Central Nervous System (CNS) & Drug Discovery

Central nervous system • Brain • Spinal cord • Relay neurones what is the CNS? • 86 billion neurons in the human brain • 1000s of connections per neuron How many neurons in the human brain? • Trillions of synapses = +++ combinations of signals What is the PNS? peripheral nervous system: nerves spread all over the body What is the spinal chord? A long and thin tubular bundle of nerves enclosed in the vertebral column that connects nearly all parts of the body to the brain. - Reactions to pain What reflexes does the spinal chord con- Control of local blood flow or gastrointrol? testinal movements What is the lower brain? It is located deep inside the skull and regulates basic functions such as breathing and blood pressure. - Anger, excitement, sexual response, reaction to pain, reaction to pleasure Medulla, pons, mesencephalon, hypothalamus, thalamus, cerebellum, and basal ganglia Cortical Level What is the higher brain? The higher cortical functions include language, vision, recognizing objects in space (visuospatial recognition), and awareness. The three characteristics of all higher-order functions are as follows: The cerebral cortex must be involved—complex interactions occur within the cortex and between it and other brain areas. 1 / 16 CNS structure: Brain structure: What comes under the PNS? somatic and autonomic What comes under autonomic system? sympathetic and parasympathetic What is the somatic nervous system? the division of the peripheral nervous system that controls the body's skeletal muscles. concious. the part of the nervous system responsible for control of the bodily functions not What is the autonomic nervous system? consciously directed, such as breathing, the heartbeat, and digestive processes. What is the sympathetic nervous system? "Fight or flight" Blood pressure/heart rate increase, digestive slowing. What is the parasympathetic nervous system? "Rest and digest" Blood pressure/heart rate decrease, digestive increases. large network of neurons surrounding the digestive organs. What is the enteric nervous system? How does the PNS work? The enteric nervous system comprises the intrinsic nerve plexuses of the gastrointestinal tract, which are closely interconnected with the sympathetic and parasympathetic systems. The peripheral (sensory) nervous system receives stimuli, the central nervous system interprets them, and then the peripheral (motor) nervous system initiates responses What is a neurotransmitter? 2 / 16 a chemical that travels from one neuron to another What are Ach and NA nerves? Nerves that release Ach are called cholinergic nerves Nerves that release NA are called adrenergic nerves > Ach - memory & learning; stimulation of parasympathetic system What are some known neurotransmit- > NA/NE - mania-depression & emotions ters? stimulation of sympathetic system > Serotonin - biological rhythms, sleep, emotion, and pain What is a synapse? Gap between neurons What are the main neurones? Sensory neurons. ... Motor neurons. ... Interneurons. ... Neurons in the brain. Structure of a neuron: What are the stages of a synapse? Synthesis: Neurotransmitters are synthesized within the presynaptic neuron. Storage: Neurotransmitters are stored in synaptic vesicles within the presynaptic terminal. Release: Action potentials trigger the release of neurotransmitters from the presynaptic terminal into the synaptic cleft. Diffusion: Neurotransmitters diffuse across the synaptic cleft. Binding: Neurotransmitters bind to receptor sites on the postsynaptic membrane. Response: Receptor activation triggers changes in the postsynaptic neuron, ei3 / 16 ther excitatory or inhibitory. Reuptake: Neurotransmitters not bound to receptors are reabsorbed by the presynaptic neuron through reuptake channels. Degradation: Some neurotransmitters are broken down by enzymes in the synaptic cleft. Termination: Neurotransmitter action ends, and the synapse returns to its resting state. What is an inhibitory receptor? An inhibitory receptor - reduces activity or transmitter release in the neuron. However, if that neuron is a GABAergic interneuron then the functional consequence will be reduced inhibition or disinhibition and an increase in activity from that region. What is an exhibitory receptor? An excitatory receptor - increases activity or transmitter release in the neuron. However, if that neuron is a GABAergic interneuron then the consequence will be increased inhibition and a decrease in activity from that region. Within the brain, neuropeptides can modulate the activity of co-released neurotransmitters to either increase or decrease the strength of synaptic signaling. Within the periphery, neuropeptides can What are neuropeptide neurotransmitfunction similar to peptide hormones and ters? modulate nearly all bodily functions. Hypothalamic releasing hormones e.g. thyrotropin-releasing hormone Pituitary peptides e.g. vasopressin Fast acting, acute effect Individual amino acids, such as gluta4 / 16 mate and GABA, as well as the transmitters acetylcholine, serotonin, and histaWhat are small molecule neurotransmitmine, are much smaller than neuropepters? tides and have therefore come to be called small-molecule neurotransmitters. What is acetylcholine? This is a primary neurotransmitter that transmits impulses across the synaptic cleft. What are ion channels? channel proteins that transport ions Cation channels Na+ channels opened by excitatory transmitters Na+ influx leads to excitation What are cation and anion channels? Anion channels Cl- channels opened by inhibitory transmitters Cl- influx leads to inhibition the primary messenger activates a second messengre inside the cell to make changes. Prolonged changes in neuron Example: G-protein, the release of the What is the second messenger system? portion results in different specific effects: opening of ion channels activation of cyclic GMP, AMP activation of intracellular enzymes activation of gene transcription cyclic AMP What is cAMP? can result in structural and functional changes. Example: Activation of intracellular enzymes. 5 / 16 Synthesis: Acetylcholine (ACh) is synthesized in the cytoplasm of the presynaptic neuron's terminal through the combination of choline and acetyl coenzyme A (acetyl-CoA). Storage: ACh molecules are stored in synaptic vesicles located in the presynaptic terminal. Release: Upon arrival of an action potential at the presynaptic terminal, voltage-gated calcium channels open, allowing calcium ions to enter the terminal. This influx of calcium triggers the fusion of the synaptic vesicles with the presynaptic membrane, leading to the release of ACh into the synaptic cleft. Diffusion: ACh diffuses across the synaptic cleft, which is a narrow extracellular space between the presynaptic and poststages of a synapse using acetylcholine synaptic neurons. as an example: Binding: ACh binds to nicotinic or muscarinic receptors on the postsynaptic membrane. Nicotinic receptors are ligand-gated ion channels, while muscarinic receptors are G-protein coupled receptors (GPCRs). Response: Binding of ACh to nicotinic receptors causes them to open, allowing the influx of cations such as sodium and potassium, leading to depolarization of the postsynaptic membrane. Binding of ACh to muscarinic receptors activates intracellular signaling pathways, which can lead to various cellular responses depending on the receptor subtype and cell type. Reuptake: Any remaining ACh in the synaptic cleft is rapidly hydrolyzed by the enzyme acetylcholinesterase (AChE) 6 / 16 into choline and acetate. Choline is then taken back up into the presynaptic neuron via a specific transporter to be used for the synthesis of new ACh. Degradation: Acetylcholinesterase breaks down acetylcholine into choline and acetate within the synaptic cleft. Termination: ACh action ceases, and the synaptic transmission returns to baseline levels. any voltage change in the direction of What is excitatory postsynaptic potential threshold that makes a neuron more like(EPSP)? ly to fire Hyperpolarization refers to a state where the potential across the membrane is more negative than the resting potential. What is hyperpolarization? An inhibitory synapse opens Cl- channels allowing Cl- to enter the postsynaptic neuron drugs that increase the action of a neurotransmitter. What are agonists? A drug mimics the neurotransmitter and stimulates the receptor on its own There is a decrease in the rate of degradation or diffusion from the receptor site. More impulses are sent by the transmitter if it remains on the receptor site too long drugs that block the function of a neurotransmitter. What are antagonists? The receptor site is blocked by an inhibitor or antagonist so that the normal neurotransmitter cannot interact to send an impulse. 7 / 16 The rate of synthesis and storage of transmitter is decreased. What are CNS drugs? drugs that act on the brain and spinal cord What are examples of CNS drugs? Selective Serotonin Reuptake Inhibitors (SSRIs): SSRIs are a class of antidepressant drugs commonly used to treat various mood disorders such as depression, anxiety disorders, obsessive-compulsive disorder (OCD), and certain eating disorders. Examples of SSRIs include fluoxetine (Prozac), sertraline (Zoloft), and escitalopram (Lexapro). SSRIs work by increasing the levels of serotonin, a neurotransmitter involved in regulating mood, by blocking its reuptake in the brain. Benzodiazepines: Benzodiazepines are a class of psychoactive drugs that exert sedative, hypnotic, anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties. They are commonly prescribed to treat anxiety disorders, panic disorders, insomnia, and certain seizure disorders. Examples of benzodiazepines include diazepam (Valium), alprazolam (Xanax), and lorazepam (Ativan). Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) by binding to specific receptor sites in the brain, which leads to a calming and sedative effect. 8 / 16 Anxiolytics are a class of medications aimed at treating patients with panic disorders, generalized anxiety, and various other uses. Sedatives(hypnotics) are a class of drugs used in different situations ranging from treating insomnia to treating someone connected to a mechanical ventilator. What are Selective Anxiolytic & Hypnotic Sedatives (anxiolytic drugs) reduce anxdrugs? iety Hypnotics produce drowsiness and encourage onset of sleep The benzodiazepines are the most important drug in this group They all have a seven membered heterocyclic ring structure Halogen or nitrogen group required for sedative hypnotic activity What are some anxiety disorders? Generalised anxiety disorder - an ongoing state of excessive anxiety lacking any clear reason or focus. Social anxiety disorder or social phobia - fear of being with and interacting with other people. Phobias - strong fears of specific objects or situations, e.g. snakes, open spaces, flying. Panic disorder - sudden attacks of overwhelming fear that occur in association with marked somatic symptoms, such as sweating, tachycardia, chest pains, trembling and choking). Post-traumatic stress disorder (PTSD) distress triggered by recall of past stressful experiences). Obsessive-compulsive disorder (OCD) recurrent obsessive ruminations, images or impulses, and/or recurrent physical or 9 / 16 mental rituals driven by unfounded and specific anxieties, e.g. fear of contamination. Illness anxiety disorder - a somatic symptom related disorder characterised by excessive or disproportionate preoccupations with having or acquiring a serious illness. What drugs are used to treat anxiety? Selective serotonin reuptake inhibitors (SSRIs) - SSRIs tend to be prescribed as a first-line treatment for anxiety disorders. Medications such as sertraline, fluoxetine and citalopram fall under this category. SSRIs work by increasing the levels of serotonin in the brain. Antianxiety medications, minor tranquilizers. What are Benzodiazipines? Therapeutically, Benzodiazepines are GABAA receptor agonists. At least 2 Benzodiazepine receptors exist in the brain with different substrate affinities. GABA is the major inhibitory transmitter in the brain. Absorption: Varies and depends on lipophilicity Distribution: The more lipid-soluble drugs (diazepam, How are benzodiazipines absorbed and triazolam) enter the CNS more quickdistributed? ly than less lipid-soluble molecules (lorazepam) As lipid-soluble drugs they bind plasma proteins Drugs are re-distributed easily Crosses the placental barrier 10 / 16 Metabolism: Required for elimination Transformation to more water soluble form Determines half-life of elimination How are benzodiazepines metabolized? Most by microsomal oxidation and excreted? N-dealkylation or hydroxylation catalysed by CYP3A4 Conjugated to form glucuronides Excretion: Via kidney in urine What are the effects of benzodiazepines? 1. Induces sleep 2. Anti-anxiety 3. Anti-xconvulsant 4. Enhances response to GABA by opening up GABA-activated chloride channels. What are Anaesthetics? drugs which are used to prevent pain for a limited period of time for surgical or other procedures A state of unconsciousness produced by anaesthetic agents with absence of pain sensation over the entire body. What is general anaesthesia? inhalation anaesthetics take a few minutes to act. I.v. anaesthetics act more rapidly, producing unconsciousness in ~20s Drugs typically used: propofol, thiopental and etomidate 11 / 16 Nephrotoxicity > Fluoride ion can be toxic with prolonged exposure Haematotoxicity > Prolonged exposure to NO inhibits methionine synthase - results in megaloblastic anaemia How is anaesthesia toxic? Hepatotoxicity > Only in a very small number of patients (roughly 1:30,000) and usually after previous exposure Chronic Toxicity > Very very rarely do inhaled anaesthetics act as mutagens or carcinogens > NO (at high levels) is teratogenic in animals Medication that is used to help people that are depressed. What are anti depressants? low mood, excessive rumination of negative thought, misery, apathy and pessimism low self-esteem: feelings of guilt, inadequacy and ugliness indecisiveness, loss of motivation anhedonia, loss of interest in previously rewarding activities. retardation of thought and action loss of libido sleep disturbance and loss of appetite What are NA receptors? Noradrenaline How do anti-depressants work? >Increase release of NA >Prevent inactivation of NA >Prevent the re-uptake of NA 12 / 16 1. Selective Serotonin Reuptake Inhibitors (SSRIs) Examples: Fluoxetine (Prozac), Sertraline (Zoloft), Escitalopram (Lexapro). What are SSRIs for depression? MoA: SSRIs inhibit the reuptake of serotonin (a neurotransmitter) in the brain, leading to increased serotonin levels in the synaptic cleft. This enhances serotonin neurotransmission, which is thought to alleviate symptoms of depression. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) Examples: Venlafaxine (Effexor), Duloxetine (Cymbalta), Desvenlafaxine (Pristiq). What are SNRIs for depression? MoA: SNRIs inhibit the reuptake of both serotonin and norepinephrine, thereby increasing the levels of both neurotransmitters in the brain. This dual action is believed to contribute to their antidepressant effects. Tricyclic Antidepressants (TCAs) Examples: Amitriptyline, Imipramine, Nortriptyline. What are TCAs in anti depressants? What are recreational drugs? MoA: TCAs block the reuptake of serotonin and norepinephrine, similar to SSRIs and SNRIs. Additionally, TCAs block certain receptors for histamine, acetylcholine, and alphaadrenergic receptors, which may contribute to their side effects. They are used for pleasure and affect the brain and nevous system. They can be legal or illegal. 13 / 16 What is the cycle of addiction? Use -> abuse -> dependency -> increased dose/tolerance = continued use and abuse Depressant What is alcohol? > CNS affected by acute alcohol intake > Alcohol is a CNS depressant inducing coma, respiratory depression and even death > It affects neurotransmitter receptors for amines, amino acids and opioids, enzymes such as NA+/K+ ATPase and acetylcholinesterase, and calcium ion channels The addictive drug found in tobacco leaves. Nicotine alters action potential firing characteristics of ventral tegmental area (VTA) dopaminergic neurons in freely moving rats. What is nicotine? The main health risks: •Cancer - particularly of the lung and upper respiratory tract but also of the oesophagus, pancreas and bladder. Smoking 20 cigarettes per day is estimated to increase the risk of lung cancer about 10-fold. •Coronary heart disease and other forms of peripheral vascular disease. The mortality among men aged 55-64 from coronary thrombosis is about 60% greater in men who smoke 20 cigarettes per day than in non-smokers. 14 / 16 • Tar & irritants e.g. nitrogen dioxide and formaldehyde. • Nicotine probably accounts for retarded fetal development because of its vasoconstrictor properties. What are the main causes of harm for nictotine? • Carbon monoxide. Cigarette smoke contains about 3% carbon monoxide. Carbon monoxide has a high affinity for haemoglobin, and the average carboxyhaemoglobin content in the blood of cigarette smokers is about 2.5% (compared with 0.4% for non-smoking urban dwellers). In very heavy smokers, up to 15% of haemoglobin may be carboxylated, a level that affects fetal development in rats. Fetal haemoglobin has a higher affinity for carbon monoxide than adult haemoglobin, and the proportion of carboxyhaemoglobin is higher in fetal than in maternal blood. • Increased oxidative stress may contribute to atherogenesis and COPD What are psychedelic drugs? drugs whose primary action is to alter perception, emotion, and cognition like LSD a powerful hallucinogenic drug; also known as acid. What is LSD? • Mimics serotonin • has a higher affinity for serotonin receptors • Prevents serotonin from sending neural messages in the brain • Psychedelic hallucinations and visions 15 / 16 result once the sense interpretive centres are stimulated What is the glymphatic system.? a lymphatic system in the brain that participates in removal of wastes and the movement of nutrients and signaling compounds What is Cerebral Oedema? swelling of the brain 16 / 16