Arthritis Drug Inspires Promising Epilepsy Treatment
An arthritis drug has been shown to prevent brain-damaging seizures in mouse models of epilepsy, restoring memory.
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While some drug treatments for epilepsy have been successful in addressing seizure symptoms, there are currently no US Food and Drug Administration (FDA)-approved therapies that can eliminate spontaneous seizures and reverse cognitive deficits.
Now, researchers from the University of Wisconsin–Madison may have found a solution in the form of an existing arthritis drug. Testing the drug, called tofacitinib, in mouse models of epilepsy, they found it suppressed seizures and rescued deficits in spatial memory.
The mice stayed seizure-free for two months post-treatment. If the drug proves viable in humans, it could represent a first-of-its-kind therapeutic for providing permanent seizure suppression.
The results of the study are published in the journal Science Translational Medicine.
A signaling pathway in overdrive
Around 50 million people worldwide have epilepsy, which is one of the most prevalent neurological diseases globally. The condition has a variety of causes including gene mutations and injury to the brain because of stroke. In acquired epilepsies, a common characteristic is the emergence of spontaneous, recurring seizures.
These seizures occur often randomly and for the rest of the individual's lifespan. While there are existing medicines that can limit or eliminate seizures in some individuals, studies have shown that currently available anti-epileptic drugs are effective in only two-thirds of patients. There are no existing FDA-approved disease-modifying agents for epilepsy.
“Roughly one-third of individuals with epilepsy continue to experience seizures despite trying multiple drug regimens – a condition known as drug-resistant epilepsy,” Avtar Roopra, a neuroscience professor at the University of Wisconsin–Madison, told Technology Networks. “Even when medications are effective in suppressing seizures, they do not address the underlying disease process. These drugs are symptomatic treatments, not curative ones. If a person stops taking them, the seizures often return, and there is no impact on the root causes such as neuroinflammation, synaptic dysfunction or abnormal network activity.”
“Moreover, existing treatments do little to improve the common comorbidities of epilepsy, such as cognitive impairment, mood disorders and sleep disturbances. In some cases, these problems are exacerbated by the very medications intended to treat seizures,” Roopra continued.
To identify possible disease pathways, researchers applied data science approaches to whole tissue and single-nucleus transcriptomic data collected from mouse models of epilepsy. Analyzing how thousands of genes were expressed in these cells revealed a protein called STAT3 at the center of activity in the seizure-affected mouse brains.
Signal transducer and activator of transcription 3 (STAT3)
STAT3 is a transcription factor and intracellular signaling protein that plays a key role in many cellular processes, such as cell growth. It is a vital component of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, which induces the expression of various critical mediators of inflammation.
Performing similar analyses on publicly available transcriptomic data from brain tissue removed from human epilepsy patients confirmed a pattern of rapid and transient induction of the JAK/STAT pathway within days of epileptogenic insult. This is followed by subsequent activation of the pathway weeks to months later with the onset of spontaneous seizures.
“We discovered a pathological pathway that is rapidly induced with an initiating trauma during epileptogenesis, returns to basal levels over a period of days, but then re-ignites weeks later in the chronic phase to open a second, more clinically relevant window of intervention for disease modification,” stated Roopra.
Tofacitinib reduces seizures and restores memory
To identify potential drugs that could suppress JAK/STAT activation and reignition, the researchers turned their attention to existing anti-inflammatory drugs commonly used to treat arthritis. “If you’ve had rheumatoid arthritis for that long, your doctor has probably put you on what’s called a JAK-inhibitor, a drug that’s targeting this signaling pathway we’re thinking is really important in epilepsy,” Olivia Hoffman, lead author of the study and a postdoctoral researcher at the University of Wisconsin–Madison said in a press release.
Targeting the first wave of JAK/STAT activation with tofacitinib in mice administered a brain-damaging drug did not prevent seizures. The mice still developed epilepsy.
Instead, the researchers looked to see if tofacitinib would influence the reignition of seizures following an initial brain-damaging event. Tofacitinib was given to 25 mice in 10 doses during weeks 11–12 post-status epilepticus and recorded daily for seizures. Of the mice, 80% responded to treatment, which was defined as exhibiting a seizure frequency and burden reduction of at least 50%.
Status epilepticus
Status epilepticus is defined as a seizure with five minutes or more of continuous clinical and/or electrographic seizure activity or recurrent seizure activity without recovery.
“Drug responders exhibited an 8-fold reduction in seizure frequency and a 12-fold reduction in seizure burden,” the researchers stated.
To assess the durability of tofacitinib, the researchers withdrew the drug from responders and continued monitoring seizure frequency and burden. Two months after the last dose, they observed a continued reduction in seizure frequency and burden.
Not only was tofacitinib effective in reducing seizure frequency, but it also improved epilepsy-associated deficits in spatial memory in the mice. Cognitive decline is a leading comorbidity of epilepsy and to the researcher's knowledge tofacitinib “is the first pharmacological agent that may be administered transiently after the onset of spontaneous seizures to rescue spatial memory for weeks after drug withdrawal.”
“Most excitingly, it [tofacitinib] is robustly disease modifying: The protective effects of the drug endure long after the drug has been withdrawn,” explained Roopra.
Discussing the next steps for this research, Roopra said, “The first [step] is to understand how tofacitinib can have such long-lasting impact on the epileptic brain so long after drug withdrawal: a result which holds up across animal models and laboratories and came as an utter surprise to us. Understanding that will open up a whole new field in epilepsy research where for the first time in history we can ask ‘What molecular and cellular targets allow for long-term disease control?’.”
In addition to identifying which types of brain cells are shifted back to healthy behavior by tofacitinib, the researchers hope to continue to push for the clinical use of tofacitinib. “Ideally, this will be a clinical trial where patients with poorly managed adult-onset epilepsy will have Tofacitinib added to their drug regimen,” Roopra said. “Broadly speaking, the outcome measure will be whether seizures come under better control leading to reduced dosing of their conventional anti-seizure medications. Short of a trial, we hope that our manuscript will spur clinicians to prescribe Tofacitinib off-label and publish case reports. This will hopefully increase interest in a full trial later.”
As an already FDA-approved medicine for arthritis, the path from animal studies to human trials for tofacitinib may be shorter than it would be for a new drug.
Reference: Hoffman OR, Koehler JL, Espina JEC, et al. Disease modification upon 2 weeks of tofacitinib treatment in a mouse model of chronic epilepsy. Sci Transl Med. 17(790):eadt0527. doi: 10.1126/scitranslmed.adt0527
About the interviewee
Avtar Roopra is a professor of neuroscience at the University of Wisconsin–Madison. Roopra holds a PhD in pharmacology from University College London. His lab aims to further the search for treatments and cures for epilepsy and cancer using state-of-the-art bioinformatics, looking at whole genome expression profiles in cell lines, human cancer and epilepsy patient data.
