A NEUROPEPTIDE THAT DRAMATICALLY ENHANCES

LEARNING AND MEMORY 

POTENTIAL FOR COGNITIVE DRUG DEVELOPMENT

  

John M. Stewart 

Department of BiochemistryUniversity of Colorado Medical School

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 behaviorCentral regulation of blood pressureStimulation of amine neurotransmitter release (Dopamine)

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 fragmentsSP-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).

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.

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)

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

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

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 symptomsNeuroleptics for schizophrenia cause Parkinson-like symptoms

(tardive dyskinesia)

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

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

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.

SUMMARY 1.      SP-N offers great hope for development of new drugs:

For Cognitive EnhancementFor Parkinson’s diseaseFor Alzheimer’s disease

 2.      Much research is needed to develop these drugs 3.      Financial support is required for progress in this field.