Med Phys Pharm 551 L21 Neuropharm Glutamate PDF

Lecture #21: Neuropharmacology – Glutamate Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx) ...

Lecture #21: Neuropharmacology – Glutamate Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L21: Learning Objectives 1. Compare and contrast glutamate and GABA neurotransmission 2. How is glutamate ”recycled” and how do glutamate receptors signal? 3. Relate the pathological process of excitotoxicity and how it connects to the to symptoms of neurodegenerative diseases 4. Connect the mechanism of action of pharmacological interventions for neurodegenerative diseases to their underlying pathophysiology 5. Define neuroglia and describe their role in health and disease Unless otherwise noted, figures in today’s lecture are from: Principles of Pharmacology 3e Baca, Golan (Ch. 12,14), Lippincott Illustrated Reviews: Pharmacology 6e Yellepeddi (Ch. 8,10,12)  Glutamatergic Neurotransmission Glutamatergic synapses exist throughout the CNS Binding of glutamate to its receptors initiates excitatory neuronal responses Clinical applications of glutamate ht tp:/ /clinicalgate.com/wp-conten t/u ploads/ 2015/06/ B9780443103216000072_f007-003-9780443103216.jpg pharmacology are currently limited Becoming an increasingly important area of neuropharmacology LO1  Glutamate Receptors Divided into ionotropic and metabotropic subgroups Ionotropic Glutamate Receptors Mediate fast excitatory synaptic responses Cation-selective channels permit the flow of Na+, K+, Ca2+ ions across plasma membranes Three main subtypes classified by selective agonists: AMPA, kainate, and NMDA (N- LO2 methyl-D-aspartate)  Glutamate Receptors - Ionotropic NMDA receptors Expressed primarily in the hippocampus, cerebral cortex, and spinal cord Activation requires simultaneous binding of glutamate and glycine opens a channel that allows K+ efflux as well as Na+ and Ca2+ influx LO2  Glutamate Receptors - Ionotropic NMDA receptors When receptors occupied by glutamate and glycine, Mg2+ ions blocks the channel pore in the resting membrane Depolarization of the membrane concurrent with agonist binding is required to relieve this voltage-dependent Mg2+ block LO2  Pathophysiology and Pharmacology of Glutamatergic Neurotransmission Increased release or decreased reuptake of glutamate in pathologic states can lead to a positive feedback cycle Increased intracellular Ca2+ levels, cellular damage, and further glutamate release Process can lead to excitotoxicity - neuronal death caused by excessive cellular excitation from glutamate (or other excitatory NTs) Implicated mechanism in many diseases: Rutin im prove s g lutam ate upta ke a nd i nhibits glutam ate e xcitotoxic ity in ra t bra in slic es - S cie nti fic Fi gure on Re se archG ate. Av aila ble from : https://www.res ea rchga te. net/figure/Rutin -protects-the-brain -a ga inst-g luta ma te-exci totoxic ity-by-im provement-in- GL AST _ fig 4_348758309 neurodegenerative syndromes (HD, PD, ALS), stroke, and epilepsy LO3,4  Neuroglia – The Support Staff Two major types of cells that serve as building blocks of the nervous system: 1. Neurons 2. Neuroglia Neuroglia Unexcitable cells that support the neuronal function Form and maintain myelin Control local ion concentrations Junquiera’s Basic Histology, Mescher (2018) Recycle neurotransmitters Provide neurons with nutrients LO5  Neuroglia – The Support Staff LO5 Blau sen.com sta ff. "Blau sen ga llery 20 14". Wikiver sity Journ al o f Medicine. DOI:10.153 47/wjm/2014.010. ISSN 200 18762.  Neuroglia – The Support Staff Spatial Buffering Blau sen.com sta ff. "Blau sen ga llery 20 14". Wikiver sity Journ al o f Medicine. DOI:10.153 47/wjm/2014.010. ISSN 200 18762. LO5  How does neuroglia assist with NT spillover? LO2,5  Pathophysiology and Pharmacology of Glutamatergic Neurotransmission Increased release or decreased reuptake of glutamate in pathologic states can lead to a positive feedback cycle Increased intracellular Ca2+ levels, cellular damage, and further glutamate release Process can lead to excitotoxicity - neuronal death caused by excessive cellular excitation from glutamate (or other excitatory NTs) Implicated mechanism in many diseases: Rutin im prove s g lutam ate upta ke a nd i nhibits glutam ate e xcitotoxic ity in ra t bra in slic es - S cie nti fic Fi gure on Re se archG ate. Av aila ble from : https://www.res ea rchga te. net/figure/Rutin -protects-the-brain -a ga inst-g luta ma te-exci totoxic ity-by-im provement-in- GL AST _ fig 4_348758309 neurodegenerative syndromes (HD, PD, ALS), stroke, and epilepsy LO3,5  Neurodegenerative Diseases: ALS Progressive neurodegenerative disease that afflicts ~16,000 people in the United States Average life expectancy is three to five years after diagnosis Only 10 percent of patients survive for more than 10 years Death is usually due to respiratory failure Few treatment options exist for these patients LO3  Neurodegenerative Diseases: ALS Motor neurons degenerate in the ventral horn of the spinal cord, brainstem, and motor cortex, resulting in weakness and atrophy of skeletal muscles The CNS areas affected in ALS express diverse populations of AMPA and NMDA receptors https://amyotrophiclateralsclerosis.files.wordpress.com/2012/11/url3.gif?w=930 Patients with ALS have impaired glutamate transporters in the spinal cord LO3,5 and motor cortex  Neurodegenerative Diseases: ALS Ri∙lu∙zole is a voltage-gated sodium channel blocker Appears that riluzole acts in part by reducing Na+ conductance and thereby decreasing glutamate release May also directly antagonize NMDA receptors http: //www.mdpi.c om/mole cule s/m ol ec ul es-20-07775/a rtic le _de ploy/html/im ag es /mole cule s-20-07775-g 002-1024.png Delays the onset of ventilator-dependence or tracheostomy in some people May increase survival by two to three months LO3,4  Neurodegenerative Diseases: Alzheimer’s Disease Three distinguishing features: 1) accumulation of β-amyloid plaques 2) formation of numerous Tau neurofibrillary tangles 3) loss of cortical neurons - particularly cholinergic Pharmacologic intervention is only palliative and provides modest short- term benefit None of the available therapeutic agents B rei jyeh Z, K aram an R. Comprehensive Review on Alzheim er’ s Disease: Causes and T reat ment. M olecul es. 2020; 25(24):5789. ht tps:/ /doi. org/ 10.3390/ molecules25245789 alter the underlying neurodegenerative LO3,4 process – UNTIL 2021!  Neurodegenerative Diseases: Alzheimer’s Disease Mem∙an∙tine NMDA receptor antagonist Indicated for moderate to severe Alzheimer's disease Clinical studies - slows the rate of clinical deterioration in patients Can be given in combination with an AChE inhibitor LO3,4 http://slideplayer.com/slide/8015356/25/images/11/Memantine:+Mechanism+of+Action.jpg  Neurodegenerative Diseases: Alzheimer’s Disease Sevigny, J., Chiao, P., Bussière, T. et a l. The antibody aducanumab reduces Aβ plaques in Alzheimer’s Aducanumab (Aduhelm) disease. Nature 537, 50–56 (2016). https ://doi.org/10.1038/nature19323 Antibody directed against aggregated soluble and insoluble forms of LO3,4 amyloid beta – approved Summer 2021 via FDA accelerated approval