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A NEUROPEPTIDE THAT DRAMATICALLY ENHANCES LEARNING AND MEMORY

Explore the potential of Substance P (SP) and its fragments for the development of drugs to enhance learning and memory, treat Alzheimer's and Parkinson's, and provide new analgesics. Learn about the actions of SP and its receptors in the central and peripheral nervous systems. Discover the current progress in SP receptor research and the need for financial support to advance this field.

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A NEUROPEPTIDE THAT DRAMATICALLY ENHANCES LEARNING AND MEMORY

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  1. A NEUROPEPTIDE THAT DRAMATICALLY ENHANCES LEARNING AND MEMORY POTENTIAL FOR COGNITIVE DRUG DEVELOPMENT John M. Stewart Department of Biochemistry University of Colorado Medical School

  2. Substance P (SP) is a neuropeptide. It is synthesized by neurons and used as a neurotransmitter, neuromodulator, and neurohormone. SP has the structure: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-amide 1 2 3 4 5 6 7 8 9 10 11 SP performs many functions in both the central and peripheral nervous systems (CNS and PNS). PNS Functions: Sensory neurotransmitter for pain and other signals Neurohormone for smooth muscle contraction in gut and vasculature CNS Functions: Regulation of learning and memory Regulation of behavior Central regulation of blood pressure Stimulation of amine neurotransmitter release (Dopamine)

  3. SUBSTANCE P RECEPTORS All neurotransmitters act via membrane-imbedded protein receptors. SP receptors are coupled to GTP-binding proteins (G-proteins) for action. There are 2 receptors for SP in the CNS: NK-1 and SP-N receptors. NK-1 receptors bind SP(5-11) (SP-C) and shorter C-terminal fragments SP-N receptors bind SP(1-7) (SP-N) The SP active fragments are produced by specific enzymes that cleave SP. Neprilysin (NEP, 3.4.24.11) yields SP(5-11) (SP-C). Prolyl endopeptidase yields SP-(1-7) (SP-N).

  4. PROGRESS OF SP RECEPTOR RESEARCH NK-1 receptors are well known (cloned, sequenced, expressed in cells) SP-N receptors have not been characterized We are now actively working to clone, sequence and express SP-N receptors Expressed SP-N receptors are the required tool to find new drugs to enhance learning and memory (Cognitive Enhancement). SP-N produces no effects in the periphery.

  5. SP HAS POWERFUL EFFECTS ON LEARNING AND MEMORY SP-C Destroys learning and memory SP-N Strongly enhances learning and memory These effects are mediated by the Nucleus Accumbens (these results are from experiments in rats and mice)

  6. A PROGRAM OF RESEARCH ON SP-N 1.Clone, sequence and express SP-N receptors (work in progress) 2.Locate brain locations and circuitry of SP-N receptors 3.Synthesize SP-N agonists that will enter the brain (cross the BBB) 4.Develop new drugs for Cognitive Enhancement, Alzheimer’s and Parkinson’s

  7. POTENTIAL FOR DRUG DEVELOPMENT SP-N Agonists for Cognitive Enhancement SP-N Agonists for Alzheimer’s and Parkinson’s SP-N Agonists for new analgesics SP-C Antagonists for schizophrenia

  8. SUBSTANCE P REGULATES CNS DOPAMINE RELEASE SP-C stimulates dopamine release in the mesolimbic system This circuit is over-active in schizophrenia SP-N stimulates dopamine release in the nigro-striatal motor system This circuit is failing in Parkinson’s disease Drugs based on SP-C and SP-N offer promise of fully selective drugs for these diseases. Present drugs have bad cross-over side effects: L-DOPA for Parkinson’s causes Schizophrenia-like symptoms Neuroleptics for schizophrenia cause Parkinson-like symptoms (tardive dyskinesia)

  9. ACTIONS OF SUBSTANCE P AND FRAGMENTS ON BEHAVIOR TEST INTACT SP SP-N SP-C Learning/Memory Enhances Enhances Blocks Normal Motor Mixed Increases Reduces Functions Stress-Motivated Mixed Reduces Increases Behaviors Aggression Inhibits Inhibits Increases Pain Responses Inhibits Inhibits Increases

  10. SUBSTANCE P AND ALZHEIMER’S DISEASE Toxic symptoms are caused by the amyloid Ab peptide produced by abnormal processing of precursor protein (APP) SP is deficient in Alzheimer’s brains SP-N prevents toxic symptoms of Ab peptide Drugs based on SP-N may help Alzheimer’s disease

  11. SUBSTANCE P AND PAIN SENSATIONS SP is a neurotransmitter for peripheral pain signals This action is mediated by SP-C SP acting centrally is analgesic This action is mediated by SP-N SP-N research may yield new analgesics.

  12. SUMMARY 1.SP-N offers great hope for development of new drugs: For Cognitive Enhancement For Parkinson’s disease For Alzheimer’s disease 2.Much research is needed to develop these drugs 3.Financial support is required for progress in this field.

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