Neurotoxicity.pptx principles of toxicology M pharm

Introduction, mechanisms involved, different neuro toxic agents

1. Neurotoxicity By: G krishna sri 24T21S0105 M pharm 1 st year Depatment of pharmacology

2. Introduction : The nervous system consists of two fundamental anatomical divisions: the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS includes the brain and spinal cord, while the PNS consists of all other nervous tissue that lies outside the CNS. brain, there is a forebrain region that consists of the cerebrum ( cerebral cortex and basal ganglia ), the thalamus , and the hypothalamus . There is also a small midbrain region, and a hindbrain consisting of the medulla , pons , and cerebellum . The fourth major area is the spinal cord . The PNS includes both afferent nerves that relay sensory information from specialized receptors to the CNS and efferent nerves that relay motor information from the CNS to various muscles and glands

3. The nervous system is a vulnerable target for toxicants due to the critical voltages that must be maintained in cells and the all-or-nothing response very active tissue metabolically consists of a complex network of cells spread throughout the body The role of the nervous system in directing many critical physiological operations also means that any damage may well have widespread and significant functional consequences Damage to neurons is sustained more permanently than other cells due to the relative lack of regeneration, particularly in the central nervous system .

4. T he effects of toxicants on the nervous system can be grouped into several functional categories. toxicants affect the passage of electrical impulses down the axon A second category of toxicants affects synaptic transmission between neurons toxicants that affect myelin toxicants that damage axons Exposure to other toxicants can lead to neuronal cell death final category of toxicants are produced through unknown mechanisms.

5. EFFECTS OF TOXICANTS ON ELECTRICAL CONDUCTION Toxicants Origin MOA Effects Tetrodotoxin frogs, fish, blue-ringed octopus and puffer fish blocks the generation of an action potential by binding to a site on the outside of the neuronal membrane and blocking the sodium channels motor weakness and paresthesias Higher doses- paralysis (skeletal muscle, smooth muscle) may then lead to severe hypotension and circulatory failure saxitoxin (STX) dinoflagellates food source for various shellfish and fish blocks sodium channels shellfish may be eaten by unsuspecting humans who may then become ill or perhaps even die batrachotoxin (BTX), South American frogs increases the permeability of the resting neuronal membrane to sodium by preventing closing of the sodium channels. high degree of lipid solubility , modifies the selectivity of the channel It is extremely toxic

6. scorpion and sea anemone toxins and plant alkaloids aconitine and veratridine delays the closing of sodium channels prolong action potential duration from several milliseconds to several seconds DDT and synthetic pyrethroid insecticides Blocks sodium ion channel voltage gating was altered

7. EFFECTS OF TOXICANTS ON SYNAPTIC FUNCTION

8. Release of Ach : Hemicholinium ( HC-3) and Botulinum toxin (with an LD50 in some animals as low as 10 ng /kg), binds to the nerve axon and interferes with the release of acetylcholine Nicotinic Receptors : poisoning with nicotine(agonist) leads to a mix of sympathetic and parasympathetic symptoms, including increased heart rate, increased blood pressure, and increased gastrointestinal motility and secretion, psychoactive effects (mild euphoria, relaxation) Curare ( d- tubocurarine ) nicotinic antagonist compete with acetylcholine for binding and block the receptor, preventing the initiation of an action potential in the postsynaptic neuron-motor weakness and paralysis, decrease in blood pressure and heart rate

9. Muscarinic receptors : Atropine and Scopolamine are muscarinic blockers found in plants . Atropine blocks parasympathetic neurons' effects on muscles and glands, leading to an autonomic system imbalance. A dose of 2.0 mg can cause tachycardia, pupil dilation, bronchiole dilation, decrease in peristalsis, and decrease in saliva secretions. On cholinesterases : Organophosphates and carbamates can inhibit acetylcholinesterase . Poisoning results in slowing heart rate, pupil constriction, bronchoconstriction, and increased secretions.Symptoms include salivation, lacrimation, urination, and defecation. Antidotal treatment includes atropine and pralidoxime (2-PAM).

10. Biogenic Amines: A second major group of neurotransmitters and neurohormones is the biogenic amines, which includes the neurotransmitters norepinephrine , epinephrine , dopamine , serotonin , and histamine Release and storage . • Reserpine interferes with the storage of biogenic amines, causing a decrease in sympathetic activity • Amphetamine stimulates the release of norepinephrine .

11. Receptors Alpha blockers decrease blood pressure, increase gastrointestinal muscle activity, and cause nasal stuffiness. Ergot alkaloids, produced by Claviceps purpurea , interact with alpha receptors in a complex manner. Ergot alkaloids stimulate smooth muscle contraction, causing gangrene in extremities and spontaneous abortion . Beta receptor blocking drugs like propranolol are commonly used to manage cardiovascular disorders by reducing heart rate and blood pressure . Recent drugs specifically target beta one receptors, eliminating the side effect of bronchoconstriction if beta two receptors are also blocked .

12. Reuptake Catecholamines are deactivated through a reuptake mechanism, which requires sodium and potassium and is energy-dependent. Catecholamines can be broken down by monoamine oxidase (MAO) and catechol-O- methyltransferase (COMT) enzymes. MAO-A and MAO-B enzymes, like chlorpromazine, can increase catecholamine levels in the brain by inhibiting these enzymes MAO in the gastrointestinal system is responsible for the metabolism of tyramine , which interacts with the sympathetic nervous system and can cause a sharp increase in blood pressure . Cocaine, for example, can overstimulate the postsynaptic neuron and stimulate dopamine release, causing euphoria and other psychoactive effects.

13. Amino Aci dN eu r o tra nsmi tt e r s Gamma- Aminobutyric Acid (GABA) Neurotransmitter Overview • GABA is a significant amino acid neurotransmitter, produced by neurons and acting at the inhibitory GABA receptor and chloride ion channel. • GABAergic pathways are crucial for emotion control. • Antianxiety drugs like Valium and Librium interact with GABA, but are ineffective without GABA. • Picrotoxin , derived from East Indian plant seeds, antagonizes GABA effects and blocks benzodiazepines' action. • Dieldrin and chlordane, cyclodiene insecticides, block GABA receptor.

14. • Glycine, an inhibitory transmitter, primarily affects brain stem and spinal cord. • Tetanus toxin and strychnine prevent glycine release by binding to presynaptic membranes. • Antagonism of glycine's inhibitory effect leads to sustained muscle contraction. • Excitatory amino acids like glutamate and aspartate. Kainic acid is a glutamate agonist that kills neurons, as can glutamate itself in large concentrations • Mechanisms of neuronal death due to excitotoxic effects of glutamine and related amino acids are discussed .

15. Neuroactive Peptides neuropeptides differ in several ways from the other transmitters in the nervous system. This category includes enkephalins and endorphins neuropeptides may affect membrane potential, or they may be released along with a neurotransmitter and alter its release or binding. Opioid peptides, a group of neuropeptides, have inhibitory effects on pain impulse transmission pathways. Opioids interact with opioid receptors, including morphine and codeine. Heroin, a derivative of morphine, produces drowsiness and pain relief but also euphoria Naloxone , an opioid receptor antagonist, can block effects of both endogenous peptides and opioid

16. Axonopathy Axonopathy , damages to the axon, are most common in the peripheral nervous system, and the resulting sensory and motor dysfunction is often referred to as a neuropathy. Axonopathies are generally categorized as either proximal or distal. The axon requires a high synthetic capacity of molecules to function, which are then transported down the axon, often traveling several feet for some motor neurons of the spinal cord. This process is known as anterograde transport, originating from the cell body and moving down the axon, and retrograde transport, which returns materials to the cell body.

17. Types of Axonal Transport: • Fast axonal transport: Moves substances at a rapid rate of about 400 mm/day. • Slow transport: Moves most axonal proteins, including enzymes and structural proteins. • Intermediate transport process: Transports organelles like mitochondria. Impact of Disease States and Toxant -Induced Injuries on Axon Transport Systems • Mutations in genes for proteins involved in transport systems can lead to conditions like Charcot–Marie–Tooth disease and hereditary spastic paraplegia. • Recent studies show that proteins involved in Alzheimer’s disease interact with transport system proteins, leading to swelling and abnormal accumulation effecting the axonal transport

18. Proximal Axonopathies Proximal axonopathies involve swelling of the proximal axon, a phenomenon known to be caused by the synthetic aminonitrile compound, IDPN.(beta- iminodiproprionitrile ) Exposure to IDPN leads to the accumulation of neurofilaments , causing giant axonal swelling.The swelling results in the distal portions of the axon atrophy, possibly due to a blockade of slow transport. Distal Axonopathies Distal axonopathies , also known as dying-back neuropathies, involve pathological changes in the distal portions of axons, including swelling, damage to mitochondria, and accumulation of neurofilaments . Distal axonopathies may occur following a single exposure to some toxicants or may be a result of chronic exposure. Organophosphates , a group of compounds that produce distal axonopathies.Symptoms of distal axonopathy typically begin 1–2 weeks after acute exposure and include weakness and possibly paralysis of the lower limbs .

19. Acrylamide , a monomer that can be polymerized to form polyacrylamide gels, inhibits fast axonal transport and produces distal axonopathy . Chronic exposure to solvents used in glues and cleaning fluids leads to accumulation of neurofilaments in the distal portions of the axon, followed by disruption of myelin. Carbon disulfide produces a similar neuropathy, likely through cross-linking of neurofilaments and various neurobehavioral effects.

20. MYELINOPATHIES The axons of many neurons in both the central and peripheral nervous systems are covered by an insulating substance called myelin . Myelin contains proteins such as proteolipid protein in the CNS and P1 protein in the PNS, but consists mostly of lipids, including cholesterol, phospholipids e.t.c Damage to myelin can disrupt normal nervous system function, causing numbness, weakness, and paralysis . Damage to myelin can also lead to spontaneous action potentials in demyelinated neurons.

21. Saltatory conduction, a faster and more efficient process, jumps impulses from one node to another in myelinated axons, unlike continuous conduction in unmyelinated neurons . Triethyltin (TET) and hexachlorophene (HCP) can cause damage to myelin, leading to remyelination . Lead can cause demyelination, but its effects are limited to the peripheral nervous system. Multiple Sclerosis (MS) is an autoimmune disease that affects myelin, causing sensory disturbances and motor weakness in young adults. MS is cyclic, with relapses and improvements likely coinciding with periods of demyelination and remyelination .

22. EFFECTS OF TOXICANTS DIRECTLY ON NEURONS AND GLIAL CELLS Neurotoxicants damage neurons and glial cells, causing structural changes like swelling, organelle breakdown, and synaptic membrane damage. Chronic exposure leads to neurofibrillary tangles, accumulations in diseases like Alzheimer's, and functional changes like decreased protein synthesis and oxidative metabolism, potentially causing cell death . Excitotoxicity : Glutamate , an excitatory neurotransmitter, is a cytotoxic neurotoxicant.Overstimulation of the glutamate system can lead to toxic and disease states. Low levels of monosodium glutamate (MSG), a food additive, can cause symptoms like Chinese restaurant syndrome. High levels of endogenously produced glutamate can cause severe central nervous system effects, known as excitotoxicity .

23. The NMDA receptor, which responds to N-methyl-d-aspartate, is the main receptor involved in excitotoxicity . They act as an ion channel for Na+, K+, and Ca2+ ions, requiring simultaneous binding of glutamate and glycine. • Calcium enters the cell following activation and binds to the regulatory protein calmodulin , leading to the production of nitric oxide. • Nitric oxide synthase inhibitors offer partial protection against excitotoxicity . • The time course of excitotoxicity can determine whether a cell undergoes apoptosis or necrosis. • Other compounds like Kainic acid and AMPA receptor also produce excitotoxicity . • Exposure to cycasin and BMAA, an excitatory amino acid found in cycad seed, may be associated with the development of the neurodegenerative disease amyotrophic lateral sclerosis–Parkinsonism dementia ( ALS/PD)

24. Other cytotoxic compounds Organometal trimethyltin (TMT) damages neurons in the hippocampus and surrounding areas . MPTP   (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a contaminant of MPPP, produces symptoms similar to Parkinson’s disease and kills cells in the substantia nigra Carbon disulfide also directly destroys CNS neurons . Glial Cells and Toxicants • Toxicants' effects on glial cells are increasingly studied due to their crucial role in neurological functioning. • Ammonia accumulation affects neurons and astrocytes, affecting glutamate levels. • Dinitrobenzene targets astrocytes through mitochondrial effects . OTHER NEUROTOXICANTS Organic mercury compounds like methylmercury produce tremors, motor dysfunction, and sensory disturbances. Halogenated hydrocarbon solvents enter the central nervous system easily, causing disorientation, euphoria, and confusion . Ethanol, a central nervous system depressant, produces depression of inhibitions and mild euphoria at low levels but leads to impairment of reflexes, decreased sensory function, loss of consciousness, coma, and even death at high levels.

25. Effects on Special Sensory Organs • Toxicants indirectly affect peripheral neurons, but some directly affect specialized sensory organs like the eye or ear. • Methanol, an excitatory neurotransmitter, causes edema in the optic nerve, leading to blindness. • Certain compounds like 2,4-DNP, corticosteroids, and naphthalene can cause cataracts by reducing lens transparency. • High doses of streptomycin can cause dizziness and hearing loss due to damage to the vestibular apparatus and cochlea. • Excessive noise exposure can also damage the cochlea, leading to significant hearing loss. • Aspirin may cause temporary hearing impairment by tinnitus.