http://www.cdfin.iastate.edu/update/...5/project5.htm
Title: Neuroprotective Effect of Phytic Acid on Parkinson's Disease
Investigators:
Manju B. Reddy, Ph.D., Department of Food Science & Human Nutrition
Anumantha G. Kanthasamy, Ph.D.,Department of Biomedical Sciences
Type of Project: Renewal
Overall Objective and Specific Aims:
The overall objective of this study is to determine the therapeutic
effect of phytic acid in preventing the neurodegeneration of
1-methyl-4-phenyl-1,2,3,6-tetrahydropryidine (MPTP)-induced
Parkinson's Disease (PD). We will specifically test for:
Protective effect of phytic acid and its metabolites on cell death
using a cell culture model
Protective effect of phytic acid given orally at therapeutic doses in a
mouse model
PROGRESS REPORT: A Graduate student has been identified in the
interdepartmental toxicology program this fall and currently she is
getting training under Dr. Kanthasamy for behavioral, neurochemical,
and neuropathalogical indicators of PD.
JUSTIFICATION AND BACKGROUND:
1. Hypothesis: We hypothesize that phytic acid at therapeutic doses
will protect against PD by preventing MPTP-induced neurodegeneration.
This hypothesis is based on phytic acid's antioxidant and metal
chelating properties (Graf and Eaton, 1990).
2. Rationale and Related Work: Parkinson's disease is characterized
by a selective degeneration of dopaminergic neurons in the substantia
nigra, resulting in irreversible motor dysfunction. The cardinal
symptoms of PD include resting tremor, bradykinesia, and rigidity.
This debilitating neurodegenerative disorder affects more than 1% of
the US population over 50 years of age, and causes an estimated
economic obligation of $25 billion annually (Scheife et al, 2000).
Recent research interest has been directed to understand the
pathogenesis of the disease as well as neuroprotective therapy. There
have been many developments in the area of dopamine replacement
strategies to neutralize the motor deficits resulting from the
degeneration of dopaminergic neurons. These developments, however, are
limited to symptomatic relief. Other limitations of these approaches
include drug tolerance, drug-induced involuntary movements, and most
importantly, dopamine therapy is ineffective in attenuating the
progression of the illness. Therefore, alternate therapeutic
strategies are warranted in identifying novel neuroprotective agents
that effectively prevent the progression of the neurodegenerative
process.
3. Related Work: Body iron concentration generally increases with age
including brain iron content. Substantia nigra has about 20 ng/mg iron
during the first year of life and increases to 200 ng/mg by the fourth
decade (Zeccal et al, 2001). The role of iron in PD has recently
gained attention because excessive iron accumulation in substantia
nigra was found in postmortem brains from Parkinson's patients (Berg el
al, 2002). The central role of iron in the pathogenesis of PD is by
its involvement in oxygen free- radical production. Brain tissues are
rich in polyunsaturated fatty acids, thus they are especially
vulnerable to free radical mediated lipid peroxidation (Schafer et al,
2000). Because of association of excess iron and PD with age, we can
speculate that iron has a definite role in PD development or
progression. Although the alteration in brain iron pathways are
discussed in relevance to PD, whether that is a cause or effect, is
still obscure (Berg et al, 2001).
In Parkinson's and Alzheimer's disease there is a disruption in the
iron metabolism, such that there is an accumulation of iron in senile
plaques and altered distribution of iron transport and storage
proteins. These diseases are associated with elevated brain iron
concentrations relative to the iron storage protein, ferritin.
Ferritin, the primary nonheme iron storage protein, is believed to keep
iron in a non-reactive form, where it can not promote redox reactions.
Therefore ferritin could protect tissues against iron-catalyzed
oxidative damage (Kaur et al, 2003). A rise in iron concentrations
without concomitant change in ferritin provides "free iron" for
free radical generation (Berg et al, 2001; Bishop et al, 2002).
Selective cell death in the substantia nigra brain region is associated
with oxidative stress, which may be exacerbated by the presence of
excess iron. It is well know that iron is involved in the Haber-Weiss
reaction in producing ·OH production, which is the most reactive
oxygen species (ROS), damaging cells and causing many diseases.
O2- + Fe3+ ® Fe2+ + O2
Fe2+ + H2O2 ® Fe3+ + ·OH + OH-
Oxidative stress causing cell damage, including apoptosis, may play a
prominent role in neurological degeneration associated with PD (Jenner
and Olanow, 1996; Fahn, 1996; Burke et al, 1998; Kaul et al, 2003).
Research on the use of antioxidants, free radical scavengers, and
inducers of cellular antioxidant systems as therapeutic adjuncts in the
treatment of PD continues to provide hope towards more effective
therapies that not only treat symptoms, but also might slow the process
of neurodegeneration. Based on this evidence, antioxidants are thought
to have a great potential as therapeutic agents for treatment in the
early stages of PD. For example, co-enzyme Q10 has recently been shown
to have a protective effect against PD (Kanthasamy et al, 2001). In
addition, estrogens, at endogenous concentrations or at pharmacological
doses, are shown to offer neuroprotection in PD and other
neurodegenerative disorders such as Alzheimer's disease. Dluzen and
colleagues (1996) have found that dopaminergic toxicity induced by MPTP
in ovarectomized female mice or rats can be attenuated by exogenous
estrogen administration. Iron chelation via either transgenic
expression of the iron-binding protein ferritin or oral administration
of the metal chelator clioquinol (CQ) reduced the susceptibility to the
MPTP for inducing PD, suggesting that iron chelation may also be an
effective therapy for prevention and treatment of the disease (Kaur et
al, 2003).
Phytic acid (myo-inositol hexakiphosphate) is a food component that is
considered an antinutrient by virtue of its ability to chelate divalent
minerals and prevent their absorption (Reddy et al, 1996). Its unique
chelating action with iron provides phytic acid with antioxidant
characteristics. Phytic acid was shown to inhibit ·OH formation and
decrease lipid peroxidation catalyzed by iron and ascorbate in human
erythrocytes (Graf and Eaton, 1990). This suppression of
iron-catalyzed oxidative reactions was suggested by the phytic acid's
ability to form a unique chelate with Fe(III) occupying all of the
coordinating sites (Graf et al,1984). Phytic acid's antioxidant
ability in vivo is not clear, but in our study we showed a reduction of
60% in lipid peroxidation and 48% in liver iron stores with dietary
phytic acid in a genetically overloaded-mouse model (Reddy and Guo,
2000). Recently, we also showed in a human study that feeding phytic
acid containing soy protein for 6-weeks to postmenopausal women reduced
body iron stores significantly compared with the low-phytic acid soy
protein (Barwick et al, 2003). These results together suggest that
phytic acid may have a protective effect in alleviating the iron-
induced oxidative stress. Interestingly, phytic acid may influence
oxidative stress independent of its hydroxyl radical inhibiting
characteristics. It may alter cell signaling pathways (Shamsuddin et
al, 1997) or may influence the activity and expression of key enzymes
in the antioxidant defense system, which detoxifies the ROS. Our
previous data support this hypothesis because liver catalase
concentration increased significantly after feeding phytic acid in the
diet for 10 weeks to iron-overloaded mice (Reddy and Guo, 2000).
Based on the positive effect of iron chelators and antioxidants on PD
and the antioxidant property and iron chelating ability of phytic acid,
we hypothesize that phytic acid may protect against the
neurodegeneration associated with PD. We would like to test this
hypothesis at therapeutic doses based on the cancer prevention rat
studies (Ullah et al, 1990) and human studies to treat idiopathic
hypercalcuria (Henneman et al, 1958) with phytic acid. The results of
this study will be useful to possibly develop phytic acid as a
therapeutic nontoxic iron chelator for ameliorating the extent of
oxyradical-induced damage as was seen in an ischemia heart- perfusion
injury model (Rao et al, 1991). To date, no such studies have been
reported in PD. This project defines work that is within the long-term
goals of the investigators regarding their specialty areas of
iron-induced oxidative stress and neuroprotection.