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CNS - Sarah Bailey > SB L2 - Novel Treatments > Flashcards

SB L2 - Novel Treatments Flashcards

1
Q

8 alternative theories of depression

A
  1. Stress (GC antagonists)
  2. Neuropeptides
  3. Neurogenisis
  4. Anticonvulsants (gabapentin)
  5. Inflammation
  6. Gene-enviroment interation (diet and excercise)
  7. Life long well-being
  8. Chronic illness-depression intereaction
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2
Q

Explain the HPA

A

Stress ->
Hypothalamus releases CRF

Pituitary releases ACTH

Adrenals release cortisol

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3
Q

CRF

A

Corticotrophin releasing factors

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4
Q

ACTH

A

Adrenocorticotrophic hormone

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5
Q

Effect of cortisol?

A

fight or flight response

metabolic effects, metabolizing fats for energy, glucose into the blood

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6
Q

Theory about early life stresses

A

Early life stresses known to percipitate MDD - thought that hyperactivity of HPA axis

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7
Q

Evidence of HPA involvement in depression I - depressed patients show ….

A
  1. Increased HPA axis acitvity
  2. Elevated CRF levels in the CSF
  3. increased CRF mRNA expression in the PVN

compared to non-depressed controls

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8
Q

Evidence of HPA involvement in depression I - what is the effect of antidepressant treatments on the HPA?

A

reduce CRF conc in the CS of healthy and depressed patients

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9
Q

6 Neurpeptides transmitters implicated in anxiety

A

We dont focus on these but could give e.g.:

CRF
Neurokinins (NK, substance P)
Neuropeptide Y
Cholecystokinin (CCK)
Galanin
Bombesin
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10
Q

What are neuropeptide transmitters?

A

short chain amino acid neromodulators

exerting “long-term” effects

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11
Q

Where do we find neuropeptide transmitters

A

brain regions mediating emotional behavior/respond to stress

e.g. hypothalamus, amgdala

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12
Q

Neropeptide transmitters modulate ………………….. known to be involved in anx/depression

A

Neropeptide transmitters modulate neurotrasmitter systems known to be involved in anx/depression (e.g. 5HT, NA)

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13
Q

CRF has 3 relat4ed peptides:

A

urocortin 1,2,3

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14
Q

Describe the receptors for CRF

A

GPCRs - two types

CRFR1 and CRFR2

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15
Q

What happens when CRF binds to it’s receptor

A

intiates HPA resonpse to stress

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16
Q

What happens when CRF binds to it’s receptor

A

initiates HPA response to stress

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17
Q

describe the regions of the CRF molecule

A

agonist blinding/activation on each side

CRFBP binding in the middle (where the binding protein binds)

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18
Q

What is CRFBP and its function?

A

CRF binding protein - we don’t know what it’s for but perhaps to regulate CRF availability?

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19
Q

Where is CRFBP found?

A

ditributed in the plasma

20
Q

What has higher affinity, CRFBP or CRFR?

A

binding protein!

21
Q

What has higher affinity, CRFBP or CRFR?

A

binding protein!

22
Q

Where are the CRF pathways in the brain?

A

Extend to the central nucleus of amygdala, PVN of the hypothamaus, and raphe nuclei

23
Q

Where is CRFR1 and CRFR2 found

A

CRFR1 - WIDESPREAD DISTRIBUTION (frontocortical areas, amygdala, locus coeruleus, cerebellum, pituitary)

CRFR2 - DISCRETE LOCALISATION - (hypothalamus, amygdala, raphe)

24
Q

What happens in the cell when the CRFR is stimulated (2)

A
  1. Transcriptional regulation (e.g. POMC)
  2. Stumulation of NO synthase, prostaglandins
  • Different ligands may differentially activate signalling cascades in a cell-type specific manner
25
Q

3 animal evidences that CRF is axiogenic

2 refs - these refs are not in the extra reading so maybe only learn the facts

A

Overproduction of CRF in transgenic mice increases anxiety-related behaviour (Stenzel-Poore et al. 1994)

Injections of CRF into rats increases anxiety-related behaviours

ICV injection of antisense oligonucleotides to CRF in rats is anxiolytic (Skutella et al. 1994)

26
Q

Evidence that CRFR1 (across whole brain) receptor knockout mouse has reduced anxiety
1 ref

A
  1. stress-induced release of adrenocorticotropic hormone (ACTH) and corticosterone is reduced
  2. increased exploratory activity and reduced anxiety-related behaviour (Timpl et al. 1998, Smith et al. 1998)
27
Q

1 human evidence that CRF is axiogenic

1 ref - these refs are not in the extra reading so maybe only learn the facts

A

Increased CRF plasma/CSF concentrations evident in anxiety and depression patients (Banki et al. 1992)

28
Q

what is ICV injection

A

intracerebroventricular

29
Q

Evidence that CRFR1 (forebrain only) receptor knockout mouse has reduced anxiety
1 ref

A

Conditional knockout of forebrain CRFR1 in mice showed reduced anxiety, and the activity of the HPA system was normal (Muller et al. 2003)

30
Q

Evidence that CRFR1 (forebrain only) receptor knockout mouse has reduced anxiety
1 ref

A

Conditional knockout of forebrain CRFR1 in mice showed reduced anxiety, and the activity of the HPA system was normal (Muller et al. 2003)

31
Q

Explain the counter-regulatory mechanism for CRFR1/2?

2 therapeutic targets this presents?

A

See diagram
CRF stimulates CRFR1 increasing anxiety

Urocortin stimulates CRFR2 decreasing anxiety

Targets: CRFR1 antagonism & CRFR2 agonism

32
Q

do CRFR2 agonist work?

A

No - they actually increase anxiety showing that our theory is a bit wrong?

33
Q

Activity of CRFR1 antagonists may be dependant on…

how is this shown and name of molecule

A

base line stress

becuse CRA1000 reverses swim-stress induced behaviour in the light dark box but is ineffective in non-stressed animal

34
Q

3 molecules that show CRFR1 is anxiolytic

A

1 CP154,526 and R121919 are anxiolytic in a defensive withdrawal paradigm
2 Antalarmin reduces the behavioural, neuroendocrine and autonomic responses to stress in non-human primates
3 DMP904 increases time spent in open arms of EPM

35
Q

Talk about R121919:

  • type of molecule?
  • crosses the BBB?
  • action on humans? how?
A

Non-peptide antagonist of CRFR1.
Good solubility/corsses BBB

Improved anxiety and depression states in humans - reduces HPA hyperactivity without entirely inhibiting ACTH or cortisol release

36
Q

why is R121919 not used

A

hepatotoxic

37
Q

why is it good to not entiresly supress the HPA?

A

You still need some basal cortisol levels

38
Q

why is it good to not entiresly supress the HPA?

A

You still need some basal cortisol levels

39
Q

What canc MDD patients tell us? 3

A
  1. Conc of cortisol in urine is increased - evidence of HPA involvement in depression
    2 feedback of HPA is inhibited (shown by dexamethasone supression test)
    3 sucessful antidepressant treatments restores HPA function
40
Q

Dexamethasone supression test is a key indicator of

A

whether a patients will relapse

41
Q

How does dex supression test work?

A

Dex given at night - it feedsback preventing normal morning cortisol levels being produced. Test cortisol levels at 8am. In a normal person they are low. If depressed this doesn’t happen as they don’t get -ve feedback - the HPA isn’t working.

42
Q

2 e.g. of cortisol synthesis inhibitors

A

e.g. ketoconazole, metyrapone

43
Q

do cortisol synthesis inhibitors work?

Problem?

A

yes - provided you give a maintenance dose of cortisol in addition.

It targets the synthesis of all the hormones in the pathway - really we would like to inhibit the final step (selective inhibition of CYP11b1)

44
Q

2 types of receptors cortisol binds to

A

Type 1 (Mineralocorticoid)

  • activated by aldosterone
  • activated by basal glucocorticoid receptor
Type 2 (Glucocorticoid)
-activated by elevated levels of glucocorticoid
45
Q

Name a glcocorticoid antagonist

is it good?

A

mifepristone (RU-486) (abortion treatment)

not extensively used but shows less time spent immobile in forced swim test

short period evidence says it help depression and particularly psychiatric symptoms

CNS - Sarah Bailey (9 decks)

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