1. Rahul G. Kadam
PhD Scholar
Roll No. P-1661
PATHOLOGY & PATHOGENESI S OF TOXI NS &
POI SONS AFFECTI NG THE NERVOUS SYSTEM,
OTHER THAN TERATOGENI C
DIVISION OF VETERINARY PATHOLOGY
Major Credit Seminar
On

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

3. Overlook on anatomy and physiology nervous system

4. Mechanism of Neurotoxicity
Neuronopathies
Axonopathies
Myelinopathies
Neurotransmission-associated
Dendrite
Soma
Nucleus
Axon
Myelin
Schwann cell
Nodes of
Ranvier
Axon terminal

5. 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

6. Neuronal Necrosis
Greater degrees of anoxia is sufficient to kill astroglia as well as neurons, result in softening
Inhalation
Burning 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 sensitive
Within the cerebral cortex, neurons of deeper laminae are more sensitive
than those in the superficial laminae

7. 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 oxidative
phosphorylation

9. 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

10. 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)

11.  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.

12. 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

13. 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 neuritis
Microscopically:
 Pericellular oedema, plasmatic impregnation of the vascular walls, plasmolysis,
and karyolysis of the neurons.

14. 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

15. 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

16. 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

17. PLY
BoNTs
TeNT
Direct extension
Heamatogenous
Leukocytic trafficking
Retrograde axonal
Etx

18. 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.

19. 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.

20. Tetanus
C. Tetani
wound 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

21. 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.

22. 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.

23. 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

24. 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)

25. 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

26. Mycotoxins
Neurotoxic Mycotoxins Sources
Fumonisin B1
T2 toxin
Ochratoxin
Patulin
Penitrem-A
Ergot

27. Fumonisin B1
Fusarium 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.

28. 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.

29. 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).

30. 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

31. 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)

32. 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

33. 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.

34. Strychnine
Strychnos 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.

35. Curare
Strychnos toxifera
Toxic principle:
strychnine, brucine, curarine
 Curare competes with
acetylcholine--or Ach--for receptors on
muscle cells
Effects
 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.

36. 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.

37. 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)

38. Locoweeds
Astragalus spp and Oxytropis spp. (existing throughout the world)
Principal Toxin:
Swainsonine (first isolate from Swainsona canescens) – previously called locoine
Average 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.

39. Amatoxin
Amanita phalloides or A. Ocreata
Common 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.

40. 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.

41. Psilocybin and Psilocin
Psilocybe cubensis
Common 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.

42. Zootoxins
 Snakes
 Toads
 Apitoxin (bees and wasps)
 Scorpion
 Spider
 Tick
 Fish (ciguatera)

43. 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.

44. 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.

45. 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+
channel
Burning or stinging pain,
swelling, redness

46. Scorpion toxin
Toxins: Agitoxin, Charybdotoxin, Iberiotoxin
MoA:
Blocks potassium channels
Impair nerve impulse due to failure of polarization

47. 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

48. 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.

49. 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.

50. 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.

51.  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.

52. 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.

53.  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–
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55. • 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/2011/12/11
1215094811.htm>.

56. 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)