120

Ann. N.Y. Acad. Sci. 991: 120-131 (2003). 2003 New York Academy of Sciences.
Mitochondria. Oxidative Damage. and
Inflammation in Parkinson`s Disease
M. ELINT BEAL
Department of Neurologv and Neuroscience. Weill Medical College of Cornell Universitv.
New York Presbvterian Hospital. New York. New York 10021. USA
ABSTRACT: The pathogenesis of Parkinson`s disease (PD) remains obscure. but
there is increasing evidence that impairment of mitochondrial function. oxida-
tive damage. and inflammation are contributing factors. The present paper re-
views the experimental and clinical evidence implicating these processes in PD.
There is substantial evidence that there is a deficiency of complex I activity of
the mitochondrial electron transport chain in PD. There is also evidence for in-
creased numbers of activated microglia in both PD postmortem tissue as well
as in animal models of PD. Impaired mitochondrial function and activated
microglia may both contribute to oxidative damage in PD. A number of thera-
pies targeting inflammation and mitochondrial dysfunction are efficacious in
the MPTP model of PD. Of these. coenzyme Q
10
appears to be particularly
promising based on the results of a recent phase 2 clinical trial in which it sig-
nificantly slowed the progression of PD.
KEYWORDS: inflammation; microglia; mitochondria; oxidative damage; creat-
ine; coenzyme Q
10
THE ROLE OF FREE RADICALS AND IMPAIRED ENERGY
METABOLISM IN PARKINSON`S DISEASE
All aerobic organisms are continually exposed to oxidative stress.
1
Oxidative
phosphorylation involves the transIer oI electrons. which can lead to the generation
oI Iree radicals. independently existing species that contain one or more unpaired
electrons. Most Iree radicals are unstable reactive species that can extract an electron
Irom neighboring molecules to complete their own orbital. This leads to oxidation
oI neighboring molecules. Critical biologic molecules including DNA. proteins. and
membrane lipids are subiect to oxidative damage.
Mitochondria are believed to be the most important cellular source oI Iree radi-
cals generating superoxide radicals at ubiquinone and NADH dehydrogenase (com-
plex I).
2
Superoxide is normally converted by superoxide dismutase (SOD) to H
2
O
2
.
H
2
O
2
reacts with transition metals to generate hydroxyl radicals. the prime media-
tors oI cell damage. Superoxide can also react with nitric oxide to the Iorm oI per-
Address Ior correspondence: M. Elint Beal. M.D.. Chairman. Department oI Neurology and
Neuroscience. Weill Medical College oI Cornell University. 525 East 68th Street. Room E610.
New York. NY 10021. Voice: 212-746-6575; Iax: 212-746-8532.
Ibeal(med.cornell.edu
121 BEAL: MITOCHONDRIA. OXIDATIVE DAMAGE. AND INFLAMMATION
oxynitrite (ONOO

).
3
This reaction occurs at the rate oI 6.7 10
9
M
1
S
1
. threeIold
Iaster than the rate oI superoxide dismutation by superoxide dismutase. Peroxyni-
trite generation thus depends on the concentration oI superoxide and nitric oxide in
the cell. Peroxynitrite can exist in an activated 'hydroxyl radicallike transitional
state. At physiologic pH. peroxynitrite may diIIuse over several cell diameters to
produce cell damage by oxidizing lipids. proteins. and DNA. Peroxynitrite can react
with Cu.Zn SOD to Iorm nitronium ion. which may then nitrate tyrosine residues.
4
The 3-nitrotyrosine so generated is an excellent biochemical marker oI peroxyni-
trite-mediated oxidative damage.
Much oI the current interest in the association between neurodegeneration and
mitochondrial dysIunction/oxidative damage stems Irom studies oI 1-methyl-4-
phenyl-1.2.3.6-tetrahydropyridine (MPTP)-induced parkinsonism. The MPTP mod-
el oI PD results in a clinical syndrome that replicates the maior Ieatures oI PD in man
and nonhuman primates.
5
MPTP is metabolized to MPTP
+
and MPP
+
(1-methyl-4-
phenylpyridinium) by the enzyme monoamine oxidase B. MPP
+
is subsequently se-
lectively taken up by dopaminergic terminals and concentrated in neuronal mito-
chondria in the substantia nigra. In vitro experiments demonstrated that
nicotinamide dehydrogenase (NADH). complex I oI the electron transport chain. is
weakly and reversibly inhibited by MPP
+
. leading to reductions in mitochondrial
ATP production.
6
MPP
+
can also cause irreversible inactivation oI complex I by gen-
erating Iree radicals and increasing lipid peroxidation.
7
Inhibition oI NADH dehy-
drogenase by MPP
+
leads to superoxide production in isolated bovine heart
submitochondrial particles and in vivo.
8.9
Einally. MPTP-induced damage is attenu-
ated in transgenic mice overexpressing superoxide dismutase.
10
We previously
showed that mice deIicient in either MnSOD or glutathione peroxidase show in-
creased vulnerability to MPTP toxicity.
11.12
Thus. the MPTP model oI parkinsonism
has already set a precedent Ior a causal relationship between mitochondrial dysIunc-
tion and oxidative cellular damage.
Evidence extending this hypothesis to the pathogenesis oI idiopathic PD comes
Irom a 3040 decrease in complex I activity in the substantia nigra.
1316
Reduced
staining Ior complex I subunits in PD substantia nigra. but preserved staining Ior
subunits oI the other electron transport complexes. has been demonstrated immuno-
histochemically.
17
Strong support Ior a mitochondrial DNAencoded deIect comes
Irom studies that showed that complex I deIects Irom PD platelets are transIerable
into mitochondrial-deIicient cell lines.
18.19
These deIects are associated with in-
creased Iree radical production. increased susceptibility to MPP
+
. and impaired mi-
tochondrial calcium buIIering.
20
Direct sequencing oI mitochondrial complex I and
tRNA genes. however. Iailed to show homoplasmic mutations.
21
OXIDATIVE DAMAGE IN PD
A great deal oI interest has been Iocused on the possibility that oxidative damage
may play a role in the pathogenesis oI PD. There are studies showing increased lev-
els oI malondialdehyde and cholesterol lipid hydroperoxides. markers Ior lipid per-
oxidation. in PD substantia nigra.
22.23
There are widespread increases in protein
carbonyls in PD postmortem brain tissue.
24
Concentrations oI 8-hydroxy-2-deoxy-
guanosine. a marker oI oxidative damage to DNA. are signiIicantly increased in PD
122 ANNALS NEW YORK ACADEMY OF SCIENCES
substantia nigra and striatum.
25.26
However. attempts to detect increased Iree radi-
cals using electron spin resonance have been unsuccessIul. Evidence Ior nitrosyl
radicals in PD substantia nigra was recently obtained.
27
Another means oI looking
Ior oxidative stress is to measure concentrations oI reduced glutathione. Reduced
glutathione is decreased in PD substantia nigra by approximately 50.
2831
Individ-
uals with incidental Lewy body disease may have presymptomatic PD. and they have
a 35 reduction in reduced glutathione as compared with age-matched controls.
32
INFLAMMATION AND PD
There is increasing evidence that inIlammation may contribute to PD pathogene-
sis. There is an increase in reactive microglia in the striatum and substantia nigra oI
patients with idiopathic PD.
33.34
Although gliosis may in some circumstances be
beneIicial. at other times it exerts deleterious eIIects. Microglial cells. which are the
resident macrophages in the brain. respond to many insults with rapid proliIeration.
hypertrophy. and expression oI a number oI cytokines.
35.36
The brain area that en-
compasses the substantia nigra has the highest density oI microglia in the brain.
37
Activated microglia upregulate cell surIace markers such as the macrophage antigen
complex-I (MAC-1). and they produce a variety oI proinIlammatory cytokines.
There appears to be a graded response with diIIerential expression depending on the
severity oI the insult.
36
A consequence oI activation oI microglia is the production
oI reactive oxygen species. They can originate Irom NADPH oxidase. which produc-
es superoxide (O
2

); COX-2. which produces Iree radicals as a byproduct oI prostag-

landin synthesis; and Irom inducible nitric oxide synthase (iNOS). which generates
NO

. iNOS. because it does not require Ca

2+
Ior activity. produces much higher lev-
els oI NO

Ior longer periods (hours) than do the endothelial and neuronal isoIorms
oI NOS. which require Ca
2+
Ior activity. NADPH-oxidase is a maior source oI activ-
ity-dependent superoxide.
38
The reaction oI O
2

with NO

generates peroxynitrite
ONOO

. which is strongly implicated in PD pathogenesis. Prior studies showed that

Lewy bodypositive substantia nigra neurons in PD stain with antibodies to 3-nitro-
tyrosine. which is thought to be a speciIic marker Ior peroxynitrite-mediated dam-
age.
39
More recent studies showed that Lewy bodies react with antibodies to nitrated
-synuclein. the maior protein component oI Lewy bodies.
40
It was reported in a small number oI cases that the mRNA Ior the Clq and C9
components oI complement are increased in PD substantia nigra.
41
A number oI cy-
tokines including interleukin (IL)-1. IL-6. and tumor necrosis Iactor (TNE)- con-
tribute to inIlammatory processes. Studies oI TNE showed it to be increased 366
in the striatum and 432 in the cerebrospinal Iluid (CSE) oI PD patients.
42
Eurther-
more. an increase in TNE imunoreactive glial cells was reported in the substantia
nigra oI PD patients. as compared to controls.
43.44
The density oI glial cells expressing IL-1 and interIeron (IEN)- was also in-
creased in PD substantia nigra.
44
Others Iound increased levels oI Il-1 and IL-6 in
the caudate. putamen. and cerebral cortex oI postmortem PD brains.
45
Both IL-1
and IL-6 were also Iound to be increased in the CSE oI PD patients.
46
Another group
Iound an increase in IL-6 in the CSE oI PD patients and reported that levels inversely
correlate with the severity oI PD.
47
Last. an IL-1 polymorphism was reported to in-
crease the risk oI PD.
48.49
123 BEAL: MITOCHONDRIA. OXIDATIVE DAMAGE. AND INFLAMMATION
INFLAMMATION IN ANIMAL MODELS
Although there has been tremendous progress in genetic models oI PD. they are
not yet ideal in producing the cardinal Ieatures oI PD.
5
The most experience has been
with toxin models oI PD including MPTP. rotenone. and 6-hydroxydopamine. An
activation oI microglia in both the striatum and in the substantia nigra has been well
documented to occur in the MPTP model oI PD.
5052
The microglial activation was
associated with elevated IL-6 levels.
50
MPTP toxicity is also associated with in-
creases in IL-1.
53
We demonstrated that mice deIicient in IL-1 converting enzyme
are markedly resistant to MPTP neurotoxicity.
54
A recent study showed that mino-
cycline prevented MPTP-induced activation oI microglia. as well as the Iormation oI
IL-1. activation oI NADPH-oxidase. and induction oI iNOS.
52
This was associated
with reduced 3-nitrotyrosine Iormation. and reduced loss oI substantia nigra dopam-
inergic neurons.
52
Another group showed protection as well
55
but suggested that
minocycline may also have direct neuroprotective eIIects. This was recently shown
to be the case with direct eIIects on the mitochondrial permeability transition and
cytochrome c release.
56
The importance oI inIlammation was underscored by a
study oI humans exposed to MPTP in which persistent activation oI microglia was
associated with oxidative degeneration oI substantia nigra neurons.
57
Recently sys-
temic administration oI rotenone to rats was shown to produce an excellent animal
model oI PD.
58
Studies oI rotenone toxicity in neuron/glia cultures Irom rat mesen-
cephalon show enhanced neurodegeneration in the presence oI glia.
59
A critical Iea-
ture oI the toxicity was the release oI O
2

Irom microglia. which was attenuated by
inhibitors oI NADPH oxidase.
There is also substantial evidence Ior neuroinIlammation playing a role in pro-
gressive neurodegeneration Iollowing administration oI 6-hydroxydopamine.
60
Studies using PET and PK1195 (a ligand Ior activated microglia) showed that an in-
crease in activated microglia occurs coincident with loss oI dopaminergic neurons.
61
Minocycline was reported to inhibit microglial activation and to protect nigral cells
aIter 6-OHDA iniection into mouse striatum.
62
Chronic inIusion oI lipopolysaccha-
ride Ior 2 weeks into the substantia nigra results in rapid activation oI microglia. Iol-
lowed by a delayed and gradual loss oI nigral neurons beginning at 46 weeks and
reaching 70 at 10 weeks.
63
ANTIINFLAMMATORY AGENTS FOR NEUROPROTECTION
A number oI antiinIlammatory agents have shown promise Ior the amelioration
oI degeneration oI dopaminergic neurons induced by MPTP. Approaches have uti-
lized both transgenic mice as well as pharmacologic agents. MPTP-induced activa-
tion oI microglia is associated with an upregulation oI iNOS and 3-nitrotyrosine
Iormation.
64
Studies in iNOS-deIicient mice show that degeneration oI dopaminer-
gic neurons is signiIicantly attenuated; but there is no protection oI dopaminergic
terminals.
64.65
However. there have been no reports oI the eIIects oI pharmacologic
inhibition oI iNOS on MPTP neurotoxicity. Another inIlammatory pathway impli-
cated in neurodegeneration is cyclooxygenase 2 (COX-2). COX-2 is expressed and
regulated in glial cells by cytokines and lipopolysaccharide.
66
However. in excito-
toxic lesions. synaptic excitation. apoptotic neuronal death. and cerebral ischemia
124 ANNALS NEW YORK ACADEMY OF SCIENCES
COX-2 is expressed primarily in neurons.
6770
Cyclooxygenase catalyzes the Iorma-
tion oI prostaglandins. which involves reduction oI the hydroperoxide resulting in
the generation oI Iree radicals. Superoxide radicals. a COX-2 reaction product. can
react with NO

to Iorm the strong oxidant peroxynitrite. A recent study showed that

overexpression oI COX-2 can activate cell cycle genes. which may contribute to ap-
optotic cell death.
71
Mice overexpressing COX-2 show increased vulnerability to
kainic acid and have elevated lipid peroxidation. COX-2 inhibitors inhibit lipo-
polysaccharide-induced increases in TNE-. which can stimulate astrocytic
glutamate release.
72.73
Neuronal death mediated by N-methyl-D-aspartate (NMDA)
is diminished in a dose-dependent manner by COX-2 inhibitors in primary neuronal
cultures.
74
Transgenic mice that are deIicient in COX-2 show reduced susceptibility
to Iocal ischemia and to NMDA neurotoxicity.
75
The COX-2 inhibitor meloxicam
signiIicantly attenuated both the reduction oI striatal dopamine levels and the deple-
tion oI substantia nigra dopaminergic neurons.
76
In COX-2deIicient mice. however.
there was protection against loss oI dopaminergic neurons in the substantia nigra. but
no protective eIIect against lowering oI striatal dopamine levels.
77
Another promising approach is to use thalidomide. Thalidomide reduces COX-2
levels and also inhibits TNE production.
78-80
Mice deIicient in both TNE recep-
tors are resistant to MPTP toxicity.
81
Thalidomide has been reported to attenuate
MPTP-induced decreases in striatal dopamine levels. but the numbers oI dopamin-
ergic neurons in the substantia nigra were not examined.
82
Another approach is to
use phosphodiesterase IV inhibitors. which inhibit the breakdown oI cAMP. Phos-
phodiesterase IV is selectively localized to immune cells and the central nervous sys-
tem. Type IV phosphodiesterase inhibitors are eIIective against inIlammatory
lesions in the central nervous system. such as those produced in experimental auto-
immune encephalomyelitis.
83.84
Rolipram inhibits lipopolysaccharide-induced in-
creases in plasma levels oI TNE in rats.
85
Phosphodiesterase IV inhibitors are also
neuroprotective against MPTP neurotoxicity.
86
In these studies. several phosphodi-
esterase IV inhibitors produced neuroprotection against both MPTP-induced deple-
tion oI striatal dopamine and as loss oI substantia nigra neurons.
Last. peroxisome proliIeratoractivated receptor (PPAR) agonists show good
antiinIlammatory eIIects. A broad range oI proinIlammatory genes are transcription-
ally regulated by the nuclear hormone receptor PPAR-. PPARs are a subIamily oI
ligand-activated transcription Iactors structurally related to the steroid and retinoic
acid receptor Iamilies.
87
The PPAR- isoIorm is expressed in adipocytes. where it
regulates lipid metabolism and reduces insulin resistance. Newly developed drugs oI
the thiazolidinedione class target the PPAR- receptor and reduce plasma glucose in
type 2 diabetics. although they do not alter glucose levels in nondiabetic animals and
humans.
88
PPAR- agonists suppress the expression oI the proinIlammatory cytok-
ines IL-1. TNE. and IL-6.
89. 90
as well as oI MMP-9 and iNOS.
9193
The PPAR-
agonist troglitazone reduces cell death in cultured cerebellar neurons aIter
glutamate exposure.
94
The PPAR- agonist pioglitazone reduced the severity and in-
cidence oI experimental allergic encephalomyelitis.
95
Pioglitazone was recently
shown to exert neuroprotective eIIects against MPTP-induced degeneration oI sub-
stantia nigra neurons; however. it did not protect against striatal dopamine depletion.
96
Lipopolysaccharide induces iNOS expression and release oI nitric oxide in microglia.
and COX-2 expression in neurons.
97
PPAR- agonists inhibit lipopolysaccharide-
induced cell death as well as increases in nitric oxide and COX-2 activity.
97
125 BEAL: MITOCHONDRIA. OXIDATIVE DAMAGE. AND INFLAMMATION
COENZYME Q
10
AND CREATINE AS POTENTIAL THERAPIES FOR PD
Coenzyme Q
10
. which is also known as ubiquinone. is an essential coIactor oI the
electron transport chain. where it accepts electrons Irom complexes 1 and 2.
98
Co-
enzyme Q
10
also serves as an important antioxidant in both mitochondria and lipid
membranes.
99.100
It is a lipid-soluble compound composed oI redox-active quinone
as well as a hydrophobic tail. It is soluble and mobile in the hydrophobic core oI the
phospholipid bilayer oI the inner membrane oI the mitochondria.
Considerable interest has been shown in the potential utility oI coenzyme Q
10
Ior
treatment oI mitochondrial disorders.
101
There have been several reports oI beneIi-
cial eIIects in patients with mitochondrial deIects; and we have demonstrated that
coenzyme Q
10
increased brain mitochondrial coenzyme Q
10
concentrations in ma-
ture and older animals.
102
It also decreased -tocopherol concentrations in mito-
chondria consistent with a sparing eIIect. We Iound that coenzyme Q
10
exerts
neuroprotective eIIects against the mitochondrial toxins malonate and 3-nitropropi-
onic acid.
103.104
It also showed neuroprotective eIIects against MPTP toxicity in old-
er mice.
105
We Iound that coenzyme Q
10
levels were signiIicantly reduced in
mitochondria Irom PD patients.
106
We also demonstrated that coenzyme Q
10
supple-
mentation signiIicantly increased plasma levels in PD patients. Recently a small
phase II clinical trial was undertaken.
107
Patients were assigned to placebo or coen-
zyme Q
10
at 300. 600. or 1200 mg daily. They were evaluated using the UniIied Par-
kinson`s Disease Rating Scale at screening. baseline. and up to 16 months. In this
pilot trial the administration oI coenzyme Q
10
showed a signiIicant slowing oI dis-
ease progression.
We also investigated whether creatine can exert neuroprotective eIIects. The cre-
atine kinase system can shuttle high-energy phosphates such as phosphocreatine
(PCr) to sites oI energy usage in the cell. such as ion pumps in organelles. the plasma
membranes. and the endoplasmic reticulum.
108.109
Creatine may exert neuroprotec-
tive eIIects by increasing PCr levels and thereby providing extra energy Ior ion ho-
meostasis and the Iunctional and structural integrity oI mitochondria. Creatine exerts
neuroprotective eIIects in vitro as well as in vivo. Creatine protects against both
glutamate and -amyloid toxicity in rat hippocampal neurons.
110.111
Creatine also
protects against 3-nitropropionic acid and glutamate neurotoxicity in rat hippocam-
pal and striatal neurons.
112
We Iound that creatine protects against both malonate
and 3-nitropropionic acid striatal neurotoxicity in vivo;
102
and against MPTP toxic-
ity in a dose-dependent manner.
111
Creatine administration also exerts neuroprotec-
tive eIIects in transgenic mouse models oI both amyotrophic lateral sclerosis and
Huntington`s disease.
113115
We recently demonstrated that creatine can exert addi-
tive neuroprotective eIIects when administered in combination with COX-2 inhibi-
tors against MPTP neurotoxicity (unpublished data).
CONCLUSIONS
The pathogenesis oI PD is unknown. but a substantial body oI evidence impli-
cates both mitochondrial dysIunction. oxidative damage. and inIlammation in dis-
ease pathogenesis. Agents targeting both mitochondrial dysIunction and
inIlammation are eIIective in attenuating damage to dopaminergic neurons in the
126 ANNALS NEW YORK ACADEMY OF SCIENCES
MPTP model oI PD. One oI these agents. coenzyme Q
10
. has shown initial promise
as an agent to slow the progression oI PD. Clinical trials oI other agents to slow the
progress oI PD are urgently needed. We suspect that combinations oI agents target-
ing diIIerent disease mechanisms may produce additive or synergistic neuroprotec-
tive eIIects that will lead to eIIective therapies to slow or halt PD.
ACKNOWLEDGMENTS
I wish to thank Sharon Melanson Ior secretarial assistance. This work was sup-
ported by grants Irom The Department oI DeIense and the Parkinson`s Disease
Eoundation.
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