3.2 autocoids substance p

3.2 autocoids substance p

1. Autocoids - Substance P

Dr. Muthuraman A. JSS College of Pharmacy, Mysuru

2. Substance P(SP)

" Belongs to the tachykinin(TAC) neuropeptide family.

" Undecapeptide- a peptide composed of a chain of 11 amino acid
residues

"Receptors- NKIR- GPCR

Amino acid residues that are responsible for the binding of SP and

its antagonists are present in the extracellular loops and transmembrane
regions of NK1.

"SP antagonist (SPA)-Capsaicin is clinically used as an analgesic and an
antiinflammatory agent to reduce pain associated with arthritis and many
types of neuralgia(Capsaicin has been shown to reduce the levels of
substance P).

"SPA — Aprepitant used as antiemetic drug in treatment of chemotherapy
induced delayed vomiting.

"Substance P could promote wound healing of nonhealing ulcers in
humans.

"Substance P as a potent vasodilator. Substance P induced vasodilatation
is dependent on nitric oxide release.

3. SUBSTANCE P
OS

cz CNS — neurotransmitter

c GIT — transmitter in ENS and as a local hormone

cx Involved in behavior, anxiety, depression, nausea, and emesis
© a potent arteriolar vasodilator

© causes contraction of venous, intestinal, and bronchial

smooth muscle
© stimulates secretion by the salivary glands

C4 causes diuresis and natriuresis by the kidneys

4. + Tachykinins are a family of neuropeptides that share the carboxy-
terminal sequence of Phe-X-Gly-Leu-Met-NH2, where X is an
aromatic (Tyr or Phe) or hydrophobic (Val or Ile) amino acid.

“ This common sequence is essential for the tachykinin’s receptor
interaction and activation.

“ Five tachykinin peptides have been identified in mammals:
substance P (SP), neurokinin A, neuropeptide K, neuropeptide-g,
and neurokinin B.

“ SP was discovered by von Euler and Gaddum (1931).

5. + They reported that extracts of equine brain and intestine contained a

hypotensive and spasmogenic factor.

+ The preparation termed preparation P, was later found to be

proteinaceous.

+ The isolation from bovine hypothalamus and characterization of SP

was carried out by Leeman’s group in 1970-1971.
+ The structure of SP is as follows.
SP : Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2
“ SP is synthesized in the ribosome as a larger protein and then

enzymatically converted into the active undecapeptide.

6. “SP participates in neurotransmission of pain and
noxious stimuli and modulates autonomic reflexes

including the micturition reflex.

«In the peripheral system, SP is localized in the
primary sensory neurons and neurons intrinsic to
the gastrointestinal, respiratory tracts and

genitourinary tracts.

7. “ Substance P is an 1l-amino acid peptide belonging to the
tachykinin family.
“+ It is widely distributed throughout the nervous system of human

and animal species.

* Peptides are synthesized through translation and transcription,

different from the classic neurotransmitters.

Substance P is synthesized from a large precursor protein in the
endoplasmic reticulum then transferred to the Golgi apparatus for
packaging and finally transported to the cell membrane for

exocytotic release.

8. “+ Substance P is normally present at relatively high concentrations in
nerve endings in selected regions of the mammalian brain, hence it

is functionally available.
“+ Peptides almost always coexist with classic transmitters, suggesting
that their actions are complementary to these classic transmitters.

“ For example. substance P co-exists with serotonin, thyrotropin
releasing hormone and probably glutamate in some bulbo-spinal

neurons.

< Transmitters are synthesized in nerve terminals and are taken back

up into the presynaptic nerve ending after release.

9. “*Peptides are synthesized from DNA in the cell body,
transported to the synapse and once released metabolized
requiring new synthesis and axonal transport for further

action.

“It is interesting that levels of substance P (and other
peptides) can change dramatically in response to
traumatic environmental events, and it is thought that
increases or decreases in peptide release and in neuronal
sensitivity to peptides can help neural systems adapt to

trauma, enhance survival and promote recovery.

10. + Scientists have speculated that peptides exert their main actions
when the nervous system is challenged or stressed, suggesting
involvement with diseases of the brain and their availability as

targets for therapeutic intervention.

“+ In fact, an antidepressant action of a substance P antagonist (NK1)
was reported in 1998, but this effect could not be confirmed in
subsequent trials.

+ Substance P plays the role of neurotransmitter and neuromodulators

in the central and peripheral nervous system.

11. + Substance P is secreted by nerves and inflammatory cells such as
macrophages, eosinophils, lymphocytes and dendritic cells and acts
by binding to the neurokinin-1 receptor (NK-1R).

“+ SP has proinflammatory effects in immune and epithelial cells and
participates in inflammatory diseases of the respiratory, g.i.t. and
musculoskeletal systems.

+ Many substances induce neuropeptide release from sensory nerves
in the lung including allergen, histamine, prostaglandins and
leukotrienes.

« Patients with asthma are hyperresponsive to SP and NK-IR

expression is increased in their bronchi.

12. + Substance P is secreted by nerves and inflammatory cells such as
macrophages, eosinophils, lymphocytes and dendritic cells and acts
by binding to the neurokinin-1 receptor (NK-1R).

“ SP has proinflammatory effects in immune and epithelial cells and
participates in inflammatory diseases of the respiratory, g.i.t. and
musculoskeletal systems.

+ Many substances induce neuropeptide release from sensory nerves
in the lung including allergen, histamine, prostaglandins and
leukotrienes.

« Patients with asthma are hyperresponsive to SP and NK-IR

expression is increased in their bronchi.

13. + Elevated levels of SP and upregulated NK-1R expression have been
reported in the rectum and colon of patients with inflammatory
bowel disease (IBD).

++ Increased levels of SP are found in the synovial fluid and serum of
patients with rheumatoid arthritis and synoviocytes.

“ P can specifically stimulate the chemotaxis of lymphocytes,

monocytes, neutrophils, and fibroblasts

14. THE ROLE OF SP IN INFLAMMATION

“ SP enhances lymphocyte proliferation and immunoglobulin
production and enhances cytokine secretion from lymphocytes,
monocytes, macrophages and mast cells.

+ SP-induced release of inflammatory mediators such as cytokines,
oxygen radicals, arachidonic acid derivatives and histamine
potentiates tissue injury and stimulates further leukocyte
recruitment, thereby amplifying the inflammatory response

“ SP elicits local vasodilatation and alters vascular permeability,
thus enhancing the delivery and accumulation of leukocytes to

tissues for the expression of local immune responses.

15. SP AND IMMUNOREGULATION

TABLE 2. Proinflammatory effects of SP in immune cells

Cell type Effects

Lymphocytes Potent chemoattractant
B lymphocyte differentiation cofactor
Increases immunoglobulin secretion
Stimulates T lymphocyte proinflammatory cytokine release
Stimulates T lymphocyte natural killer ac:
Stimulates T lymphocyte proliferation
Lymphocytes can produce SP
Monocytes macrophages Potent chemoattractant
Stimulates proinflammatory cytokine release
Induces oxidative burst
Stimulates synthesis and release of arachidonic acid metabolites
Macrophages express NK-1R and secrete SP
Neutrophils Chemoattractant
Stimulates degranulation and respiratory burst
Increases adherence to epithelial cells (upregulates adhesion molecule
exp! jon)
Stimulates proinflammatory cytokine release
Mast cells Close contact between mast cells and nerves
Induces degranulation
Induces histamine and serotonin release
Stimulates proinflammatory cytokine release
Eosinophils Chemoattractant
Stimulate activation, degranulation, release of O,, and thromboxane
Eosinophils can secrete SP

16. “ SP has been shown to have antiapoptotic effects in many cells,
including macrophages, neutrophils and thymocytes.

+ NEP maintains low levels of SP in the extra-cellular fluid under basal
conditions and terminates its proinflammatory effects.

+ NEP has been localized in the lungs of different animal species.

+ NEP (enzymes neutral endopeptidas) is present in the basal cells of
the epithelium, type II alveolar cells, neutrophils, submucosal glands.
airway smooth muscle, and postcapillary venules and nerves.

% SP regulates smooth muscle contractility, epithelial ion transport,
vascular permeability, and immune function in the gastrointestinal

tract

17. Table I. Tachykinins: sequences and encoding genes [48]

Name
substance P (SP)

neurokinin A (NKA)
neurokinin B (NKB)

hemokinin-1 (hHK1)
(human)

Endokinin A/B (EKA; EKB)

CI4TKL-1 (chromosome 14
tachykinin-like peptide 1)

Sequence Gene (alternative name)
Arg-Pro-Lys-Pro-Gln-Gin-Phe-Phe-Gly-Leu-Met-NH, TAC-1

(PPT-A or PPT-I);

human chromosome 7
His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH, TAC-1
Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH, TAC-3

(PPT-B or PPT}:

human chromosome 12

Thr-Gly-Lys-Ala-Ser-Gln-Phe-Phe-Gly-Leu-Met-NH,

Gly-lys-Ala-Ser-Gn-Phe-Phe-Gly-Leu-Met-NH,

Arg-His-Arg-Thr-Pro-Met-Phe-Tyr-Gly-Leu-Met-NH,

Gly-lle-Pro-Glu-Leu-lle-His-Tyr-Thr-Arg-Asn-Ser-Thr-Lys-Lys-Phe-
-Tyr-Gly-Leu-Met-NH,

18. Tachykinin_receptors (GPCR)

Activated TAC receptors release the Gq subunit from
the heterotrimeric G protein complex. This Gq subunit
in tum leads to activation of phospholipase C & hence
formation of phosphoinisitol triphosphate.

Agonist- Substance P Neurokinin A Neurokinin B
Antagonist-
Aprepitant, casopitant, — =
Fosaprepitant, Maropitant_ | Anticmetic drugs .
(treatment of chemotherapy induced

delayed nausea/emesis)

19. Hyperalgesia - Peripheral Component
Chemical Mediators of Sensitization

Substance P
__ Histamine
- DRG neuron
Lesion
— Prostaglardirt
N hromboxane K*
Q (o) Ne P
Le] Blood vessel vasodilation flare Spinal cord

from arterioles/
Extravasation of plasma proteins from
capillaries due to vasogenic edema

20. The Normal Pain Processing Pathway

4. The descending tract carries
modulating impulses back to the
dorsalhorn

3. A signalis sent via the
ascending tracttothe
brain, and perceived as
pain

. Impulses from afferents depolarize
dorsalhorn neurons, then,
extracellular Ca** diffuse into
neurons causing therelease of
Pain Associated Neurotransmitters
- Glutamate and Substance P

Kam

Glutamate | H

1. Stimulus sensedbythe ns à :
peripheral nerve (ie, haat p

= Ww

21. + Substance P is a neuropeptide that functions as both a
neurotransmitter and a neuromodulator.

+ Substance P is associated with mood regulation, anxiety, stress,
neurogenesis, respiratory rhythm, neurotoxicity, vasodilation,
nausea, emesis, and pain perception.

+ Substance P is a neurotransmitter in the nociceptive pathway. Itis
involved in the transmission of pain.

+ Substance P may play a role in fibromyalgia.

+ The pain reliever capsaicin (active ingredient in peppers) has been
shown to reduce Substance P levels.

22. Substance P/Neurokinin 1 Receptor

Antagonists
* Actions

— Act directly in the CNS to block receptors associated with
nausea and vomiting

* Indications

— In combination with other agents to prevent nausea and
vomiting

« Pharmacokinetics

— Given orally, metabolized in the liver, and excreted in
urine and feces

23. Neurokinin 1NK1) antagonist)

+ Aprepitant [Emend]

+ (substance P receptor antagonist) used in
delayed nausea caused by chemotherapy

« It can be used in a combination with
benzodiazepines and 5-HT3 antagonists, or alone.

mua EMO EST
pe U 1

1 Capsule

Qu —

24. @ Prototype Summary: Aprepitant

Indications: In combination with other agents for

the prevention of acute and delayed nausea and
vomiting associated with severely emetogenic cancer
chemotherapy.

Actions: Selectively blocks human substance P/
neurokinin 1 (NK1) receptors in the central nervous
system, blocking the nausea and vomiting caused by
highly emetogenic chemotherapeutic agents.

Pharmacokinetics:
Route Onset Peak

Oral Rapid 4h
T, 9 to 13 hours, metabolized in the liver and
excreted in urine and feces.

Adverse effects: Anorexia, fatigue, constipation, diarrhea,
liver enzyme elevations, dehydration.

25. Thank you

Dr. Muthuraman A. JSS College of Pharmacy, Mysaru