Neuropeptides and Neurotrophic Factors

Neuropeptides and Neurotrophic
Factors
Presentor
Dr Jaspreet Singh
JR1, Psychiatry
Moderator
Dr Deepak Singh, MD
Asst Prof (Psychiatry)
1

Outline
Neuropeptides
• Introduction
• Classification
• Historical background
• Biosynthesis, Distribution &
Regulation
• Neuropeptide Signalling
• Relevance to Psychiatry
• Future Directions
• Recent Advances
Neurotrophic Factors
• Introduction
• Classification
• Historical background
• Biosynthesis and Regulation
• Neurotrophic receptors and
Development
• Relevance in Psychiatry
• Future Directions
2
• Take Home Message

Introduction
• Definition :
• Neuropeptides are chains of 02 or more
amino acids linked by peptide bonds
• Exert direct & neuromodulatory effects
• Over 100 unique biologically active peptides
identified in brain
• Neuropeptides are implicated in regulation of
variety of behavioural and physiological
processes
4Brothers SP, Young LJ, Nemeroff CB. Neuropeptides: Biology, Regulation, and Role in Neuropsychiatric Disorders. In: Sadock B, Sadock VA,
Ruiz P. Kaplan & Sadock's Comprehensive Textbook of Psychiatry (Tenth Edition). Philadelphia; Walters Kluwer;2017

Classification of Neuropeptides
5
Mains RE, Eipper BA. The Neuropeptides. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular
and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 2009. Available from: https://www.ncbi.nlm.nih.gov/books/NBK28247/

Historical Background
• 1895 : Vasopressor effects of posterior pituitary hormones described
• 1953 : OT first peptide hormone – structure explained & chemically
synthesized
• 1955 : Nobel Prize in Chemistry to Vincent du Vingeaud
Oxytocin &
Vassopressin
• 1950 : Research concluded pituitary ext. stimulate and release ACTH
• 1981 : Vale et al isolated and characterised CRF
Corticotrophin
Releasing Hormone
• 1969 : First hypothalamic hormone – isolated & characterized
• 1977 : Nobel prize for Andrew Schally and Roger Guillemin
Thyrotropin
Releasing Hormone
• 1973 : Isolated from Bovine hypothalamus for its hypotensive
propertiesNeurotensin

Biosynthesis of Neuropeptides
Peptidergic
Neuron

Transcription of
mRNA from
specific gene
• Nucleus
Translation of
polypeptide
preprohormone
• Rough
endoplas
mic
reticulum
Posttranslational
processing of
preprohormone
• Golgi
Complex
and
Granules
Neuropeptide
8

9
Brothers SP, Young LJ, Nemeroff CB. Neuropeptides: Biology, Regulation, and Role in Neuropsychiatric Disorders. In: Sadock B, Sadock VA,

Distribution and Regulation
Hypothalamus &
Adenohypophysis
• TRH
• CRH
Hypothalamus &
Neurohypophysis
• Oxytocin
• Vasopressin
Co-localization within classial
Neurotransmitters
Circuits
• NP Y with
serotonin, norepinephrine
• NT, CCK, Substance P with
Dopamine
10

Neuropeptide Signalling
Neurotransmitter
• Released from axonal terminals into
synapse
Neuromodulator
• Modulation via 2nd messenger pathway
• G-Protein Coupled Receptors (Gs, Gi, Gq)
Neurohormone
• Act after diffusing at a distance
• Paracrine Secretion

Neuropeptides with Relevance to
Psychiatry
1. Thyrotropin Releasing Hormone
2. Corticotrophin Releasing Factor and Urocortin
3. Oxytocin & Vasopressin
4. Neurotensin
5. CCK, Somatostatin
6. Substance P
7. Neuropeptide-Y
8. Orexins
9. B-Endorphins
12

Thyrotropin Releasing Hormone
• TRH immunoreactive neurons –
Hypothalamus, hippocampus, amygdala,
midbrain ,olfactory , entorhinal cortex
• Role in HPT axis
• Negative feedback by thyroid hormones
limited to hypothalamic TRH neurons.
Extrahypothalamic TRH neurons continue
to function optimally even with high TSH,
T3, T4 concentrations

• Primary hyperthyroidism associated with depressive symptomatology ~~~~>
involvement of HPT axis
• TRH stimulation test
• Blunting of TSH secretion
• TSH blunting present even when thyroid hormones are normal
• Points TRH receptor downregulation due to median eminence secreting
endogenous TRH
• Modulates several neurotransmitters like Dopamine, serotonin, Ach and opioids

• CSF quantitative measurements ~~~~~> elevated TRH concentration in
depressed patients ~~~~~> possible TRH role in causation
• In future, role of TRH receptor antagonists in depression

Corticotrophin Releasing Factor
• CRF neurons found in PVN of hypothalamus
sending extension to median eminence
• CRF released into hypophysio-hypothalmic portal
System in response to stress
• Extrahypothalmic CRF neurons – Neocortex,
amygdala, brain stem and spinal cord
16Brothers SP, Young LJ, Nemeroff CB. Neuropeptides: Biology, Regulation, and Role in Neuropsychiatric Disorders. In: Sadock B, Sadock VA, Ruiz P. Kaplan &
Sadock's Comprehensive Textbook of Psychiatry (Tenth Edition). Philadelphia; Walters Kluwer;2017

• CRF along with Urocortins, intergrates endocrine,
autonomic and behavioural responses to stress
• Increased CSF CRF concentration
• Child abuse or neglect
• Major depression
• PTSD
• Antisocial personality Disorder
• Chronic stress syndrome
• Possibilty of treatment of anxiety and depression
with CRF Receptor Antagonist
Brothers SP, Young LJ, Nemeroff CB. Neuropeptides: Biology, Regulation, and Role in Neuropsychiatric Disorders. In: Sadock B, Sadock VA, Ruiz P.
Kaplan & Sadock's Comprehensive Textbook of Psychiatry (Tenth Edition). Philadelphia; Walters Kluwer;2017
17

CRF Dopamine Interaction
• Motivation is facilitated by activity of mesolimbic dopamine projections from the
VTA to Nucleus Accumbens
• Stress can lead to decrease in motivation - drug addiction and depression
• Severe stress ~~~~~> Nucleus Accumbens Dopamine neurons become
insensitive to CRF ~~~~~> Decreased dopamine release ~~~~~> anhedonia
18Wanat MJ, Bonci A, Phillips PE. CRF acts in the midbrain to attenuate accumbens dopamine release to rewards but not their predictors.
Nature neuroscience. 2013 Apr;16(4):383.

Neurotensin (NT)
• Endogenous Anti psychotic like substance
• NT producing cells bodies
• Midbrain (VTA), ventral striatum, Extended
amygdala
• Co-localized & co-released with DA in
mesolimbic and medial prefrontal cortex
through NT receptors (NT1, NT2, NT3)
• Anti psychotics increase NT concentrations
• Increased NT mRNA concentration
• C-fos gene expression

Neurotensin (NT)
• NT acts on GABAergic neurons ~~~~~> release of GABA on dopaminergic
nerve terminals ~~~~~> inhibiting release of DA ( Antipsychotic action )
• Development of NT receptor agonist awaited which can cross BBB.
Brothers SP, Young LJ, Nemeroff CB. Neuropeptides: Biology, Regulation, and Role in Neuropsychiatric Disorders. In: Sadock B, Sadock VA, Ruiz P.
Kaplan & Sadock's Comprehensive Textbook of Psychiatry (Tenth Edition). Philadelphia; Walters Kluwer;2017
20

Cholecystokinin (CCK)
• Originally discovered in GI tract where it inhibits gastric emptying
• Increases the secretion of GH IH (somatostatin)
• Receptors found in area associated with emotion, motivation and sensory
processing
• Co-localised with mesolimbic and mesocortical dopamine circuits
• Like NT, CCK decreases Dopamine release
• Panic disorder patients – increased CCK sensitivity
• Pentagastrin, a synthetic CCK agonist, causes autonomic activation and Panic
like symptoms

Neuropeptide Y
• 36 AA peptide found in Hypothalamus, Brain stem, Spinal Cord & Limbic
structures
• Involved in regulation of appetite, reward and energy balance
• Co localized with serotonergic and noradrenergic neurons
• Has a role in stress, anxiety and stress resilience

Neuropeptide Y
• Low CSF NPY ~~~~~> increased
vulnerability to depression and PTSD on
exposure to stress
• Suicide victims (Depression) - Reduced
levels in frontal cortex and caudate nucleus
• Antidepressants – increase NPY
concentration in frontal cortex and
hippocampus

Substance P
• Pain neurotransmitter
• Synthesized in amygdala, hypothalamus, locus coeruleus
• Co-localised with Norepinephrine and Serotonin
• Depressed and PTSD patients – elevated CSF Substance P concentrations
• Administration in animals – behavioural and cardiovascular effects resembling
Stress response
• Animal studies - Substance P receptor antagonist capable of passing through
BBB as effective as Paroxetine in depressive symptoms

Oxytocin
• Synthesized by Paraventricular nucleus and
Supraoptic nucleus of Hypothalamus
• Oxytocin Receptors (OTR) - Uterine smooth
muscles, lactation ducts, Limbic system
• Projections to forebrain and brainstem by extra
hypothalamic neurons from Magnocellular and
parvocellular Nucleus
• Neuromudulatory effects – Anxiolytic, role in
learning and memory
• Love hormone

Oxytocin
• Studies have proved that intranasal administration improves social cognition in
form of emotional recognition, social reciprocity, enhanced activation of reward
system in autism
• Dysregulation of Oxytocin (deceased levels in CSF)
• Social deficits in psychiatric disorders
• Increased vulnerability to depression and anxiety

Vasopressin
• Synthesized by Paraventricular nucleus and Supraoptic nucleus of
Hypothalamus
• Separate neurons for oxytocin and Vasopressin
• Role – maintenance of fluid homeostasis in the body
• Vassopressin receptors
• V1a – widely distributed in CNS, mediate behavioural aspects of AVP
• V1b – Anterior Pituitary colocalised with corticotrophs to modulate effects of
CRF on ACTH secretion
• V2 – Collecting ducts in Kidney

Vasopressin
• Extra hypothalamic VP receptors in amygdala and mesolimbic dopamine
pathway
• Animal studies
• Stimulates pair bonding between male and its mate
• Facilitates social bonding
• It is implicated that human behavior patterns depend on distribution of receptors
in CNS
• V1a receptor antagonists – anxiolytic & antidepressant effects in animal models

Endorphins
• Opioid Neuropeptide
• Acts on mu receptors
• Term coined by Dr Eric Simon – endogenous + morphine
• Role in
• Neural transmission
• Pain suppression
• Increases relaxation
• Feeling of well - being, euphoria & self confidence
4 types of Opiod receptors
1. Mu
2. Kappa
3. Delta
4. sigma

Orexin
• 33 amino acid peptide
• Also K/a Hypocretin
• Role in arousal, wakefulness, and appetite
• Drug – Orexin receptor antagonist
• Lemborexant (Rx), brand name Dayvigo*
• Indication – Insomnia
30
Boss C, Roch C. Recent trends in orexin research—2010 to 2015. Bioorganic & medicinal chemistry letters. 2015 Aug 1;25(15):2875-87.
*New Drug Therapy Approvals 2019 (internet). Available from : https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-
new-therapeutic-biological-products/new-drug-therapy-approvals-2019

Future Directions
• Development of drugs that can cross BBB and modulate neuropeptide receptor
activity
• Development of novel PET ligands to visualize the peptide receptors in CNS
• More genetic studies to accurately identify novel neuropeptides associated with
psychiatric disorders
• Next generation of pharmacological interventions

Recent Advances
Lemborexant (Rx)
• Formula : C22H20F2N4O2
• FDA approval : December 2019
• Brand name : Dayvigo
• Mechanism of Action : Dual orexin antagonist (DORA)
• Indications : Insomnia
• Dosing : 5 mg HS before going to bed; can be
increased to 10 mg HS
32*New Drug Therapy Approvals 2019 (internet). Available from : https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-
biological-products/new-drug-therapy-approvals-2019
Orexins are neuropeptides that
regulate the sleep-wake cycle;
orexins promote wakefulness
by binding G-protein-coupled
receptors, OX1R and OX2R

Recent Advances
Bremelanotide (Rx)
• Formula : C50H68N14O10
• FDA approval : Jun 2019
• Brand name : Vyleesi
• Mechanism of Action : Non selective melanocortin receptor (MCR) agonist
• Indications : Hypoactive Sexual Desire Disorder
• Dosing : 1.75 mg/0.3 ml SC as needed, at least 45 minutes before anticipated
sexual activity , not >1 dose/24 hr, >8 doses/month not recommended
Neurons expressing MC4R
are present in many areas of
the central nervous system

Recent Advances
Ubrogepant (Rx)
• FDA approval : Dec 2019
• Brand name : Ubrelvy
• Mechanism of Action : Calcitonin gene-related
peptide (CGRP) receptor antagonist, Highly potent
• Indications : Acute treatment of migraine with or without aura
• Dosing : 50-100 mg PO for acute migraine, Maximum dose: 200 mg/24 hr
CGRP receptor, which is
thought to be causally involved
in migraine pathophysiology

Recent Advances
Rimegepant (Rx)
• FDA approval : Feb 2020
• Brand name : Nurtec ODT
• Mechanism of Action : Calcitonin gene-related
peptide (CGRP) receptor antagonist, Highly potent
• Indications : Acute treatment of migraine with or without aura, additionally
efficacious for nausea
• Dosing : 75 mg PO for acute migraine, Maximum dose: 300 mg/24 hr
CGRP receptor, which is
thought to be causally involved
in migraine pathophysiology

Introduction
• Neurotrophins – a unique family of polypeptide growth factors influencing
proliferation, differentiation, survival and death of neuronal and nonneuronal
cells.
• Actions of Neurotrophins depend on
• Level of availability
• Affinity to transmembrane receptors
• Downstream signalling cascades
• Larger in Size as compared to Neuropeptides – 12 to 14 kDA
37Lee FS, Chao MV. Neurotrophic Factors. In : Sadock B, Sadock VA, Ruiz P. Kaplan & Sadock's Comprehensive Textbook of Psychiatry (Tenth
Edition). Philadelphia; Walters Kluwer;2017

Introduction
Functions of Neurotrophic factors
Regulation of synaptic connections, structure &
neurotransmitter release
Synaptic Plasticity
Long Term Potentiation
Mechanosensation and pain

Historical Background
• Victor Hamburger, American neuroembryologist
• Proposed that differentiation, specialization of nerve cells depends on
their final destination in the body
1934
• Rita Levi Motalcini, Italian neurohistologist
• Failure of neurons to thrive in the absence of target tissue was a
degenerative process rather than failure of differentiation as proposed
earlier
• Led to the discovery of NGF
1951
• BDNF, the 2nd member of the “neurotrophic” family of neurotrophic
factors by Barde et at
• Promote survival of a subpopulation of dorsal root ganglion neurons and
subsequently purified from pig brain
1982
39Lewin GR, Carter BD. Neurotrophic factors. Berlin, Germany: Springer; 2014 Mar 25.p.12-15

Neurotrophin family
Nerve growth Factor
(NGF)
Brain Derived
Natriuretic Factor
(BDNF)
Neurotrophin-3
(NT-3)
Neurotroohin-4
(NT-4)
Glial Derived
Neurotrophic factor
(GDNF)
Ciliary Neurotrophic
Factor (CNTF)
40

Biosynthesis of Neurotrophic factors
Expressed in neuronal development for selective neuronal survival
Active proteins
Undergo proteolytic cleavage
Proneurotrophins
Nonneuronal cells
41

Neurotrophin Receptors
42
Mediate differentiation &
Survival signalling
 MAPK
 PI3-K
 PLC-ỿ pathway
 CREB
Mediates apoptotic and cell Migration
responses
NF-kB
JNK pathway

Neurotrophic Factors and Development
Neurotrophin Hypothesis
• Neurons compete for limited quantities of
neurotrophins in target regions during
development
• Levels of target derived neurotrophins +
Neurotrophin receptors determine the
survival & responsiveness of neurons
• Lack of trophic support + incorrect
targeting ~~~~> Apoptosis
Lee FS, Chao MV. Neurotrophic Factors. In : Sadock B, Sadock VA, Ruiz P. Kaplan & Sadock's Comprehensive Textbook of Psychiatry (Tenth Edition).
Philadelphia; Walters Kluwer;2017 43

Retrograde Axonal Transport of
Neurotrophins
Neurotrophin binds to transmembrane
receptor
Internalisation
Signalling endosome travel at 3-10 mm/hr
Phosphorylation and activation of
transcription factors in nucleus
Cellular response and survival
44

Relevance of Neurotrophins to Psychiatry
45

Neurodegenerative Disorders
• In animal models of motor neuron disease, BDNF and CNTF increased number
motor neurons and improved performance
• Striatal specific atrophy in Huntington disease may be a consequence of ↓
BDNF, a target for mutant Huntington Protein
• Human challenges – delivery of adequate quantities of drugs to CNS without
peripheral side affects
46
Lee FS, Chao MV. Neurotrophic Factors. In : Sadock B, Sadock VA, Ruiz P. Kaplan & Sadock's Comprehensive Textbook of Psychiatry (Tenth

Depression
• Dysregulation of synaptic plasticity & neuronal survival in hippocampus – role in
depression
• Decrease in BDNF levels + decrease in Hippocampal volume
• In animal models, exogenously given BDNF – comparable to chronic treatment
with antidepressants
• SNRIs found to upregulate CREB and BDNF in 10 to 20 days – corresponds to
the therapeutic action of antidepressants
47

Other Psychiatric Disorders
Psychiatric Disorders Neurotrophic Factors
BPAD ↓ BDNF
Lithium & valproate increase BDNF in
corticolimbic pathway
Anxiety BDNF – increases the susceptibility to
stress and anxiety
Schizophrenia Mixed results
Addiction ↑ BDNF expression ~~> LTP &
synaptic plasticity ~~~> increased
drug seeking behavior
48

Genetics
Single nucleotide polymorphism in BDNF gene related to Psychiatric
disorders
• SNP ~~~~> change from Valine to methionine at position 66 in BDNF gene
~~~~~> improper folding of BDNF ~~~~~~> Depression, Bipolar affective
Disorder, Schizophrenia
• Polymorphism noted with an allele freq of 20-30% in Caucasian populations
• Humans heterozygous with Met allele
• Smaller hippocampal volumes
• Perform poorly at hippocampal dependent memory tasks

Future Directions
• Strategies for delivery of sufficient quantities of neurotrophin based drugs that
cross BBB
• Application of neurotrophins with viral vectors or engineered progenitor cells
• Deeper understanding of newer drugs & physical exercise in treatment of
depression and improvement in cognitive function
• Newer strategies in pain management based on Neurotrophins (NGF)
50

Take home message
Neuropeptides
• Neuropeptides are chains of two or more amino acids linked by peptide bonds
which have a role in various behavioural and physiological processes
• Neuropeptides can act as Neuromodulators, Neurotransmitters and
Neurohormones
• Complexity of brain’s neuropeptide systems and their contribution to mental
health is beginning to be understood
• Possibility of next generation of pharmacological interventions for psychiatric
disorders with the ongoing research in the field
51

Take home message
Neurotrophic factors
• Neurotrophic factors are polypeptide growth factors influencing proliferation,
differentiation, survival & death of neuronal and nonneuronal cells
• Expansion in the research during the last 20 years, sparked by the discovery of
BDNF has lead to their implication in pathophysiology of mood disorders
• Prospect of neurotrophic factors being used in the clinical therapy of
neurodegenerative disorders remains uncertain
• With the inability to cross BBB, treatment strategies, similar to antidepressants
which enhance or support the synthesis or release of endogenous neurotrophic
factors, are likely to become widespread in the future
52

References
• Brothers SP, Young LJ, Nemeroff CB. Neuropeptides: Biology, Regulation, and Role in
Neuropsychiatric Disorders. In: Sadock B, Sadock VA, Ruiz P. Kaplan & Sadock's
Comprehensive Textbook of Psychiatry (Tenth Edition). Philadelphia; Walters Kluwer;2017
• Lee FS, Chao MV. Neurotrophic Factors. In : Sadock B, Sadock VA, Ruiz P. Kaplan & Sadock's
Comprehensive Textbook of Psychiatry (Tenth Edition). Philadelphia; Walters Kluwer;2017
• Sharp T. The contribution of Neurosciences. In : Geddes JR, Andreasen NC. New Oxford
textbook of psychiatry (Second edition). Oxford University Press, USA; 2009:p 171
• Sadock B, Sadock VA, Ruiz P. Kaplan & Sadock's Synopsis of Psychiatry: Behavioral sciences/
Clinical Psychiatry( Elenventh Edition). New Delhi; Walters Kluwer;2017:585
• Sadock B, Sadock VA, Ruiz P. Kaplan & Sadock's Synopsis of Psychiatry: Behavioral sciences/
Clinical Psychiatry( Elenventh Edition). New Delhi; Walters Kluwer;2017:585
54

References
• Wanat MJ, Bonci A, Phillips PE. CRF acts in the midbrain to attenuate accumbens dopamine
release to rewards but not their predictors. Nature neuroscience. 2013 Apr;16(4):383.
• World Health Organization. The ICD-10 classification of mental and behavioural disorders:
clinical descriptions and diagnostic guidelines. Geneva: World Health Organization; 1992.
• Lewin GR, Carter BD, editors. Neurotrophic factors. Berlin, Germany:: Springer; 2014 Mar 25
• Mains RE, Eipper BA. The Neuropeptides. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors.
Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia:
Lippincott-Raven; 2009. Available from: https://www.ncbi.nlm.nih.gov/books/NBK28247/
• Boss C, Roch C. Recent trends in orexin research—2010 to 2015. Bioorganic & medicinal
chemistry letters. 2015 Aug 1;25(15):2875-87.
• New Drug Therapy Approvals 2019 (internet). Available from : https://www.fda.gov/drugs/new-
drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-
therapy-approvals-2019
55

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