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neurohumoral transmission in cns

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neurohumoral transmission in cns

  1. 1. Neurohumoral Transmission in CNS K Ravi kumar M.Pharm 1st semester Reg no: 170604017 Department of pharmacology Manipal university
  2. 2. CONTENTS • Introduction • Neurohumoral transmission • Neurotransmitters • Neurodegenerative diseases • Conclusion • References
  4. 4. Anatomic organisation of the cns
  5. 5. Chemical mediators in the CNS • Small molecules • Biogenic amines • Serotonin • Dopamine • Histamine • Epinephrine • Norepinephrine • Amino acids • Glutamate • Aspartate • GABA • Glycine • Others • Acetylcholine • Nitric oxide • Neuromodulators • Neuropeptide-y • Substance-p • Lipid mediators • prostaglandins • Growth factors • Nerve growth factor • Brain derived growth factor
  6. 6. Chemical mediators in the CNS Mediator type Examples Targets Mainfuntional role Small molecule mediators Glutamate ,GABA, Acetylcholine, Dopamine ,5HT Ligangated ion channels G-PCR Fast & slow synaptic neurotransmission Neuromodulation Neuropeptides Substance P, Neuropeptide Y Endorphins G-PCR Neuromodulation Lipid mediators Prostaglandins Endocannabinoids G-PCR Neuromodulation Neutrophins Cytokines Nerve growth factor Kinase-linked receptors Neuronal growth , survival & functional plasticity
  7. 7. Amino acid neurotransmitters
  8. 8. Metabolism and release of aminoacids
  9. 9. Glutamate Synthesis
  10. 10. Glutamate pathway MEMANTINE REMACIDINE PIRACETAM
  11. 11. NMDA receptor
  12. 12. Ionotropic glutamate receptors NMDA AMPA Kainate Agonists Glutamate Aspartate Glycine D-serin Glutamate AMPA Quisqualate Glutamate Antagonists Ap-5,CPP NBQX NBQX ACET Modulators Polyamines Cyclothiazide Piracetam Channel blockers Phencyclidine Ketamine Remacidine Location Postsynaptic Glial cells Post synaptic Glial cells Pre & post synaptic Function Synaptic plasticity Excitotoxicity Fast epsp Fast epsp Presynaptic inhibition
  13. 13. Metabotropic glutamate receptors Group 1 Group 1 Group 1 mGlu1 , mGlu5 mGlu2 , mGlu3 mGlu4 , mGlu6 , mGlu7 mGlu8 G-PCR Gq Gi/Go Gi/Go Agonist DHPG CHPG LY354740 L-AP4 Antagonist LY367385a S-4-CPG LY341495 CPPG Location somatodendritic Somatodendritic & Nerveterminal Nerveterminals
  16. 16. GABA Receptors
  17. 17. Glycine • Glycine particularly present in high concentrations in the grey matter of spinal cord
  18. 18. Properties of Inhibitory amino acid receptors GABAA GABAB Glycine Agonist Muscimol Gaboxadol Baclofen Glycine Taurine Antagonist Bicuculline Gabazine 2-hydroxy- saclofen Channel blocker Picrotoxin Strychnine Effector mechanism Ligandgated chloride channel GPCR Ligandgated chloride channel Location GABAergic neurons Pre & post synaptic Postsynaptic mainly in brain stem &spinal cord
  20. 20. Dopamine pathway
  21. 21. Dopamine pathway in Brain
  22. 22. DOPAMINE Receptors D1 D5 D2 D3 D4 D1 D2 Corpus striatum Hippocampus hypothalamus Substantia nigra Limbic system Midbrain Medulla oblongata Excitatory Inhibitory
  23. 23. 5HT PATHWAY
  24. 24. 28978077 Metoclopramide Ergotamine Methysergide Granisatron Ergotamine
  25. 25. Serotonin pathway in the brain
  26. 26. 5HT receptors 5HT1 5HT2 5HT3 5HT4 GPCR GPCR GPCRIONOTROPIC Inhibitory Excitatory Ligandgated Excitatory cAMP IP3 & DAG NA+, K+ cAMP
  27. 27. Receptors Location Agonists Antagonists 5HT1A 5HT1B 5HT1D 5HT1F CNS Vascular smooth muscles Blood vessels Uterus, heart, GIT Buspirone Ergotamine 5-CT Trip tans Trip tans Ergotamine Methiothepin Ergotamine 5HT2A 5HT2B CNS,PNS Smooth muscles Gastric fundus LSD Methysergide Cyproheptadiene 5HT3 PNS,CNS Chloromethyl biguanide Granisetron Ondansetron 5HT4 GIT Metoclopramide
  28. 28.  Neurodegenerative diseases • Parkinsonism • It is defined as a neurodegenerative disorder of extrapyramidal Nigrostriatal pathway • Therapy : MAO & COMT inhibitors • Alzhiemers • loss of cholinergic neurons results in shrinkage of the brain and other pathological conditions • Therapy : Nootropic agents • Antiamyloid antibodies • NMDA receptor blocker
  29. 29.  Huntington  Depletion of GABA neurons  Therapy : GABA-B Agonist  Ischaemic Brain Damage  Decrease blood supply results in hypoxia  Therapy : NMDA receptor blocker
  30. 30. CONCLUSION • The optimistic view is that a better understanding of the particular functions of the many molecular subtypes of these targets, and the design of more subtype- specific ligands, will lead to future breakthroughs.
  31. 31. References 1. Bleakman, D., Lodge, D., 1998. Neuropharmacology of AMPA and kainate receptors. Neuropharmacology 37, 187–204. (Review giving molecular and functional information on these receptors), 2. Barnard, E.A., 2000. The molecular architecture of GABAA receptors. In: Möhler, H. (Ed.), Pharmacology of GABA and glycine neurotransmission. Handbook of experimental pharmacology 150. Springer-Verlag, Berlin, pp. 79–100. (Authoritative review on the molecular subtypes of GABAA receptors
  32. 32. 3. Bylund, D.B., 2007. Receptors for norepinephrine and signal transduction pathways. In: Ordway, G.A., Schwartz, M.A., Frazer, A. (Eds.), Brain norepinephrine. Cambridge University Press, London. Head, G.A., Mayorov, D.N., 2006. Imidazoline receptors, novel agents and therapeutic potential. Cardiovasc. Hematol. Agents Med. Chem. 4, 17–32. (Provides an update on the elusive imidazoline receptors