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Research from the University of Wisconsin-Madison reveals that tofacitinib, a drug commonly used to treat arthritis, can effectively halt seizures related to epilepsy in mouse models. This groundbreaking study shows that the medication not only suppresses brain-damaging seizures but also appears to restore short-term and working memory, while reducing inflammation in the brain associated with epilepsy. If confirmed in human trials, this could mark a significant advancement in epilepsy treatment, potentially offering long-lasting relief even after discontinuation of the drug.
“It comprehensively addresses our objectives for a new treatment,” notes Avtar Roopra, a neuroscience professor at the UW-Madison School of Medicine and Public Health, who is the senior author of the study published in Science Translational Medicine last week.
More than 50 million individuals globally are affected by epilepsy, making it one of the most prevalent neurological disorders. The condition can arise from various causes, most notably after brain injuries such as concussions or strokes.
Following such injuries, the affected brain can lose its ability to self-regulate its electrical activity, leading to episodes of uncontrolled neuron firing. “The neural circuits become overly excited, leading to seizures that can result in significant cellular damage,” explains Roopra. These episodes can occur unpredictably and recur indefinitely. While some medications manage seizure symptoms or mitigate inflammation and memory issues, around one-third of epilepsy patients do not respond to existing treatments. In severe cases, surgical intervention to remove brain tissue responsible for the seizures has been the main course of action.
In their quest to explore tofacitinib’s prospects for treating epilepsy, Hoffman and her colleagues employed advanced data science techniques to analyze thousands of genes expressed in the brains of both epileptic and non-epileptic mice. They identified a protein known as STAT3, which is central to the JAK signaling pathway, as significantly active in the brains of the mice that experienced seizures.
Hoffman adds, “Analyzing brain tissue from human patients with epilepsy revealed similar activation of STAT3.” This discovery linked the mechanisms in mice to patterns seen in humans.
During her research, Hoffman discovered a prior study involving thousands of arthritis patients in Taiwan, which coincidentally highlighted a surprising trend: epilepsy was notably more prevalent in those with rheumatoid arthritis. However, it was less common among arthritis patients who had been on anti-inflammatory medications for over five years.
“Patients with prolonged rheumatoid arthritis are often prescribed JAK inhibitors, drugs targeting the same signaling pathways implicated in our epilepsy research,” Hoffman explains.
The UW research team then administered tofacitinib to their mice following a treatment that induced brain damage, which typically leads to seizures. Initially, there was no impact; the mice still developed epilepsy. However, they recognized that epilepsy often does not manifest immediately following brain damage—it can take years. The lab mice usually experience a period of stability before seizures begin anew. This insight prompted them to test tofacitinib right at the onset of seizure activity.
“I was skeptical about its efficacy at first,” admits Hoffman. “But it seems that initial brain damage sensitizes this pathway, causing problems down the line. Our intervention at this critical point led to remarkable results.”
The findings exceeded expectations. Following treatment, the mice remained seizure-free for up to two months. Collaborators at other institutions including Tufts and Emory Universities replicated these success stories in their respective mouse models, which reflected slight variations of epilepsy.
Roopra’s lab has since observed mice that managed to stay seizure-free for four to five months post-treatment, and these mice showed recovery of their cognitive functions.
“Initially, these mice experienced frequent seizures and struggled with tasks such as navigating mazes. Their behavior was significantly impaired—similar to humans suffering from chronic epilepsy who deal with learning deficits and daily challenges,” Roopra elaborates. “Post-treatment, we’ve been able to eliminate the seizures while also enhancing cognitive function. This suggests that the drug might be impacting multiple neurological systems simultaneously, unlike other medications which typically focus on individual aspects.”
Given tofacitinib’s established safety record for human use in treating arthritis, the transition from animal studies to human clinical trials may be expedited compared to completely new drugs. Funding for Roopra’s epilepsy research has consistently come from the National Institutes of Health, along with early support from local organizations such as Lily’s Fund for Epilepsy Research and CURE Epilepsy.
Currently, the pathway to initiating human trials is contingent on further reviews from the NIH, which has paused new studies amid structural changes at the agency.
For the time being, the research team is intensely focused on identifying the specific brain cells that exhibit normalized behavior due to tofacitinib and continuing their studies to cover a broader range of epilepsy types. Additionally, Hoffman and Roopra have sought to patent their findings related to the drug’s application in epilepsy.
This research received partial funding from multiple grants from the National Institutes of Health.
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