August 15, 2006
CONTACT: Karen Kreeger
karen.kreeger@uphs.upenn.edu
Penn Researchers Find Link Between
Autism and Abnormal
Blood-Vessel Function and Oxidative Stress
New Findings Could Help Explain Pathology of Autistic Syndrome
(Philadelphia, PA) - Researchers at the University of Pennsylvania
School of Medicine discovered that children with autism showed
signs of abnormal blood-vessel function and damaging levels of oxidative
stress compared to healthy children. The children with autism possessed
levels of biochemicals that indicate the presence of constricted blood
vessels via the endothelium (the cells that line vessels) with a higher
tendency to form clots (through cells called platelets).
By exploring the relationship between oxidative stress and blood-vessel
function in autistic patients, investigators hope to find new therapeutic
options for this syndrome. The researchers, led by Domenico Pratico,
MD, Associate Professor of Pharmacology, published their findings
in the August issue of the Archives of Neurology.
According to the Autism Society of America, the reported number of autism
cases is increasing 10 to 17 percent per year in the United States. Autism,
an early onset neurological disorder, is characterized by impaired social
interactions, limited verbal and nonverbal communication, and repetitive
and restricted behavioral patterns. Patients with autism can differ in
the severity and scope of their symptoms, suggesting that multiple factors
contribute to explaining the disorder’s symptoms. Previous studies
at other institutions have shown that autistic patients have reduced cerebral
blood flow, presumably due to constricted blood vessels in the brain,
versus healthy controls.
Urinary samples of autistic children who were similar in age and healthy
controls were provided by the Pfeiffer Treatment Center, where patients
were diagnosed with autism disorder and evaluated. Patients were excluded
from analysis if they had ever received anti-oxidant treatments or medicine
with any known anti-oxidant effect; if they suffered from chronic illnesses,
such as depression, psychosis, or inflammatory disorders; and/or if they
were sick at the time of the sample collection. These strict criteria
resulted in the small sample size in this preliminary study: 26 children
with autism and 12 healthy controls.
Pratico’s team measured isoprostane, a biomarker for oxidative stress;
thromboxane, an index of platelet activation; and prostacyclin, a measure
of blood vessel activation in the samples. “This study represents
the first observation that the rates of thromboxane and prostacyclin synthesis
are both not only significantly increased in autism, but are closely correlated
with the rate of oxidative stress,” says Pratico. Compared with
controls, children with autism had significantly higher urinary levels
of isoprostane, thromboxone, and prostacyclin.
Oxidative stress is the result of an excessive formation of chemically
unstable byproducts, called free radicals, within the cell. Under normal
conditions, the cell is able to destroy the free radicals. However, when
excessive free radicals accumulate, these molecules mount an attack against
the cell in search of chemical stability.
“During oxidative stress, it is as if the free radicals have only
one leg,” explains Pratico. “They are searching for the second
leg in order to keep from falling. Unfortunately, the ability of the excessive
free radicals to reestablish their chemical equilibrium comes always with
a price for the organ -- irreversible cellular and organ damage.”
Free radicals can damage cell membranes, proteins, and genes by oxidation
-- the same chemical reaction that causes iron to rust.
Pratico and colleagues measured levels of isoprostane, the chemical byproduct
of free radicals attacking fat cells and found that patients with autism
possess nearly double the level of oxidative stress than that measured
in healthy controls.
The samples from autistic patients also revealed a biochemical imbalance
in the patients’ blood vessels, resulting in high levels of thromboxane
- an indicator of platelet activity - and prostacyclin, an indicator of
constricting endothelial cells. During normal function, thromboxane and
prostacyclin work together to maintain the integrity of vessels. In response
to different kinds of stress, platelets release thromboxane, which causes
vessels to contract. The endothelium responds to elevated levels of thromboxane
by releasing prostacyclin. This event counterbalances the effect on vessels,
inducing dilation of the vessel and, in turn, more blood flow.
Autism is a complex neurological disorder and oxidative imbalance is one
feature of the autistic syndrome. Several lines of evidence support the
hypothesis that oxidative imbalance may also play a role in this disease:
autism is characterized by an impaired anti-oxidant defense system, higher
free-radical production, and improvement of behavioral symptoms after
taking anti-oxidants.
“In general, it is known that abnormalities in blood vessels can
be clinically reflected by an abnormal blood flow,” says Pratico.
“In this regard, it is interesting that earlier neuroimaging studies
of autistic children have demonstrated a reduced amount of blood reaching
the brain. Shedding more light on the relationship of oxidative stress
and blood-vessel health to the pathology of autism could lead to improvements
in therapy.”
Study co-authors are Yuemang Yao from Penn; William J. Walsh, Pfeiffer
Treatment Center (Warrenville, IL); and Woody R. McGinnis, Oxidative Stress
in Autism Initiative (Ashland,OR). The research was supported in part
by the Pfeiffer Treatment Center.
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This release is available online at
http://www.uphs.upenn.edu/news/News_Releases/aug06/autbldvsl.htm