Tuberous Sclerosis Complex (TSC), a multi-system disease, greatly impacts patients and their families due to the central
nervous system manifestations. It leads
to benign tumor growth in several organs, such as the brain, kidneys,
heart, eyes, skin, and lungs, as well as central nervous system
manifestations, such as epilepsy, autism, and cognitive impairment.
According to the National Institute of
Neurological Disorders and Stroke, most people with TSC will have
seizures at some point in their lives. There is evidence to support a
role for mTORC1 signaling in the neurological symptoms associated with
TSC, and mTOR inhibitors are being tested as potential treatments.
‘Anti-inflammatory treatment could be a potential therapy for epilepsy in Tuberous Sclerosis Complex (TSC) patients.’
However, understanding the mechanisms involved downstream of mTORC1 is
important for identifying more specific therapeutic targets to minimize
the side effects observed with mTOR inhibition. Dr. Michael Wong and his
laboratory have posited that inflammation may be playing a role in the
development of epilepsy in TSC patients.
Several studies have found that
proteins indicative of inflammation are present in brain tissue from
TSC patients. However, there are still many questions as to the
inflammatory mechanisms involved, including the role of mTORC1
With an Exploration - Hypothesis Development Award, Dr. Wong and
colleagues screened for markers of inflammation in a mouse model of TSC
that develops seizures around three to four weeks of age. They found the mRNA
levels of several inflammatory molecules to be different from control
mice at four weeks of age.
When the researchers checked at two weeks of age,
they found mRNA levels were different at this earlier time point for
three of the molecules, CCL2, IL-1beta, and CXCL10.
This suggests that
the increase in CCL2, IL-1beta, and CXCL10 precedes seizures, but the
difference in expression of the other molecules at four weeks of age may
have been due to seizure activity. The Wong lab further demonstrated
that protein levels of IL-1beta and CXCL10 were increased in the brain
tissue of the TSC mice.
The mice were treated with rapamycin, a known
inhibitor of mTORC1, or epicatechin-3-gallate (ECG), which has been
reported to inhibit production of IL-1beta and CXCL10. Both compounds
were able to reverse the increased production of the two proteins.
rapamycin has been previously studied in epilepsy, Dr. Wong focused on
ECG treatment in the mice and found that treatment did minimally correct
some of the brain tissue abnormalities seen in the mouse model, but,
more importantly, there was a small decrease in seizure development and
slightly improved survival in these mice.
Dr. Wong and his laboratory
have provided a proof-of-concept preclinical study suggesting that
anti-inflammatory treatment could be a potential therapy for epilepsy in