IMPROVING THE SURVIVAL AND FUNCTION OF GRAFTED DOPAMINE NEURONS: THE EFFECT OF DIETARY SUPPLEMENTATION WITH BLUEBERRY EXTRACTS
SO McGuire1*, MJ Hejna1, B Shukitt-Hale2, JA Joseph2, CE Sortwell3, TJ Collier3
1Department of Pathology, Loyola University Chicago, Maywood, IL 60153; 2USDA HNRCA, Tufts University, Boston, MA; 3Department of Neurological Sciences, Rush Presbyterian St. Luke's Medical Center, Chicago, IL 60612.
Transplantation of embryonic dopamine (DA) neurons into the striatum is
a viable treatment for Parkinson's disease (PD). However, transplanted
cells survive poorly, with ~90% of transplanted cells dying within the
first four days after transplant. Cell death is exacerbated by ~75% in
aged animals, resulting in transplants that provide little to no
therapeutic benefit. Although the exact mechanism underlying cell
death is not known, oxidative stress and inflammation are hypothesized
as major contributing factors. Multiple studies have attempted to
improve cell survival by pre-treating the cell transplant material with
various anti-apoptotic or antioxidant compounds. This study provides
evidence that dietary supplementation with blueberry extract (BBE), a
fruit extract with antioxidant and anti-inflammatory properties,
provides an efficacious, easily administered and well tolerated therapy
that can be used to treat the transplant recipient, thus improving
survival of the transplanted cells. Young adult (4 months, n=10) and
aged rats (24 months, n=3) were unilaterally lesioned with 6-OHDA to
deplete striatal DA and allowed to recover from surgery for 2 months.
Animals with stable, amphetamine-induced rotational values, indicating
unilateral striatal DA depletion, were assigned to one of two dietary
treatments that consisted of custom formulated rat chow with or without
2% BBE. After six weeks of dietary treatment, sub-optimal numbers of
primary embryonic (gestational day 14) ventral mesencephalic cells,
including the developing midbrain DA neurons, were transplanted into
the denervated striatum. Rats were assessed for amphetamine-induced
rotational behavior at two week intervals for 8 weeks
post-transplantation. Young, BBE-fed rats exhibited fewer rotations
per minute than did control-fed rats (P<0.05), indicating the presence
of a functional graft. However, no behavioral benefit was noted in
either group of aged rats. Morphological analysis revealed a greater
than two-fold increase in DA neuron survival within the grafts in both
young and aged BBE-fed rats (P<0.05) as assessed by tyrosine
hydroxylase immunoreactivity (THir). BBE-fed animals also tended to
have increased transplant areas (P=0.1) with individual graft-derived
neurons exhibiting increased THir (P=0.1). These data provide evidence
that dietary supplementation of the host with BBE can provide an easily
tolerated, non-invasive treatment for the graft recipient that has
beneficial effects on neural graft survival and function. Supported by
NS 42125 (TJC)
Key words:
Parkinson's Disease, neural transplantation, neurodegeneration, polyphenolics, flavonoids
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