gases & engines, Industrial workers

Carbon monoxide

Anoxic anoxia(previously

thought cytotoxic)

Nervous tissue could not tolerate O2 deficiency more than 2-3mins Components of nervous system are vulnerable in the order of:

Neuron < Oligodendroglia < Astroglia < Microglia < Blood vessels Regional vulnerability:

Cerebral cortex and Purkinje cells being most sensitiveWithin the cerebral cortex, neurons of deeper laminae are more sensitive

than those in the superficial laminae

Cyanide poisoning

Cytotoxic anoxia

Sources:Industrial, plants containing toxic levels of hydrocyanic bounds as glucose. Metabolism:The compounds are in general the β-glycosides of α-hydroxynitriles which is activated by endogenous glucosidase of plants or ruminal microorganism.

Sheep and Cattle are able to detoxify cyanide in the liver to form thiocyanate - Goitrogeni

Manifested as: Limb paresis with knuckling Incoordination and disturbance of equilibrium Head and body tremor

Neuronal changes:Axonal degeneration and demyelination at all levels of the spinal cord

Antidote: sodium thiosulphate

Rhodanese

Inhibit oxidativephosphorylation

Mercury

Affinity for sulfhydryl groups & interfere with DNA transcription and protein synthesis Easily cross the blood brain barrier and placenta.

Poorly soluble in water and poorly absorbed. Do not cross the BBB efficiently, but, accumulate in quantity in the placenta, fetal tissues, and amniotic fluid.

Methyl mercury is most devastating effect on the CNS by causing psychiatric disturbances, ataxia, visual loss, hearing loss, and neuropathy. Fatality is usually the result of severe exposure to mercuric salt. Inorganic mercury poisoning revealed a combination of axonal and demyelinating changes. Organic methylmercury toxicity causes prominent neuronal loss and gliosis

Thimerosal is a mercury-containing preservative used in some vaccines, e.g. JE Vax, IPOL , Typhim Vi etc‐

Lead

Lead ions are more effective than calcium ions in supporting CaM-dependent phosphorylation of brain proteins and the binding of calmodulin to brain proteins.

Sources: Environmental & domestic. Lead-based paints, including paint on the walls of old houses and toys. Batteries, solder, pipes, pottery Gasoline products

MoA: Ionic mechanism of action for lead mainly arises due to its ability to substitute other bivalent cations like Ca2+, Mg2+, Fe2+ and monovalent cations like Na+ ion. Flora et al., (2012)

Lead‘s activating effects on calmodulin perturb intracellular calcium homeostasis, which effect calcium-mediated processes intrinsic to normal cellular activity (Ferguson et al., 2000). Lead suppresses activity-associated Ca2+-dependent release of acetylcholine, dopamine and amino acid neurotransmitters (Lasley et al., 1999; Devoto et al., 2001).

Effects on Neurons: After crossing the BBB, lead accumulates in astroglial cells (containing lead binding proteins). When the blood-brain barrier is exposed to high levels of lead concentration, plasma moves into the interstitial spaces of the brain, resulting in edema. Encephalopathy and edema are mainly affects the cerebellum of the brain. Toxic effects of lead are more pronounced in the developing nervous system comprising immature astroglial cells, inhibiting the formation of myelin.

Arsenic poisoning

Source: arsenic-containing insecticide, herbicide, or rodenticide, industrial waste.

MoA (Two mechanisms)Ability to binds with SH-groups As (III), result of critical enzyme effects

inhibition of pyruvate oxidation in TCA cycle, impaired gluconeogenesis, and reduced oxidative phosphorylation.

Another mechanism involves substitution of As (V) for phosphorus. It replaced stable phosphorus anion in phosphate form which is less stable leads to rapid hydrolysis of high energy bonds in compounds such as ATP, that leads to loss of high energy phosphate bonds dysfunction of mitochondrial respiration (Rossman 2007).

Easily cross blood-brain barrier. The mechanism postulated for arsenic-induced neurotoxicity mainly involve oxidative stress with increased reactive oxygen species and lipid peroxides.

ATP + As (V)= AT-(As) + 3P

Symptoms: Headache, lethargy, mental confusion hallucination, seizures, and coma.

Neurological Lesions: Polyneuropathy usually symmetrical involvement, which resemble Landry- Guillain-Barre Syndrome in its presentation. Peripheral Neuropathy Retrobulbar neuritisMicroscopically: Pericellular oedema, plasmatic impregnation of the vascular walls, plasmolysis, and karyolysis of the neurons.

Organchlorines

Examples: DDT & its analogue Aldrin Endosulfan Lindane etc

MoA: DDT and its analogs act mainly at the nerve axon by interfering (excitatory, blocking) with Na+ and K+ conductance gating.

HCH groups (lindane) inhibiting the CNS GABA receptors.

Clinical Signs: hyperexcitability, resulting in seizures, tremors, paresthesias, ataxic gait and other neurological effects.

OC

Lindane

Organophosphate

Examples: Chlorpyriphos, Coumaphos, Dichlorvos, Malathion

MoA: Inhibition of AChE. Inactivated ACh accumulates throughout the nervous system, resulting in overstimulation of muscarinic and nicotinic receptors.

Clinical effects are manifested via activation of the autonomic and central nervous systems and at nicotinic receptors on skeletal muscle. OP

Bacterial toxin

Common Bacterial Neurotoxins Bacteria

Botulinum neurotoxins Clostridium botulinum, C. baratii, C. butyricum

Tetanus neurotoxin Clostridium tetani

Pneumolysin Streptococcus pneumoniae

Epsilon toxin Clostridium perfringens

PLY

BoNTs

TeNT

Direct extensionHeamatogenousLeukocytic traffickingRetrograde axonal

Etx

Botulism

C. botulinum Contaminated hay and fodder Scarcity of green pasture and phosphorous deficient animal having a habit of chewing bone and decayed meat. LD50 is approximately 0.09 to 0.15 μg i/v

Pathogenesis: (inhibit acetylcholine) The toxin binds to presynaptic receptors and is transported into the nerve cell through receptor-mediated endocytosis, internalized into vesicles, In the cytosol, the toxin mediates the proteolysis of components of the calcium-induced exocytosis apparatus (the SNARE proteins) to interfere with acetylcholine release.

Clinical Signs: The effects of the toxin are limited to blockade of peripheral cholinergic nerve terminals, characterized by bilateral descending paralysis of the muscles innervated by cranial and spinal nerves. The classic syndrome of botulism is a symmetrical, descending motor paralysis. Death is usually the result of respiratory failure.

Blockade of neurotransmitter release at the terminal is permanent, and recovery only occurs when the axon sprouts a new terminal to replace the toxin-damaged one Botulinum toxin A cleaves synaptosomal-associated protein (SNAP-25), Botulinum toxins B, D, F, and G cleave synaptobrevin, Botulinum toxin C cleaves SNAP-25 and syntaxin.

Tetanus

C. Tetaniwound contamination

Pathogenesis: (glycine and GABA) Tetanus toxin is a zinc-dependent metalloproteinase that targets synaptobrevin (on VAMP) Spinal cord or brainstem access via extensive retrograde transport in the axons from lower motorneurons (site of wound) and it takes 2-14 days

When the toxin reaches the spinal cord, it enters central inhibitory neurons. The TenT cleaves the protein synaptobrevin (SNARE-component), As a result, gamma-aminobutyric acid (GABA)-containing and glycine-containing vesicles are not released, and there is a loss of inhibitory action on motor and autonomic neurons, finally caused flaccid paralysis. (Freshwater Turner, 2007)

GABA

Clinical Signs:Muscle rigidity and spasms ensue, often manifesting as trismus/lockjaw, dysphagia, opistotonus, or rigidity and spasms of respiratory, laryngeal, and abdominal muscles, Death due to rigidity and spasms of the laryngeal and respiratory muscles

With this loss of central inhibition, there is autonomic hyperactivity as well as uncontrolled muscle contractions (spasms) in response to normal stimuli such as noises or lights. Once the toxin becomes fixed to neurons, it cannot be neutralized with antitoxin. Recovery of nerve function from tetanus toxins requires sprouting of new nerve terminals and formation of new synapses.

Pneumolysin

Streptococcus pneumoniae Normally found in the upper respiratory tract When host immunity is low, population flare and caused infection, characterized by a wide range of symptoms, including: otitis media, sinusitis, bacteraemia, pneumonia, arthritis, and peritonitis.

Avoid phagocytic phagocytosis by capsule-bound PdgA and Adr deacetylate surface petidoglycan. Also, by ChoP is a phase-variable structure on bacterial cell surface, an enzymes which can break down lipids.

Pathogenesis: PLY is a cytoplasmic cholesterol-dependent cytolysin (CDC) which is released on autolysis, It binds to the host cell cytoplasmic membrane cholesterol, forming large oligomeric pores, disrupting the cell membrane. PLY produces actin and tubulin reorganization and astrocyte cell, causing astrocytic process retraction, cortical astrogial reorganization and increased interstitial fluid retention, which is manifested as tissue edema (Hupp et al., 2012). It facilitate pathogen tissue penetration and produces interstitial brain edema.

Lesions: cytotoxic edema, vasculitis and acute demyelination.

Readily crossed BBB, Pneumococcus expresses ChoP on the bacterial cell surface which now binds to PafR and induces clathrin-mediated internalization

Epsilon

C. perfringens (B, D) found in soil and meat that is not cooked properly, contaminated food, water.

Etx induces pore formation in eukaryotic cell membranes via detergent-resistant, cholesterol-rich membrane domains that promote aggregation of toxin monomers into homo-heptamers, leading to transmembrane pore formation, facilitate free passage of molecules and secondary invading pathogens. Epsilon toxin is an elongated rod-shaped molecule, consisting of three domains and largely of β-sheets.

Pathogenesis: Glutamate Inhibitor LD50 of ~70 ng/kg body weight Epsilon is secreted as an inactive prototoxin, which is converted to the active form after treatment with proteases such as trypsin, chymotrypsin, and a zinc metalloprotease. (Osamu et al., 1998)

Lesions: After crossing the blood-brain barrier, it attacked myelin, causing neuronal damage predominantly in the hippocampus: pyramidal cells showed marked shrinkage and karyopyknosis, or so-called dark cells. Among neuronal cell, the neurons are most susceptible followed by oligodendrocytes and astrocytes . There can be swelling, vacuolation and necrosis in the brain. (Bradley et al., 2013)

1. a single transmembrane α-helix

2. a polytopic transmembrane α-helical protein

3. a polytopic transmembrane β-sheet protein

Mycotoxins

Neurotoxic Mycotoxins Sources

Fumonisin B1

T2 toxin

Ochratoxin

Patulin

Penitrem-A

Ergot

Fumonisin B1Fusarium verticillioides concomitant of various cereals, predominantly corn

MoA The structural similarity of fumonisins to the sphingoid bases sphinganine (Sa) and sphingosine (So) is critical to their ability to disrupt sphingolipid metabolism FB1-induced inhibition of ceramide synthesis, which a is a key enzyme in de novo sphingolipid biosynthesis. (Merrill et al., 2001; Riley et al., 2001)

FB1 is well known to cause equine leukoencephalomalacia (ELEM).On postmortem examination: the classic finding is gray to brown areas of malacia and cavitation of white matter of the cerebral hemisphere, which is usually unilateral.

Microscopically: marked multifocal, liquefactive necrosis and perivascular hemorrhage throughout the white matter of the cerebrum. Focal necrotic lesions, located primarily in the subcortical white matter is pathognomonic.

T-2 Toxin (trichothecenes)

Fusarium spp (F. sporotichioides, F. poae, F. equiseti, and F. acuminatum), which can infect corn, wheat, barley and rice crops in field or during storage

MoA: (hypothesis) T-2 toxin is inhibitor of protein synthesis through its high binding affinity to peptidyl transferase which is an integral part of the 60 s ribosomal subunit. It also Interferes with the metabolism of membrane phospholipids and increases liver lipid peroxides (Eriksen et al., 2004). Changes in amino acid permeability across the blood-brain barrier, which could lead to neurological effects (Wang et al., 1998). Oxidative stress might be the main factor behind the T-2 toxin-induced changes in the fetal brain (Sehata et al., 2004).

Lesion: It caused neuronal cell apoptosis and inflammation in the olfactory epithelium and olfactory bulb.

Ochratochin A (OTA)

Aspergillus ochraceus and Penicillium verrucosum.

MoA: Due to its chemical structure, OTA inhibits protein synthesis by competition with phenylalanine in the aminoacylation reaction of phenylalanine-tRNA and phenylalanine hydroxylase activity, leading to the impairment of the synthesis of DOPA, dopamine and catecholamines or enzymes involved in the metabolism of DNA (Creppy et al., 1983). The developing brain appears to be very susceptible to the deleterious effects of OTA (Wangikar et al., 2004).Lesions: Neuronal cell apoptosis in the substantia nigra, striatum and hippocampus. Neurotoxicity is more pronounced in the ventral mesencephalon, hippocampus, and striatum than in the cerebellum (Chung, 2003).

Patulin

Aspergillus clavatus

MoA: Patulin interaction with sodium or proton transport has been suggested based on the proven capacity to inhibit plasma membrane Na+/K+ ATPase in vivo and in vitro (Albarenque et al., 1999). This is postulate to be the mechanism of action for neurotoxicity of patulin. Chronology of cellular injury caused by patulin: Simultaneous suppression of GJIC and GSH depletion ROS generation mitochondrial membrane depolarization simultaneous increase in Ca2+ and cytoplasmic acidification depolarization of plasma membrane. (Burghardt et al., 1992).

Clinical sign: a severe neurotoxicosis comprising tremor, ataxia, paresis, recumbency and death.Necropsy revealed neuronal degeneration of CNS and axonal degeneration in peripheral NS

Penitrem A

Penicillium crustosum

MoA: Penitrem A has a substantial effect on GABAA receptors in the brain. It have a tranquilising effect on one part of the brain and a cramp-inducing effect on other parts “Oxidative stress can be related to the pathological changes found in animals exposed to penitrems, since these toxins increase the production of free radicals that can damage tissue”. (ScienceDaily, 15 December 2011. )

Lesions: Widespread degeneration of Purkinje cells and foci of necrosis in cerebral granular cell layers.

(Norwegian School of Veterinary Science, 2011)

Plant Poison

Scientific Name Common Name

Aesculus Bucked eye, horse chesnut

Artemisia filifolia Sand sage

Astragalus spp. Locoweeds

Centaurea solstitialis Yellow star thistle

Equisetum arvense Horsetail

Karwinskia humboldtiana Coyotillo

Oxytropis spp. Locoweed

Pteridium aquilinum Bracken fern

Datura stramonium Devil's trumpet, jimson weed, thornapple

S. fastigiatum and S. bonariense Solanum

Strychnos nux-vomica Strichnine

Strychnos toxifera Curare

Prunus serotina Black cherry

Datura stramonium

Medicinal uses: Solanaceae has been introduced as an analgesic plant in Iranian folk medicine (Mohsen and Masoud, 2004)Asthma treatment particularly the M2 receptors (Pretorius and Marx ,2006).

Common name: Devil's trumpet, Jimson weed, Thornapple

Toxic Principle: Hyoscyamine (stimulating) and scopolamine (depressant) which are anti-cholinergic compounds (Brown and Taylor, 2006). M1 to M5 different subtypes of muscarinic receptors have been described, all belonging to the class of G protein coupled receptors. M1 receptors localized at CNS, gastric and salivary glands. M4 receptors predominantly in CNS M5 receptors in Substantia nigra of CNS, salivary glands and in the ciliary muscle of the iris of the eye.

Signs: Dryness of the mucosa, mydriasis, photophobia and bradycardia or tachycardia nervousness, restlessness, irritability, disorientation, ataxia, seizures and respiratory depression.

StrychnineStrychnos nux-vomica (Hihdi: Bailewa)entire plant

Toxic principles: strychnine and brucine Strychnine inhibit glycine It act as post-synaptic receptor of spinal motor neuron resulting in loss of tone and producing chacteristic muscle spasm, known as spinal seizures. 30mg of these alkaloids is enough to be fatal to an adult.

Clinical Signs & Symptoms: Involvement of abdominal masculature result in respiratory paralysis which is the caused of death. Ingestion of less than 10 mg in child and 16 mg (dry weight) in an adult have been reported to be fatal.

Curare

Strychnos toxifera

Toxic principle:strychnine, brucine, curarine

Curare competes with acetylcholine--or Ach--for receptors on muscle cellsEffects When curare binds instead of acetylcholine, the receptors do not become activated, and there is loss of muscle function, paralysis and possibly death. Dosage and dosing intervals all determine the severity of curare's effect.

Solanum

S. fastigiatum and S. bonariense

Toxic principle: (The toxic dose in man in 2.8 mg/kg.) Solanine and chaconines, Alpha-solanine .MoA Solanum glycoalkaloids can inhibit cholinesterase. Solanine exposure opens the potassium channels of mitochondria, decreasing their membrane potential. This in turn leads to Ca2+ being transported from the mitochondria into the cytoplasm, which triggers cell damage and apoptosis (Gao, 2006).

Signs & Symptoms: Characterized by periodic episodes of seizures, loss of balance, nystagmus, opisthotonus, tremors and ataxia (Riet-Correa et al. 2009).Histologically, The lesions consisted of vacuolization, distention of portions of the Purkinje cells, axonal spheroids measuring 14-50 μm in the granular cell layer and adjacent white matter and, proliferation of the Bergmann’s glia.

Black cherry

Prunus serotina

Toxic principles:Cyanogenic glycosides; prunasin, prulaurasin and amygdalin

Cyanine poisoning

Clinical sign The animal show slow or stop breathing, a very slow heart rate. Eventually the animal becomes comatose and a brief period of paddling followed by convulsions before death.

Cyanosis, the blue colouration that results from deoxygenated blood, which show a grave sign of HCN poisoning since the blood remains red and well-oxygenated. Cyanogenic colouration is observed because the oxygen release from haemoglobin to the cells is blocked. Burrows and Tyrl (2001)

Locoweeds

Astragalus spp and Oxytropis spp. (existing throughout the world)

Principal Toxin:Swainsonine (first isolate from Swainsona canescens) – previously called locoineAverage concentration of swainsonine in locoweed is 0.09 - 0.23% (dry weight)

MoA: Inhibit the action of two lysosomal enzymes (α-D-mannosidase and Golgi mannosidase II) that aid in the metabolism of saccharides. Inhibition of α-mannosidase caused accumulation of complex sugars or oligosaccharides. Golgi mannosidase II caused accumulation of normal structure of oligosaccharide components of glycoproteins. As a result, oligosaccharides accumulate in the cells of the brain and many other organs and interfere with normal cellular function.

Signs: Horses show the nervous signs of locoweed poisoning more commonly than do cattle or sheep. circling, incoordination, staggering gait, and unpredictable behavior The prognosis for locoed horses should therefore always be guarded.It causes a generalized lysosomal storage disease similar to the genetically transmitted disease mannosidosis.

Amatoxin

Amanita phalloides or A. OcreataCommon name: Death cap

Toxic principle: alpha-amanitin One of the Deadliest naturally occurring compounds. 0.1 mg/kg can be fatal (a dose that is often present in a single mushroom).

MoA:Interference with RNA polymerase II, which prevents DNA transcription.

Muscarine

Amanita muscaria, A. pantherina

Common name: Fly agaric

Toxic principle: Ibotenic acid and muscimol Ibotenic acid and its metabolite is glutamic acid agonist Whereas muscimol is GABA agonist.

Symptoms is typically rapid, within 2 hours, characterized by hallucinations, dysphoria, and delirium.

Psilocybin and Psilocin

Psilocybe cubensisCommon name: boomers, magic mushrooms or gold caps

Toxic principle: Psilocybin, psilocin, baeocystin and norbaeocystin, all are indole derivates from tryptamin.

MoA: By altering the concentration of indoles, including serotonin, in CNS, which leads to interfere with the transmission and processing of external stimuli (Young et al., 1982).

Visual, auditory and tactile hallucinations together with disturbed sensory perception like visual distorsions. Example, loss of colour differentiation, sensation of objects changing shape. Other, like body image distorsions, depersonalization, derealization and altered time and space sense. Seizures may rarely occur.

Zootoxins

Snakes Toads Apitoxin (bees and wasps) Scorpion Spider Tick Fish (ciguatera)

Snake venoms

Neurotoxic venoms: Fasciculins - attack cholinergic neurons Dendrotoxins - inhibit neurotransmissions by blocking the exchange of positive and negative ions across the neuronal membrane α-neurotoxins - blocked Ach. alpha-bungarotoxin - Blocks acetylcholine (nicotinic) receptor (Krait)

Venomous snakes can be classified into three class Elapines- neurotoxic (e.g.cobra, mamba, and coral snakes) Two families of viperines, the true vipers (e.g., puff adder, Russell's viper) & the pit vipers (e.g., rattlesnakes, copperhead. Viperine venom is typically haemotoxic, necrotising (death of tissue), and anticoagulant.

Toad toxin

Batrachotoxins (BTX) are extremely potent cardiotoxic and neurotoxic steroidal alkaloids found in certain species of frogs (Arrow Frog)

LD50 in rats, the lethal dose of this alkaloid in humans is estimated to be 1 to 2 µg/kg.

MoA: Prevents sodium channels from closing Disturbance in depolarization of action potential, failure of nerve impulse. Lipid-soluble toxins such as batrachotoxin act directly on sodium ion channels involved in action potential generation and by modifying both their ion selectivity and voltage sensitivity.

Apitoxin

SK channel blockers may have a therapeutic effect on Parkinson’s disease

Bee & Wasp: Apamin is an 18 amino acid peptide neurotoxin found in apitoxin

MoA: Apamin selectively blocks SK channels, a type of Ca2+-activated K+ channel expressed in the central nervous system. Impaired of nerve impulse due to failure polarization

Ca2+-activated K+ channelBurning or stinging pain, swelling, redness

Scorpion toxin

Toxins: Agitoxin, Charybdotoxin, Iberiotoxin

MoA:Blocks potassium channelsImpair nerve impulse due to failure of polarization

Spider

Toxins: Atracotoxins hanatoxin alpha latratoxin

MoA: The mechanism of many spider toxins is through blockage of calcium channels. It will lead to inactivation of Ca++ sensitive Potassium channel -> down regulation of nerve impulse

Blocked

Intracellular

Tick

Dermacentor andersoni, Dermacentor variabilis xodes holocyclus

Tick paralysis is the only tick-borne disease that is not caused by an infectious organism. The illness is caused by a neurotoxin produced in the tick's salivary gland. It is believed to be due to toxins found in the tick's saliva that enter the bloodstream while the tick is feeding. It occurs when an engorged and gravid (egg-laden) female tick produces a neurotoxin in its salivary glands and transmits it to its host during feeding, the greatest amount of toxin is produced between the fifth and seventh day of attachment.

The toxin causes symptoms within 2–7 days, beginning with weakness in both legs that progresses to paralysis. The paralysis ascends to the trunk, arms, and head within hours and may lead to respiratory failure and death.

Ciguatera (Fish)

Ciguatera - Gambierdiscus toxicus

It is an important form of human poisoning caused by the consumption of seafood. These dinoflagellates adhere to coral, algae and seaweed, where they are eaten by herbivorous fish human and carnivorous animals are exposed at the end of the food chain. Ciguatoxins activate sodium ion (Na ) channels, affecting cell membrane excitability and instability.

Signs & Symptoms: The disease is characterised by gastrointestinal, neurological and cardiovascular disturbances. In cases of severe toxicity, paralysis, coma and death may occur.

Conclusion Understanding of anatomy and physiology of nervous system played crucial roles in

understanding the pathogenesis and mechanism of action of chemicals, poisons and poisons.

Metal associated toxicities are mainly based on availability of chelating or bonding ionic/cationic interactions: e.g. Lead caused toxicity due to its divalent cation, which can replaced cellular Ca++, Mg++, Fe++ as well as Na+.

Bacterial toxins are proteins interact with various cell types, interfering the action of cellular proteins and its associated products: e.g. Epsilon protein is transmembrane pore forming due to its β-sheet protein which transformed the normal α-helical protein into barrrel shaped pore forming β-sheet.

Mycotoxins are produced in a strain-specific way and elicit some complicated and overlapping toxigenic activities in sensitive species that include carcinogenicity, inhibition of protein synthesis, immunosuppression, dermal irritation, and other metabolic perturbations: e.g. T-2 toxin triggers a ribotoxic response through its high binding affinity to peptidyl transferase, an integral part of the 60 s ribosomal subunit and interferes with the metabolism of membrane phospholipids and increases liver lipid peroxides.

Toxic principle of poisonous plant are different according to species, main components are alkaloid, glycosides, proteinaceous compounds and organic compounds etc.

Zootoxins are produced by various animals, insects, amphibian and aquatic animals.

Still the pathogenesis and mechanisms of many poisons and toxins are obscured, further extension in studies and implementation is required.

References Bernhoft, R. A. (2012) Mercury Toxicity and Treatment: A Review of the Literature.

Journal of environmental and public health volume. 10: 1155. Burrows G.E. and R. J. Tyrl (2001) Toxic Plants of North America Ames, Iowa: Iowa State

Press. 1043-1056. Doi, K. and K. Uetsuka (2011) Mechanisms of Mycotoxin-Induced Neurotoxicity through

Oxidative Stress-Associated Pathways . Int. J. Mol. Sci. 12: 5213-5237. Flora, G., D. Gupta, A. Tiwari (2012) Toxicity of lead: A review with recent updates.

Interdiscip Toxicol. 5(2): 47–58. Hassel, B. (2013) Tetanus: Pathophysiology, Treatment, and the Possibility of Using

Botulinum Toxin against Tetanus-Induced Rigidity and Spasms. Toxins. 5: 73-83. Lehanea, L. and R. J. Lewisb (2000) Ciguatera: recent advances but the risk remains.

International Journal of Food Microbiology. 61 91–125. Lucas, R., I. Czikora, S. Sridhar, E. Zemskov, B. Gorshkov, U. Siddaramappa, A. Oseghale,

J. Lawson, A. Verin, F. G. Rick, N. L. Block, H. Pillich, M. Romero, M. Leustik, A. V. Schally and T. Chakraborty (2013) Mini-Review: Novel Therapeutic Strategies to Blunt Actions of Pneumolysin in the Lungs. Toxins. 5: 1244-1260.

Miyamoto, O., T. Minami, T. Toyoshima, T. Nakamura, T. Masada, S. Nagao, T. Negi, T. Itano and A. Okabe (1998) Neurotoxicity of Clostridium perfringens epsilon-toxin for the rat hippocampus via the glutamatergic system. Infection and immunity. 6:2501–2508.

Pohland, A. E., S . Nesheim and L. Friedman (1992) Ochratoxin a: a review. Pure & Appl. Chern. 64 (7) : 1029-1046.

Popoff, M. R. and B. Poulain, (2010) Bacterial toxins and the nervous system: neurotoxins and multipotential toxins Interacting with neuronal Cells. Toxins, 2:683-737.

Stiles, B. G., G. Barth, H. Barth and M. R. Popoff (2013) Clostridium perfringens Epsilon Toxin: A Malevolent Molecule for Animals and Man. Toxins. 5:2138-2160.

Vilar M. S., R. F.M. Maas, H. D. Bosschere, R. Ducatelle and J. Fink-Gremmels (2004) Patulin produced by an Aspergillus clavatus isolated from feed containing malting residues associated with a lethal neurotoxicosis in cattle. Mycopathologia. 158: 419–426.

Voss, K.A., G.W. Smith, W.M. Haschek (2007) Fumonisins: Toxicokinetics, mechanism of action and toxicity. Animal Feed Science and Technology. 137: 299–325.

• Norwegian School of Veterinary Science. "Fungus-induced neurological disease: An underestimated risk for animals and humans?." ScienceDaily. ScienceDaily, 15 December 2011. <www.sciencedaily.com/releases/2011/12/111215094811.htm>.

Neurotransmitter

• Two main types Excitatory synapse (EPSP) Inhibitory (IPSP)

Glutamate GABA

Catecholamine Glycine

Serotonin Seratonin

Histamine Acetyl choline

Acetylcholine

Excitatory:Na+ and K+ (Deperpolarization; >50mV)Inhibitory:Cl- and K+ (Hyperpolarization; <80mV)