A thesis from Finland, not directly related to stroke but they do discuss BDNF and IGF-1. In English at least.
https://helda.helsinki.fi/bitstream/handle/10138/29047/roleofgd.pdf?sequence=1
Abstract
Parkinson´s Disease (PD) is a neurodegenerative movement disorder resulting from
loss of dopaminergic (DA) neurons in substantia nigra (SN). Possible causative treatment
strategies for PD include neurotrophic factors, which protect and in some cases
restore the function of dopaminergic neurons. Glial cell line-derived neurotrophic factor
(GDNF) family of neurotrophic factors have been to date the most promising candidates
for treatment of PD, demonstrating both neuroprotective and neurorestorative properties.
We have investigated the role of GDNF in the rodent dopaminergic system and its
possible crosstalk with other growth factors. We characterized the GDNF-induced gene
expression changes by DNA microarray analysis in diff erent neuronal systems, including
in vitro cultured Neuro2A cells treated with GDNF, as well as midbrains from GDNF
heterozygous (Hz) knockout mice. Th ese microarray experiments, resulted in the identifi
cation of GDNF-induced genes, which were also confi rmed by other methods. Further
analysis of the dopaminergic system of GDNF Hz mice demonstrated about 40%
reduction in GDNF levels, revealed increased intracellular dopamine concentrations and
FosB/DeltaFosB expression in striatal areas. Th ese animals did not show any signifi cant
changes in behavioural analysis of acute and repeated cocaine administration on locomotor
activity, nor did they exhibit any changes in dopamine output following treatment
with acute cocaine.
We further analysed the signifi cance of GDNF receptor RET signalling in the dopaminergic
system of MEN2B knock-in animals with constitutively active Ret. Th e MEN2B
animals showed a robust increase in extracellular dopamine and its metabolite levels in
striatum, increased tyrosine hydroxylase (TH) and dopamine transporter (DAT) protein
levels by immunohistochemical staining and Western blotting, as well as increased Th
mRNA levels in SN. MEN2B mice had increased number of DA neurons in SN by about
25% and they also exhibited increased sensitivity to the stimulatory eff ects of cocaine.
We also developed a semi-throughput in vitro micro-island assay for the quantifi cation
of neuronal survival and TH levels by computer-assisted methodology from limited
amounts of tissue. Th is assay can be applied for the initial screening for dopaminotrophic
molecules, as well as for chemical drug library screening. It is applicable to any neuronal
system for the screening of neurotrophic molecules.
Since our microarray experiments revealed possible GDNF-VEGF-C crosstalk we
further concentrated on studying the neurotrophic eff ects of VEGF-C. We showed that
VEGF-C acts as a neurotrophic molecule for the DA neurons both in vitro and in vivo,
however without additive eff ect when used together with GDNF. Th e neuroprotective
eff ect for VEGF-C in vivo in rat 6-OHDA model of PD was demonstrated. Th e possible
signalling mechanisms of VEGF-C in the nervous system were investigated - infusion
of VEGF-C to rat brain induced ERK activation, however no direct activation of RET
signalling in vitro was found. VEGF-C treatment of rat striatum lead to up-regulation of
VEGFR-1-3, indicating that VEGF-C can regulate the expression level of its own receptor.
VEGF-C dopaminotrophic activity in vivo was further supported by increased vascular
tissue in the neuroprotection experiments.
No comments:
Post a Comment