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Pharmacology Of Neurological And Psychiatric Disorders > Regeneration in the optic nerve > Flashcards

Regeneration in the optic nerve Flashcards

1
Q

regeneration in the CNS vs PNS

A

CNS: poor intrinsic growth potential, inhibitory environment, olidodendrocytes (form myelin) causes inflammatory response (no regeneration), no genetic injury response
PNS: supportive environment, schwann cells form myelin (support regeneration), elevated growth potential, injury response genes

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2
Q

CNS vs PNS developmental differences

A

CNS: limited intrinsic growth capacity, developmental regenerative decline, polarised transport, poor intrinsic growth potential
PNS: high intrinsic growth capacity, regeneration maintained during development, efficient axon transport, good intrinsic growth potentials

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3
Q

glaucoma

A

neurodegenerative visual deterioration
synapse loss/axon degeneration/RGC loss
traditional therapy - lowering IOP (no treatment)
primary open area glaucoma (POAG) imbalance of input and output drainage - damages optic nerve axons loses RGCs

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4
Q

where are the optic nerve neurons located?

A

retina
extension of the CNS

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5
Q

models to study intrinsic control of axon regeneration

A

in-vitro: neuron specific, less extrinsic factors, less physiological relevance
in-vivo: neuron specific, more extrinsic factors (RGCs synapse elsewhere), more physiological relevance (eye)

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6
Q

cell cultures for the PNS/CNS

A

PNS - DRG
CNS - rodent brains

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7
Q

in-vitro models

A

laser axotomy
scratch assay - grow axons and scratch to induce injury

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8
Q

in-vivo models

A

rodents - cre recombinase, 2 loxP sites combined then the gene of interest is excised
c elegans - laser axotomy
sciatic nerve injury
optic nerve crush
adeno-associated virus (AAV) gene delivery
glaucoma model

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9
Q

AAV

A

cell specific gene delivery/editing
do not replicate
targets serotype/promoter provides specificity

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10
Q

benefits of using c elegans

A

contain few neurons, transparent, easy to manipulate

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11
Q

where does axon regeneration occur

A

axons need to connect with their targets to recover function
CNS - low intrinsic drive (retraction ball)
PNS - high intrinsic drive (growth cones)

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12
Q

growth cones

A

delineated by cytoskeleton: actin and microtubules
guided by surface receptors and activate signalling pathways, receptors internalised to deliver signals

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13
Q

where are growth cone receptors located

A

sit in membrane (transmembrane proteins)

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14
Q

growth cone receptor trafficking

A

ribosome (where protein is made) on ER
receptor inserted into ER
ER vesicle buds off
vesicle interacts with golgi
fuses with the membrane

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15
Q

what controls endosome trafficking

A

rab11

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16
Q

motor proteins

A

kinesins anterograde transport (- to +)
dyneins retrograde transport (+ to -)

17
Q

important factors needed for axon transport

A

genetic factors
signalling pathways
axon transport
cytoskeleton

18
Q

cycle of axon regeneration

A

1) transcription, translation and signalling
2) anterograde axonal transport of receptors
3) growth cone insertion and ligand binding
4) receptor activation
5) retrograde axonal signalling
6) effect of gene expression and transport

19
Q

what do transcription factors and epigenetics control

A

RAG (regeneration associated genes)
RAG upregulated in response to injury

20
Q

epigenetics

A

DNA wrapped around histones - nucleosomes - chromatin - chromosomes

21
Q

methylation

A

tightly wound
RNA pol cannot bind
no gene transcription

22
Q

histone acetylation

A

loosely bound
RNA pol binds
gene transcription occurs

23
Q

PNS injury response

A

injury in peripheral branch
positive retrograde signalling to cell body
remove HDACs (histone deacetylases)

24
Q

TFs which promote axon regeneration

A

CREB
SOX11
KLF7

downregulated during RGC development

25
Q

TFs which inhibit axon regeneration

A

KLF4
KLF9

unregulated during RGC development

26
Q

epigenetic factors which promote regeneration

A

oct4
sox2
KLF4 (OSK)
require demethylases TET1/2
restores vision loss in mouse glaucoma

27
Q

ligands and their receptors in the PI3K pathway

A

NGF - TrkA
BDNF - TrkB
NT-3 - TrkC

28
Q

PI3K pathway

A

integrins bind to ECM and promote axon regeneration
PIP2->PIP3 via PI3K
PIP3->PIP2 via PTEN (removes phosphate)

increased PIP3 delta expression in DRG increases axon regeneration

29
Q

role of PIP3

A

promotes axon transport
AKT->mTOR

30
Q

Risk of growth/neurotrophic factors

A

oncogenic
receptor down regulation/internalisation
not effective/long term
promising targets

31
Q

glaucoma therapy

A

TrkB-BDNF AAV gene therapy
self activated TrkB approach - obtain TrkB R fused with farnesylated surface

32
Q

protrudin

A

located in ER membrane
moves integrin into axons
mobilises RabII endosomes
it is a kinesin binding ER protein
kinesin I - axonal motor protein along MT
neuroprotective - prevents RGC death

33
Q

role of the ER

A

protein synthesis
quality control
calcium regulation

contains protrudin

34
Q

ARMCX1 role

A

increases mitochondrial transport to promote regeneration
links mitochondria to axonal motor protein (kinesins)

35
Q

push/pull of growth cones

A

pCofilin (inactive) actin severing
cofilin (active) better regeneration

36
Q

RhoA

A

small GTPase which opposes regeneration through growth cone actin
activates rho kinase = rigid actin

inhibit RhoA for MT protrusion

37
Q

microtubules

A

polymerisation/rescue of tubulin (growth)
depolymerisation/catastrophe (shrinking of tubulin)

38
Q

what prevents depolymerisation of tubulin

A

taxol (anti cancer treatment)
parthenolide
Epothilone B

39
Q

axon morphology

A

uninjured - straight axons
regenerated axons - branching and turning

Pharmacology Of Neurological And Psychiatric Disorders (21 decks)

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