Eliminating aged brain cells reduced seizure activity and protected cognitive function in epilepsy-affected mice.
Temporal lobe epilepsy is marked by recurrent seizures and cognitive impairment, and is now linked to accelerated aging of brain cells.
New findings show that selectively eliminating these aging cells, using either genetic or drug-based approaches, can reduce seizure frequency, improve memory, and prevent epilepsy development in some mice, highlighting a promising therapeutic direction.(1✔ ✔Trusted Source
Clearing the Brain of Aging Cells Could Aid Epilepsy and Reduce Seizures
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Senotherapy to Remove Aging Cells
The National Institutes of Health (NIH)-funded study appears in the journal Annals of Neurology.
“A third of individuals living with epilepsy don’t achieve freedom from seizures with current medications.” says senior author Patrick A. Forcelli, Ph.D., professor and chair of Georgetown School of Medicine’s Department of Pharmacology & Physiology and the Jerome H. Fleisch & Marlene L. Cohen Endowed Professor of Pharmacology. “Our hope is that senotherapy, which involves using medications to remove senescent, or aging cells, could potentially minimize the need for surgery and/or improve outcomes after surgery.”
Understanding Temporal Lobe Epilepsy and Treatment Gaps
Temporal lobe epilepsy (TLE) can be caused by several factors, including brain injuries from trauma or stroke, infections like meningitis, brain tumors, blood vessel malformations and genetic syndromes. TLE is the most common type of drug-resistant epilepsy, affecting about 40% of patients with the condition.
In one part of their study, the investigators looked at donated brain tissue in the lab that had been surgically removed from the temporal lobes of people.
They found a five-fold elevation of senescent glia cells in human TLE cases compared to autopsy tissue from people without the disease. Glia cells support and protect neurons but do not produce electrical neuronal impulses.
Translating Findings to Animal Models
Based on their human brain tissue investigation, the researchers suspected there could be an abundance of senescent cells in a mouse model that mimics TLE. Indeed, within two weeks of the initial injury that triggered TLE in the mice, the investigators found increases in cellular markers of senescence at both gene and protein levels. Treatment to remove the aging cells in mice resulted in a 50% reduction in these senescent cells, normalized their ability to navigate mazes, reduced seizures and protected a third of animals from epilepsy altogether.
Drug Strategy and Clinical Relevance
The drug treatment tested in the mice was a combination of dasatinib, a targeted therapy used to treat leukemia, and quercetin, a plant flavonoid found in fruits, vegetables, tea, and wine that can act as a powerful antioxidant and have anti-inflammatory properties.
The combination of the two drugs has been widely used to kill senescent cells in a range of diseases modeled in animal studies. The researchers also chose these drugs because they are already in early phase clinical trials for other diseases. Forcelli also notes that because dasatinib is FDA approved as a treatment for a form of leukemia, investigators already know its safety profile, meaning a potentially faster route to clinical trials in people.
Broader Implications and Next Steps
The study’s first co-authors Tahiyana Khan, Ph.D. and David J. McFall, both trainees in Forcelli’s lab, say that senescence of glial cells has recently been implicated in aging and neurodegenerative diseases such as Alzheimer’s disease, another area they are exploring.
“We have ongoing studies using other repurposed drugs that can impact senescence as well as studies in other rodent models of epilepsy. We would like to understand the critical windows for intervention in epilepsy, and the hope is that these studies will lead to clinically useful treatments,” says Forcelli.
Reference:
- Clearing the Brain of Aging Cells Could Aid Epilepsy and Reduce Seizures – (https://medicine.georgetown.edu/news-releases/clearing-the-brain-of-aging-cells-could-aid-epilepsy-and-reduce-seizures/)
Source-Georgetown University Medical Center