Neuropeptides are small protein-like molecules that neurons use to communicate with each other. They influence various brain and bodily functions. Some peptides act as both hormones and neuropeptides. Neuropeptide Y (NPY) is involved in processes like feeding, learning, and social behavior. It has therapeutic potential for treating obesity and anxiety/depression. Calcitonin gene-related peptide (CGRP) is a vasodilator that may be linked to migraines. Substance P is associated with pain and inflammation. Cholecystokinin is a gut-brain hormone involved in processes like feeding and anxiety. Many neuropeptides act through G-protein coupled receptors and have potential pharmacological applications.

1. NEUROPEPTIDES
Prepared by: Krishna Champaneria
Reasearch & Development Department
Gujarat Forensic Sciences University

2. Introduction
 Neuropeptides are small protein like molecules
(peptides) used by neurons to communicate
with each other.
 They are neuronal signalling molecules that
influence the activity of the brain and the body
in specific ways.
 Neuropeptides are related to peptide
hormones, and in some cases peptides that
function in the periphery as hormones also
have neuronal functions as neuropeptides.

3. Biological functions
 Generally, peptides act at metabotropic or G-
protein-coupled receptors expressed by
selective populations of neurons.
 In essence they act as specific signals
between one population of neurons and
another.
 Neuropeptide-containing nerves show striking
plasticity during physiological and
pathophysiological tissue remodelling
processes.

4. Pharmacological Application
 Responsible for brain function:
 Analgesia
 Food intake
 Learning and memory
 Metabolism and reproduction
 Social behaviour
 Eg: Neuropeptide Y(NPY),
Cholecystokinin(CCK), Tachykinins(substance
P, Neurokinin), Arginine Vasopressin(AVP),
Corticotropin releasing factor(CRF)

5. Neuropeptide Y ( NPY )
 NPY is a 36-amino acid peptide that acts as
neurotransmitter or neuromodulator
depending upon the context.
 Neuropeptide Y (NPY) is widely distributed in
the human body and contributes to a vast
number of physiological processes.

6. NPY Receptors
 G-protein coupled Receptors (GPCR)
 5 types:
 Y1-Y5in mammals - 4 in humans.
 Y1-NPY1R & Y5-NPY5R : feeding stimulator
(appetizer).
 Y2-NPY2R & Y4-NPY4R : appetite inhibition
(anorectic).
 Activated neuropeptide receptors release the Gᵢ
subunit from the heterotrimeric G protein
complex.
 This Gᵢ subunit in turn inhibits the production of
the second messenger cAMP from ATP.

7. Location and Types

8. Therapeutic potentials
 NPY in Obesity
 A large number of studies on NPY have investigated
its metabolic actions, especially related to food intake
and obesity.
 A prevalent model for the study of obesity is the ob/ob
mouse (Ingalls et al, 1950), which has been
characterized as leptin deficient.
 Leptin is a regulator of NPY pathways and ob/ob mice
have higher levels of NPY expression in the
hypothalamus.
 NPY knockout mice are largely normal without any
change in food intake or obesity.

9.  On the other hand, Y1R knockout mice having
higher body weights and more white adipose
tissue, while both Y2R and Y5R knockout mice
also have higher body weights, increased food
intake and greater adipose deposition.
 In contrast, Y4R knockout mice show reduced
body weight and adipose tissue, which suggests
an opposing action of Y4R in metabolism.

10. Agonist and antagonist
 Obinepitide (TM30338; 7TM Pharma), which is
a peptide agonist at both the Y2R and Y4R, is
currently in phase I/II trials for the treatment of
obesity.
 However, the other two, MK-0557 and
velneperit, both Y5R antagonists, have failed
to achieve clinically meaningful reductions in
obesity .

11. NPY in Anxiety, Depression and
Epilepsy
 In patients with major depression, for
example, several studies have found that
central NPY levels, primarily measured in the
cerebrospinal fluid, are markedly low and
correlate inversely to anxiety.
 NPY is an anxiolytic-like substance, which has
led us to speculate that a synthetic compound
that blocks the Y2 receptor mediated negative-
feedback pathway will likely also be anxiolytic.

12.  The Y1R has also been implicated in antianxiety
behaviour in rats, as well as in the mediation of
adult neuronal proliferation and hippocampal
neurogenesis .
 NPY (or a Y1R agonist) could serve as an
antidepressant (or cognitive enhancer) by
induction of neurogenesis from neural stem
cells.

13. Agonist and Antagonist
 Y2R antagonist N-[(1S)-4-
[(Aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-
1,2-diphenyl-1,2,4-triazolidin-4-
yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-
dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-
piperazinyl]-2-oxoethyl]-
cyclopentaneacetamide (BIIE0246).

14.  Also used in:
 in Alcoholism
 in Bone Physiology
 in Pain
 in Cancer
 in Cardiovascular Regulation
 in the Gastrointestinal Tract.

15. Calcitonin gene-related
peptide(CGRP)
 Calcitonin gene-related peptide is 37-amino
acid peptide and is formed from
the alternative splicing of the calcitonin/CGRP
gene located on chromosomes.
 Widely distributed in CNS, PNS, CVS .
 Two forms:
 α and β CGRP
 α- CGRP found in neuronal tissues and a potent
vasodilator.

16. Functions
 CGRP is produced in both peripheral and
central neurons.
 It is a potent peptide vasodilator and can function
in the transmission of pain.
 In the spinal cord, the function and expression of
CGRP may differ depending on the location of
synthesis.
 CGRP is derived mainly from the cell bodies of
motor neurons when synthesized in the ventral
horn of the spinal cord and may contribute to the
regeneration of nervous tissue after injury.

17.  CGRP is derived from dorsal root ganglion
when synthesized in the dorsal horn of the
spinal cord and may be linked to the
transmission of pain.
 In the trigeminal vascular system, the cell
bodies on the trigeminal ganglion are the main
source of CGRP. CGRP is thought to play a role
in cardiovascular homeostasis and nociception.

20. Receptors
 Heteromeric receptor composed of a G protein-
coupled receptor called calcitonin receptor-like
receptor (CALCRL) and a receptor activity-
modifying protein (RAMP1).
 CGRP receptors are found throughout the body
may modulate a variety of physiological functions
in all major systems.
 respiratory
 endocrine
 Gastrointestinal
 Immune
 cardiovascular.

21. Therapeutic potentials
 Role in CNS:
- modulate acetylcholine receptor function.
 Role in PNS :
- modulate antigen presentation in Langerhans cells
.
- block tolerance to morphine - potent inhibitor
of gastric acid secretion.
 Role in CVS :
- potent vasodilator, positive ionotropic and
chronotropic effect.
 CGRP is known to be closely involved in the
cascade of events that lead to a migraine attack.

22. Substance-P
 A peptide composed of a chain of 11 amino
acid residues.
 Substance P and its closely related neurokinin
A (NKA) are produced from
a polyprotein precursor after differential
splicing of the preprotachykinin A gene.

23.  Substance P is released from the terminals of
specific sensory nerves.
 It is found in the brain and spinal cord and is
associated with inflammatory processes
and pain.
 The "P" in substance "P" [SP] is mistakenly
thought to signify Pain or Psychiatric
substance. Substance P ("P" standing for
"Preparation" or "Powder") is a neuropeptide.

24. Receptor
 Neurokinin type 1 – is distributed over
cytoplasmic and nuclear membranes of many
cell types (neurons, glia, endothelia of
capillaries and lymphatics, fibroblasts, stem
cells, white blood cells) in many tissues and
organs.
 SP amplifies or excites most cellular
processes.

25. Therapeutic Potentials
 Vasodilation
 Substance P is a potent vasodilator. Substance
P-induced vasodilatation is dependent on nitric
oxide release.
 involved in the axon reflex-mediated
vasodilatation to local heating and wheal and flare
reaction. It has been shown that vasodilatation to
substance P is dependent on the NK1 receptor
located on the endothelium.

26.  Inflammation
 SP initiates expression of almost all known
immunological chemical messengers (cytokines). Also,
most of the cytokines, in turn, induce SP and the NK1
receptor.
 SP is particularly excitatory to cell growth and
multiplication.via usual,as well as oncogenic driver.
 SP is a trigger for nausea and emesis
 Substance P and other sensory neuropeptides can be
released from the peripheral terminals of sensory
nerve fibers in the skin, muscle, and joints.
 It is proposed that this release is involved
in neurogenic inflammation, which is a local
inflammatory response to certain types of infection or
injury.

27.  Pain
 Substance P coexists with the excitatory
neurotransmitter glutamate in primary afferents
that respond to painful stimulation.
 Mood, anxiety, learning
 Vomiting

28. Cholecystokinin
 Gut-brain hormone.
 CCK is secreted in the periphery as local
hormone in the gut in response to food intake.
 In CNS CCK coexists with dopamine and
neurotensin in the substantia nigra and
ventrotegmental area ;with VIP , NPY,and
GABA and with substance p and 5-HT in
medullary neurons.
 CCK neurons in spinal cord and brain stem act
as an anti-Opioid system.

29. Receptors
 Two types of CCK receptors :
 CCK- 1
 CCK-2
 CCK2 predominates in the CNS of most
mammalian species ,although this is not true
in human spinal cord and brain stem, where
CCK-1 is the most common form .
 CCK-1 antagonist (devazepide) made
morphine more effective in treating pain of
neuropathic origin.

30.  Intravenous administration of small doses of
C-terminal fragments of CCK or the gastrin
fragment pentagastrin reliably induce a
psychological panic in human subjects .
 The panic is dose related and short – lived.
 Adminstration of CCK2 antagonist L-365,260
completely blocked this chemically induced
panic in volunteers, however clinical trial of
this drug in patients who suffered spontaneous
panic attacks were negative.

31. References
 Therapeutic potential of neuropeptide Y
(NPY) receptor ligands. Shaun P
Brothers1 and Claes Wahlestedt1,*
 Calcitonin Gene-Related Peptide (CGRP)
and Migraine.Paul L. Durham, PhD
 https://en.wikipedia.org/wiki/Calcitonin_gen
e-related_peptide
 https://en.wikipedia.org/wiki/Substance_P
 http://what-when-how.com/molecular-
biology/neuropeptides-molecular-biology/