A recent study offers new hope for treating frontotemporal lobar degeneration (FTLD), a severe brain disease that affects memory, behavior, and language. Researchers have discovered that gabapentin—a widely used drug for epilepsy and nerve pain—might protect brain cells in patients with FTLD by targeting a key process involved in the disease.
FTLD is a type of dementia caused by damage to the frontal and temporal parts of the brain. One of its subtypes, known as FTLD-tau, is marked by the buildup of toxic forms of a protein called Tau inside brain cells.
This buildup leads to the death of neurons, resulting in major changes in a person’s behavior, personality, and ability to speak. Right now, there are no treatments that can stop or slow this process.
The study, published in the European Journal of Cell Biology, was led by Dr. Inoue and his team. They used advanced lab techniques to create brain cells, called cortical neurons, from stem cells taken from FTLD patients.
These lab-grown neurons, known as FTLD neurons, showed signs of overactivity (called hyperexcitability) and problems with handling calcium, a mineral that helps control brain signals. These issues appeared to be linked to Tau protein damage and cell death.
To see if calming down the overactive neurons could help, the researchers tested several anti-epileptic drugs that reduce nerve activity. Gabapentin stood out. It not only protected the neurons from damage but also reduced the amount of harmful misfolded Tau proteins.
Interestingly, it did not reduce the total amount of Tau, suggesting it worked by stopping the Tau from turning toxic.
Gabapentin and similar drugs (called gabapentinoids) work by blocking certain calcium channel helper proteins in nerve cells, especially ones called α2δ-1 and α2δ-2. These proteins help control how calcium enters the cells, which affects how excitable they are.
To find out which of these two proteins gabapentin targets in FTLD, the scientists turned off the genes responsible for making them in their lab-grown FTLD neurons. Removing the gene for α2δ-1 (called CACNA2D1) didn’t seem to help.
But when they removed the gene for α2δ-2 (CACNA2D2), either by itself or along with the other, the neurons were protected: they didn’t die as quickly, and they had fewer toxic Tau clumps.
To better understand how blocking α2δ-2 helps, the team also created 3D brain-like structures called cerebral organoids using stem cells from both healthy people and FTLD patients. In some of these organoids, they also removed the CACNA2D2 gene.
Using single-cell RNA sequencing, they discovered several changes in gene activity related to FTLD that were reversed when α2δ-2 was blocked, though more research is needed to fully understand these changes.
The key takeaway from this research is that α2δ-2 is a promising target for treating FTLD-tau. And the best part? Several approved medications—including gabapentin, pregabalin, and mirogabalin—already work by blocking α2δ-2. This opens the door to faster development of treatments, since these drugs are already on the market for other conditions.
FTLD currently has no cure and causes severe emotional, behavioral, and cognitive problems. But thanks to this breakthrough, there may soon be a drug-based approach that goes beyond just managing symptoms and targets the root of the disease.
Based on these promising results, Dr. Inoue’s team is now preparing for a clinical trial to test gabapentinoids in patients with FTLD. If successful, it could mark the beginning of a new chapter in dementia treatment.
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For more information about brain health, please see recent studies about common exercises that could protect against cognitive decline, and results showing that this MIND diet may protect your cognitive function, prevent dementia.
The research findings can be found in the European Journal of Cell Biology.
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