Semmal Sir Online Classes
Psychoendoimmunoneurology
for Medical Students
.
Time
Period Corresponding to maximum ↑ in Melatonin Serum Levels ____________?
.
Night
& Early Morning
.
Melatonin
is IL-2/IL-2 Receptor Modulator
.
Circadian
Rhythm of Melatonin is Marker For ________?
Healthy
Ageing
.
Melatonin
Metabolite
6-Hydroxymelatonin
Sulfate (Amt6s) Elevated at Night
Among
which age group _________?
All ages
.
Melatonin
is a Wonderful Multitasking Molecule
Multiple
Advantages +
Anti-Ageing
Drug Due its Amphiphilic Feature
So it can
cross BBB
.
Melatonin
acts against the Undesirable Facets of Ageing
And it
acts against ____?______degeneration
Neurodegeneration
.
Anti-Inflammation
effect of melatonin in CNS due to _______?
↓ Microglial Activity In CNS
.
Longevity
Protein Protected by Melatonin _____________?
SIRTUIN 1
.
How
melatonin ↓ DNA Damage
L1
Retrotransposons → DNA Damage
Melatonin → Inhibit L1 Retrotransposons
.
Melatonin → Inhibit B-Fibrillogenesis
Melatonin →↓B-Amyloid
Melatonin → ↓ Abnormal Nitration of Proteins
Melatonin → Inhibits Tau
Phosphorylation
Melatonin → Better Sleep Quality
………
Daily
Light / Dark Cycle is by itself a stress
.
Life must
tackle many
External
& Internal Stressors Like
↓ Food Scarcity, Pathogen Invasion,
↑ ↓ Temperatures
Hurtful
Memories & Injuries
.
Name the
HPA Axis End-Effectors for
Stress
System in Mammals ________?
Glucocorticoids
.
Locus
Coeruleus / Norepinephrine –
ANS and
its End-Effectors – NE & E
.
Circadian
Clock Dynamically Communicates With ________?
HPA Axis
.
Dysregulation
of Stress System → Deleterious
Over
Course of Time
.
HPA Axis
Attritions & Clock Disorders
Share
Common Metabolic Syndromes like ___________?
(Obesity,
Diabetes)
.
Glucocorticoids
made by Adrenal Cx →
Influences
All Organs & Tissues
Extremely
Necessary to Preserve ___?__ Vital Biologic Activities
(Homeostasis
of CNS, CVS, Intermediary Metabolism)
.
Immune/Inflammatory
Reaction → Influences ___?_____
Expression
in Genome
M
RNA
.
SCN
Modulates Secretion of Glucocorticoids by Influencing ______?
HPA Axis
.
ANS
is HPA Axis (Dep/ Indep) endent Pathway
Independent
.
Glucocorticoids
Exhibits 3 Rhythms, what are they ______?
Human Glucocorticoid Receptor Acetylation ↑ during Which time of the day ______? ______
Name some Age-Related Disorders in which Glucocorticoid Rhythms Fluctuates ?
In young ages GH Levels in blood is ↑ →
x
Human Glucocorticoid Receptor Acetylation ↑ during Which time of the day ______? ______
Name some Age-Related Disorders in which Glucocorticoid Rhythms Fluctuates ?
In young ages GH Levels in blood is ↑ →
x
Pulsatile,
Ultradian (1–2 Per Hour), Circadian
.
Circadian
Peak for Glucocorticoids
Strongly
Based on Activity Phase of body
.
Peak + in
Early Morning in Diurnal Body
.
Peak + in
Early Night in Nocturnal Animals
.
Bmal1
Gene
Plays
Significant Role in Rhythmic Expression of Glucocorticoids in Adrenals
.
Release
of Glucocorticoids - Tightly Regulated By __?____Gene
Per 1
& Per 2
.
Glucocorticoids
Exerts Circadian Regulatory Function
By
Modulating Several Clock Related Genes In
Peripheral
Clocks
.
Glucocorticoids
Exert Functions via
Glucocorticoid
Receptors (GR)
.
.
Morning
& Nadir at Evening
.
Circadian
Machinery Maintains
Counter
Regulatory Feedback to HPA Axis Via CLOCK & BMAL1
By
Blocking Active Sites of which hormone?
.
GR
This is
Very Essential for Proper Response to Stressors
.
AD,
Cushing’s Syndrome, Mood Disorders & Metabolic Syndromes
.
External
Administration of Glucocorticoids → (Mention any 9 effects)
1.↑ CVS Mortality
2.
Disrupted Glucose Homeostasis
3. Bone
Loss
4. ↑ROS Levels & Cell Death In Hippocampus
5. ↓ Learning , ↓ Memory,
6.↑ Neuronal Apoptosis
7. Amyloid
Precursor Protein,
8.↑ B-Secretase & Caspase-3
Expression
9.↑ Senescence
Aged
Hippocampus & Cortex → ↑11b -HSD1 (GC Enhancer) →
Impaired
________?______ Learning
.
Spatial
Learning
So,
Inhibition of 11b-HSD1 → Reversal of ↓ Spatial Memory to better
levels
.
Stress in
Early Life → ↑ Glucocorticoids Exposure → Shortening of _____?______→ Fast Ageing
.
Telomere
.
Pregnant
mother with ↑ Stress → Child with Shorter Telomeres at Birth → will live
less years
.
CRH MRNA in PVN
Region has Rhythmic Function
It shows ↑ Expression during
Lights On
↓ Expression
during Lights Off
.
In Ant. Pit. & Ad
Cx the Clock Genes Expression are Robust and in Synchrony with which part of
Brain?
.
.
.
.
.
.
SCN
.
ACTH → Stimulated Release of
Glucocorticoid From which part of Adr. Cx ?
.
.
.
Zona Fasciculata
.
.
.
.
Zona Fasciculata
.
Glucocorticoid &
ACTH has Circadian Rhythms
Characteristic
Feature of Adrenocortical System
.
ACTH has Nocturnal
Rhythm in Expression
Peak in _________?
.
.
Night
.
.
Night
.
Dehydroepiandrosterone
(DHEA)
Intermediate for Synthesis of Sex Steroids
Intermediate for Synthesis of Sex Steroids
Produced by
Adrenal, ______, Gonads
.
.
Brain
.
Cholesterol - Precursor Molecule
.
.
Brain
.
Cholesterol - Precursor Molecule
Acted Upon by P450
becomes Pregnenolone which becomes 17a-Hydroxypregnenolone by Cytochrome P450
Finally becomes DHEA
.
DHEA Exhibits
Rhythmic Pattern
Peak During Night
.
Gender Difference In
DHEA
.
.
.
.
.
.
↓ in Young Adult
Women
↓ due to Ageing in
both genders
.
Caucasian Women
have ↑ DHEA then Caucasian Men During Day time
Flat DHEA Diurnal
Slope → Longer Telomere Length
.
DHEA Sold in some
countries
Humans with Good
Functional Status have ↑ DHEA Levels
.
↓ DHEA in old
Men → Predicts Death In Smokers
.
DHEA → Good Cognition (Physical & Psychological) In both genders
.
How DHEA Helps to ↓ Inflammation ?
.
.
.
.
How DHEA Helps to ↓ Inflammation ?
.
.
.
DHEA → ↓ Insulin Resistance
↓ Inflammatory
Cytokines
DHEA → Inhibits IL-8,
NF-Kb, TNF-A , ROS
DHEA → Reductant for many
Enzymes which creates Oxygen-Free Radicals
.
DHEA → Inhibits ERK-1
Phosphorylation & C-Fos
.
DHEA → Good Sleep
Quality , Mood, Energy & Stress-Healing, ↓ Fat Body Mass In Men
DHEA → Improved Bone Mineral
Density (BMD), Skin Hydration, Epidermal Thickness,
Sebum Production & Pigmentation in Older Women
Sebum Production & Pigmentation in Older Women
.
Growth Hormone (GH) =
Somatotropin
Peptide Hormone → Stimulates Growth,
Cell Reproduction, Cell Regeneration
Specialized
Somatotroph Cells of Anterior Pituitary → GH production
Peak During Sleep
SCN - Site that makes
Potent GH Inhibitor, Somatostatin.
Rapid Somatic Growth
.
As age ↑ Levels ↓
After Reproductive
Maturation & Attainment Of Adult Body Size.
As Age → more Levels ↓ more
Age related ↓ in GH -
Consistent Across Different Mammalian Groups
↓ GHRH → ↓ GH
↓ GHRH → ↓ IGF-I (Key Regulator for GH)
.
Age related ↓ in activity of
Somatotropic Axis is called as ‘Somatopause’
Somatopause is due to
Interaction of IGF-I
GH Exerts Its Action
to Initiate
Synthesis of DNA,
RNA, Protein
.
Prolonged Treatment
with GH when it is deficient → ↑ QOL, ↑ Bone Mineral Density
But when we give GH
for Normal Healthy Elders using Rhgh (Recombinant Human Growth Hormone)
It is bad
It → Arthralgias, Edema,
Carpal Tunnel Syndrome, Insulin Resistance, DM
Children may get
Stroke also
.
IGF-1 - Pulsatile
Bursts from Pituitary
↑ in Night Time
Associated with
Slow-Wave Sleep
Secretion of IGF-1 -
Dependent on GHRH which releases GH
.
IGF-I - Involved in
Skeletal & Muscular Development
.
Age Related ↓ of IGF-1
Highly Consistent
Across Species & Sexes
