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Flashcards in 10: neurotrophics Deck (27):

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

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


goal of neurorestoration

to protect neurons, promote neuroregeneration


strategy of neurorestoration?

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


what are NTFs?

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


NTFs regulate which 3 main processes? bind to?

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


3 families of neurotrophic factors

neurotrophins/NTs. GDNF family of ligands. neurokines.


neurotrophins family: 4?

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


GDNF famil? (4)

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


neurkines family: which factor?

ciliary neurotrophic factor CNTF


neurotrophic factors stimulate 3 things?

neuronal survival, neuronal function, axonal growth


classical vs. current neurotrophic model

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


why use NTFs in neurodegen. disorders? (2)

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


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

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


BFCNs and relation to NTFs?

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


NGF administration into adult rat brain (2)?

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


NGF admin into mouse model of AD (2)?

reverses BFCN atrophy, improves neuronal function


2 limitations of NGF therapy

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


NTFs in HD?

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


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

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


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

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


2 other NTFs important in HD

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


5 limitations of NTFs for treatment of neurodegen disorders?

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.


what is curcial in succesful therapy?

NTF delivery to proper site


parental systemic administrcation: via? how to use?

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


what are nanocarriers? effects?

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


nanocarriers are targeted by?

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


how do nanocarriers get in?

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