Prof. Dr. Vladimir Trajkovski

Autism
Spectrum Disorders (ASD) are neurodevelopmental disorders characterized
by varying deficits in social interactions, communication, and
learning, as well as stereotypic behaviors. Despite the significant
increase in ASD, there are few if any clues for its pathogenesis,
hampering early detection or treatment. Premature babies are also more
vulnerable to infections and inflammation leading to neurodevelopmental
problems and higher risk of developing ASD. Many autism "susceptibility"
genes have been identified, but "environmental" factors appear to play a
significant role. Increasing evidence suggests that there are different
ASD endophenotypes.

We review relevant
literature suggesting in utero inflammation can lead to preterm labor,
while insufficient development of the gut-blood-brain barriers could
permit exposure to potential neurotoxins. This risk apparently may
increase in parents with "allergic" or autoimmune problems during
gestation, or if they had been exposed to stressors. The presence of
circulating auto-antibodies against fetal brain proteins in mothers is
associated with higher risk of autism and suggests disruption of the
blood-brain-barrier (BBB). A number of papers have reported increased
brain expression or CSF levels of proinflammatory cytokines, especially
TNF, which is preformed in mast cells. Recent evidence also indicates
increased serum levels of the pro-inflammatory mast cell trigger
neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which
is immunogenic. Mutations of the signal-transduction molecule mTOR and
its negative regulator Pten have been linked to autism, but also with
proliferation and function of mast cells.

Premature
birth and susceptibility genes may make infants more vulnerable to
allergic, environmental, infectious, or stress-related triggers that
could stimulate mast cell release of pro-inflammatory and neurotoxic
molecules, thus contributing to brain inflammation and ASD pathogenesis,
at least in an endophenotype of ASD patients.

There
has been an impressive, little understood increase in cases of Autism
Spectrum Disorders (ASD). The lack of any distinctive pathogenetic
mechanism has hampered the development of any effective treatments.
Increasing evidence indicates oxidative stress, brain inflammation,
gastrointestinal (GI) dysfunction and allergic symptoms may be present
in ASD patients. The flavone luteolin has anti-oxidant, anti-flammatory,
anti-allergy and neuroprotective properties. Given these findings, a
dietary supplement was developed with a unique mixture of luteolin with
the related flavonoids quercetin and rutin in a liposomal formulation of
olive kernel oil (OKO), which increases their absorption. Results are
presented for children with ASD (n=37, 4-14 years old) who had not
obtained any benefit from multiple other regimens and who used this
formulation for at least 4 months. GI and allergy symptoms improved in
about 75 percent of children, eye contact and attention in 50 percent,
social interaction in 25 percent and resumption of speech in about 10
percent. There were no adverse effects. Even though these results
represent an uncontrolled open case series, they are encouraging because
they suggest good tolerability and potential effectiveness.

Autism
Spectrum Disorders (ASD) are neurodevelopmental disorders characterized
by varying degrees of dysfunctional social abilities, as well as
learning deficits, and stereotypic behaviors. Many ASD patients have
"allergic like" symptoms and respond disproportionally to stress. We had
shown that the peptide neurotensin (NT) is increased in the serum of
young autistic children and that can stimulate extracellular secretion
of mitochondrial (mt) DNA (mtDNA), which was also increasesd in the
serum of these children.

Human mast cells were
stimulated by corticotropin-releasing hormone (CRH), mt, IgE/anti-IgE
for either 24 h for measuring vascular endothelial growth factor (VEGF)
release by ELISA or 6 h for qPCR.

Here we show
that CRH augments IgE/anti-IgE-induced human mast cell release of VEGF
and that it also induces the expression of IgE receptor (FcepsilonRI) on
mast cells. Moreover, we show that sonicated mt also augment VEGF
release, and that this effect is blocked by the natural flavone
luteolin.

These results indicate that stress
and infection-mimicking extracellular mt components augment allergic
inflammation that may be involved in the early pathogenesis of ASD.
Moreover, luteolin inhibits these processes and may be helpful in the
treatment of ASD.