10: neurotrophics

Question 1

neurodegenerative diseases characterized by? curable? why (2)?

Answer 1

death of specific neuronal populations. most CNS neurodegen. diseases are incurable: poor knowledge of etiology, difficult access of brain

Question 2

goal of neurorestoration

Answer 2

to protect neurons, promote neuroregeneration

Question 3

strategy of neurorestoration?

Answer 3

to use NTFs, neurotrophic factors, to protect neurons and achieve neurorestoration

Question 4

what are NTFs?

Answer 4

small proteins that are secreted, and regulate the NS’s development, maintenance, plasticity

Question 5

NTFs regulate which 3 main processes? bind to?

Answer 5

endogenous neuroprotection, neurogenesis, neurorestoration. bind to receptors expressed on surface of responsive cells and activate signaling mechanisms (transcriptional activation, cellular metabolism, synaptic palsticity)

Question 6

3 families of neurotrophic factors

Answer 6

neurotrophins/NTs. GDNF family of ligands. neurokines.

Question 7

neurotrophins family: 4?

Answer 7

nerve growth factor NGF. brain derived neurotrophic factor BDNF. NT3. NT4.

Question 8

GDNF famil? (4)

Answer 8

glial derived neurotrophic factor GDNF. neurturin NRTN. artemin ARTN. persephin PSPN

Question 9

neurkines family: which factor?

Answer 9

ciliary neurotrophic factor CNTF

Question 10

neurotrophic factors stimulate 3 things?

Answer 10

neuronal survival, neuronal function, axonal growth

Question 11

classical vs. current neurotrophic model

Answer 11

classical: target cells release NTFs, taken up by terminal axons then retrograde transport to cell body. current: glial cells also secrete, and NTFs onto cell body as well as and the target cell too

Question 12

why use NTFs in neurodegen. disorders? (2)

Answer 12

decrease in NTFs levels play a role in pathogenesis of AD, HD, PD. large number of studies supports their use: prevents/slows cell death, enhances regeneration after injury

Question 13

AD: degree of dementia correlates best with? what do they do?

Answer 13

degeneration of BFCNs, basal forebrain cholinergic neurons, which project to cerebral cortex, hippocampus, nucleus basalis - important for learning and memory

Question 14

BFCNs and relation to NTFs?

Answer 14

basal forebrain cholinergic neurons highly dependent on NGF supply during adulthood. depletion = reduce # of cholinergic neurons, atrophy of chol neurons, reduction in chol innervation of hippocampus

Question 15

NGF administration into adult rat brain (2)?

Answer 15

for AD treatment: prevents death of BFCNs, improves learning and memory in lesioned and aged rats

Question 16

NGF admin into mouse model of AD (2)?

Answer 16

reverses BFCN atrophy, improves neuronal function

Question 17

2 limitations of NGF therapy

Answer 17

neuronal loss in AD is widespread: hard to treat whole brain with NGFs. there are multiple NT deficits in AD

Question 18

NTFs in HD?

Answer 18

medium spiny neurons depende on cortically derived BDNF. in HD, cortical BDNF is reduced to 50%.

Question 19

HD: what gene for what NTF? mutation? post mortem HD brain shows?

Answer 19

Htt induces BDNF gene expression. mutant Htt negatively affects BDNF gene expression. lower BDNF mRNA and protein levels in cortex.

Question 20

critical role in HD: loss of what? caused by what? prime target for therapeutics?

Answer 20

loss of neurotrophic support in striatum caused by reduced levels of BDNF. restoring BDNF signalling

Question 21

2 other NTFs important in HD

Answer 21

NGF: supports cholinergic neurons in striatum, but not GABAergic neurons. CNTF: supports cholinergic and GABAergic neurons

Question 22

5 limitations of NTFs for treatment of neurodegen disorders?

Answer 22

inability to cross BBB. pleiotropic effects following systemic application. poor stability in fluid environment (short half life in vivo, poor pharmokinetic properties). limited diffusion through brain parenchyma. side effects associated with binding to extra-target receptors.

Question 23

what is curcial in succesful therapy?

Answer 23

NTF delivery to proper site

Question 24

parental systemic administrcation: via? how to use?

Answer 24

nanocarriers: injected IV, then cross BBB and reaches brain parenchyma

Question 25

what are nanocarriers? effects?

Answer 25

liposome based formulation loaded with GDNF and targeted to brain with mAb against TfR. general improvement of PD symptoms

Question 26

nanocarriers are targeted by?

Answer 26

coating the surface of the material with peptides (ex with targeting ligands)

Question 27

how do nanocarriers get in?

Answer 27

injected IV. then cross BBB: receptor mediated transcytosis, or absoprtive transcytosis (because of coating with positive charges)