A NEUROPEPTIDE THAT DRAMATICALLY ENHANCES LEARNING AND MEMORY

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
(No Transcript)
4
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).
5
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.
6
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)
7
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, Alzheimers and Parkinsons
8
POTENTIAL FOR DRUG DEVELOPMENT   SP-N Agonists
for Cognitive Enhancement   SP-N Agonists for
Alzheimers and Parkinsons   SP-N Agonists for
new analgesics   SP-C Antagonists for
schizophrenia
9
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 Parkinsons 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
Parkinsons causes Schizophrenia-like
symptoms Neuroleptics for schizophrenia cause
Parkinson-like symptoms (tardive dyskinesia)
10
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   Aggressi
on Inhibits Inhibits Increases   Pain
Responses Inhibits Inhibits Increases
11
SUBSTANCE P AND ALZHEIMERS DISEASE   Toxic
symptoms are caused by the amyloid Ab
peptide produced by abnormal processing of
precursor protein (APP)   SP is deficient in
Alzheimers brains   SP-N prevents toxic symptoms
of Ab peptide   Drugs based on SP-N may help
Alzheimers disease
12
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.
13
SUMMARY   1.      SP-N offers great hope for
development of new drugs For Cognitive
Enhancement For Parkinsons disease For
Alzheimers disease   2.      Much research is
needed to develop these drugs   3.      Financial
support is required for progress in this field.