Neurotrophic Factors: So Much Potential, So Many Challenges

http://www.pdonlineresearch.org/news...any-challenges

For the past 15 years or so, Parkinson’s disease (PD) researchers and patients alike have been excited about the potential of neurotrophic factors (or “trophic factors”) as a possible treatment for the disease. The excitement seems well-placed. Trophic factors exist in the brain to protect neurons from dying and to coax them to grow—perfect qualifications for a treatment or even a cure for a neurodegenerative disease such as PD.

“There’s very good animal data showing that they protect against an amazing, astonishing amount of different types of insults,” says Jamie Eberling, associate director at MJFF. “It seems like anything you can do to kill a neuron, they can protect against.” Fewer data are available on their restorative effects, but there are definite signs that, in animals, either dying neurons are revived or remaining healthy neurons sprout new processes in response to trophic factors, she adds.

very hopeful - thanks for posting.

jean

1. Brain Res Mol Brain Res. 1994 Jul;24(1-4):70-6.

1,25-dihydroxyvitamin D3 regulates the synthesis of nerve growth factor in
primary cultures of glial cells.

Neveu I, Naveilhan P, Jehan F, Baudet C, Wion D, De Luca HF, Brachet P.

Institut National de la Santé et de la Recherche Médicale, Unité U.298, Centre
Hospitalier Régional et Universitaire, Angers, France.

The effect of 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3) on nerve growth factor
(NGF) synthesis was investigated in primary cultures of astrocytes prepared from
brain of neonatal rats. 1,25-(OH)2 D3 elicited a dose-dependent increase of NGF
mRNA with a maximal effect at 10(-7) M, which persisted for at least 48 h.
Northern blot analysis revealed an expression of the vitamin D3 receptor (VDR)
gene in primary glial cells. Treatment of cells with 1,25-(OH)2 D3 led to an
increase in the VDR mRNA levels. Similar results were obtained in C6 glioma
cells. Exposure of primary glial cells to 10(-8) M 1,25-(OH)2 D3 caused only a
2-fold increase of the levels of cell-secreted NGF after 3 days of treatment.
However, a 5-fold increase was observed three days after a second addition of
vitamin D3. Likewise, a pretreatment with lower doses of hormone such as 10(-10)
M or 10(-9) M enhanced the responsiveness of the cells to a 24 h treatment with
10(-8) M hormone. It appears, therefore, that the duration of the treatment
influences the level of synthesis of NGF, possibly as a consequence of the
increase of the VDR gene expression. The specificity of 1,25-(OH)2 D3 is
supported by the fact that a concentration of 10(-7) M of an another vitamin D3
metabolite, 24,25-(OH)2 D3, had no effect on NGF synthesis. Several lines of
evidence indicate that astrocytes constitute the major cell type responsive to
1,25-(OH)2 D3 in primary cultures of glial cells.(ABSTRACT TRUNCATED AT 250
WORDS)


PMID: 7968379 [PubMed - indexed for MEDLINE]

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1. Neuroreport. 1996 Sep 2;7(13):2171-5.

1,25-Dihydroxyvitamin D3, an inducer of glial cell line-derived neurotrophic
factor.

Naveilhan P, Neveu I, Wion D, Brachet P.

Institut National de la Santé et la Recherche Médicale, Centre Hospitalier
Universitaire, Angers, France.

Glial cell line-derived neurotrophic factor (GDNF) has significant therapeutic
potentials, in particular for neurodegenerative disorders. To determine factors
that would enhance GDNF expression, we analysed the effect of 1,25-(OH)2 D3 in C6
glioma cells. Treatment of C6 cells with 10(-7) M, 1,25-(OH)2 D3 for 48 h
elicited an 18.5-fold increase in the level of GDNF mRNA. In addition, our
results indicate that 1,25-(OH)2 D3 is effective at concentrations as low as
10(-10) M and that retinoic acid has additive effects. These data indicate that
1,25-(OH)2 D3 is a potent inducer of GDNF expression and suggest that 1,25-(OH)2
D3 may contribute to the regulation of GDNF in vivo.


PMID: 8930983 [PubMed - indexed for MEDLINE]

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1. Brain Res Mol Brain Res. 2002 Dec;108(1-2):143-6.

1,25-Dihydroxyvitamin D(3) increases striatal GDNF mRNA and protein expression in
adult rats.

Sanchez B, Lopez-Martin E, Segura C, Labandeira-Garcia JL, Perez-Fernandez R.

Department of Physiology, School of Medicine, University of Santiago de
Compostela, Spain.

Glial cell line-derived neurotrophic factor (GDNF) has been postulated as a
possible candidate for therapeutic treatment in Parkinson's disease (PD). Recent
in vitro data suggest that 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D(3)] treatment
may enhance GDNF mRNA expression. In the present study, using semiquantitative
RT-PCR and Western blot, we have shown that 1,25(OH)(2)D(3) administration
intraperitoneally, significantly increases GDNF mRNA and protein levels in the
striatum of adult rats.


PMID: 12480187 [PubMed - indexed for MEDLINE]

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1. J Neurosci Res. 2009 Feb 15;87(3):723-32.

1,25-Dihydroxyvitamin D3 administration to 6-hydroxydopamine-lesioned rats
increases glial cell line-derived neurotrophic factor and partially restores
tyrosine hydroxylase expression in substantia nigra and striatum.

Sanchez B, Relova JL, Gallego R, Ben-Batalla I, Perez-Fernandez R.

Department of Physiology, School of Medicine, University of Santiago de
Compostela, Santiago de Compostela, Spain.

It has previously been demonstrated that 1,25-dihydroxyvitamin D(3)
[1,25(OH)(2)D(3)] administration, whether in cell cultures or in vivo to rats,
increases glial cell line-derived neurotrophic factor (GDNF) expression levels,
suggesting that this hormone may have beneficial effects in neurodegenerative
disorders. This study was carried out to explore the effects of 1,25(OH)(2)D(3)
administration in a 6-OHDA-lesioned rat model of Parkinson's disease on GDNF and
tyrosine hydroxylase (TH) expression in substantia nigra (SN) and striatum. Two
groups of animals received 1,25(OH)(2)D(3) intraperitoneally, the first group 7
days before the unilateral injection of 6-OHDA into the medial forebrain bundle
(MFB) and the second group 21 days (days 21-28) after the unilateral injection of
6-OHDA. Animals of both groups were sacrificed on day 28. In addition, two other
groups received a unilateral injection of either saline or 6-OHDA into the MFB.
Rats were killed, and the SN and striatum were then removed for GDNF and TH
determination. Striatal GDNF protein expression was increased on the ipsilateral
with respect to the contralateral side after 6-OHDA injection alone as well as in
1,25(OH)(2)D(3)-treated rats before or after 6-OHDA administration. As expected,
6-OHDA injection induced an ipsilateral decrease in TH-immunopositive neuronal
cell bodies and axonal terminals in the SN and striatum. However, treatment with
1,25(OH)(2)D(3) before and after 6-OHDA injection partially restored TH
expression in SN. These data suggest that 1,25(OH)(2)D(3) may help to prevent
dopaminergic neuron damage.


PMID: 18816795 [PubMed - indexed for MEDLINE]

Thus my interest in high dose Vitamin D.

1. Biosci Biotechnol Biochem. 2005 Apr;69(4):800-5.

Oral administration of royal jelly facilitates mRNA expression of glial cell
line-derived neurotrophic factor and neurofilament H in the hippocampus of the
adult mouse brain.

Hashimoto M, Kanda M, Ikeno K, Hayashi Y, Nakamura T, Ogawa Y, Fukumitsu H,
Nomoto H, Furukawa S.

Laboratory of Molecular Biology, Gifu Pharmaceutical University, Gifu 502-8585,
Japan.

Royal jelly (RJ) is known to have a variety of biological activities toward
various types of cells and tissues of animal models, but nothing is known about
its effect on brain functions. Hence, we examined the effect of oral
administration of RJ on the mRNA expression of various neurotrophic factors,
their receptors, and neural cell markers in the mouse brain. Our results revealed
that RJ selectively facilitates the mRNA expression of glial cell line-derived
neurotrophic factor (GDNF), a potent neurotrophic factor acting in the brain, and
neurofilament H, a specific marker predominantly found in neuronal axons, in the
adult mouse hippocampus. These observations suggest that RJ shows neurotrophic
effects on the mature brain via stimulation of GDNF production, and that enhanced
expression of neurofilament H mRNA is involved in events subsequently caused by
GDNF. RJ may play neurotrophic and/or neuroprotective roles in the adult brain
through GDNF.


PMID: 15849420 [PubMed - indexed for MEDLINE]

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Rick is this true to the degree that D3 consumption at a certain dosage could be behind the variable trial results with GDNF, the responders claiming a cure?

I don't want to hijack this thread and am going to shift this discussion over to the "High Dose Vit D" thread at this point, but I hope that anyone interested in GDNF and similar potential therapies will follow. There is a possible payoff here that must not be ignored.