Transcript Stewart - University of Colorado

A NEUROPEPTIDE THAT
DRAMATICALLY ENHANCES
LEARNING AND MEMORY
POTENTIAL FOR COGNITIVE DRUG
DEVELOPMENT
John M. Stewart
Department of Biochemistry
University 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
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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)
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).
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 symptoms
Neuroleptics 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
Functions
Mixed
Increases
Reduces
Stress-Motivated
Behaviors
Mixed
Reduces
Increases
Aggression
Inhibits
Inhibits
Increases
Pain Responses
Inhibits
Inhibits
Increases
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
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 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.