Patients with trigeminal neuralgia often describe their pain as a searing sensation akin to an electric shock in their faces. The agony primarily affects the cheek, jaw, and teeth, but given the extensive reach of the trigeminal nerve, it can radiate to the eyes and forehead. Stanford University School of Medicine neurosurgeon Michael Lim has witnessed this pain in his patients over the course of his clinical practice. “I became very interested in learning about trigeminal neuralgia because of how the disease affects people,” he said. Surgery can offer a cure for many, yet there are still others who continue to suffer. “I wanted to help them.” 

Besides surgery, there is only one FDA-approved drug for trigeminal pain, the anticonvulsant carbamazepine, which carries considerable side effects. In the quest for alternative therapies, Lim and his colleagues made a significant breakthrough. They discovered that the accumulation of reactive oxygen species (ROS) in the nerves of mice sets off a signaling pathway responsible for this pain, and they identified an approved drug that could be repurposed to treat it. Their findings, published in Science Advances, suggest a new therapeutic avenue for potentially treating this condition (1). 

The study provides insight into a new mechanism involved in trigeminal neuralgia and bridges the path towards potential clinical translation, said Michael Fischer, a pain researcher at the Medical University of Vienna who did not participate in this study. “It’s very important because the tools we have [for treating patients] are poor.” 

Exemestane is the single most promising substance in the paper. This is a classical case of drug repurposing. 
- Michael Fischer, Medical University of Vienna

For Lim and his team, the study started with the idea of peering into the cerebrospinal fluid (CSF) of patients with trigeminal neuralgia after they underwent surgery. This colorless fluid composed of water, proteins, neurotransmitters, and other molecules carries valuable information about the central nervous system. “I noticed that the CSF was something that we always drained and didn’t save, and I thought that there was a tremendous opportunity to learn from patients by studying their CSF,” said Lim. 

His team then looked for signs of oxidative stress in this fluid, since ROS may contribute to neuralgia (2). They found that patients with trigeminal pain had significantly higher ROS levels than patients without this condition. 

These findings set the stage for investigating the phenomenon in a mouse model with a constricted trigeminal nerve. They detected that ROS activate transient receptor potential ankyrin 1 (TRPA1), a pain-transducing channel. 

While previous work on animal models suggested that inhibiting TRPA1 blunts pain, clinical translation of that idea has failed (3,4). “These inhibitors have not kept up to their promise in clinical studies,” said Fischer.

Instead of targeting TRPA1, Lim and his colleagues focused on activating the cell defense mechanism against oxidative stress orchestrated by the nuclear factor erythroid 2-related factor 2 (NRF2) that regulates a network of antioxidant genes. Targeting this network in the mouse model of trigeminal neuralgia reduced sensitivity to touch and cold in mice. This motivated Lim and his colleagues to search for pharmaceutical candidates capable of modulating this network in humans.

To achieve this, the team first used an in silico approach, in which they tested how different compounds mimic the induction of the NRF2 network gene expression. Among the seven leading candidates, exemestane, an FDA-approved breast cancer drug, stood out. 

Administering exemestane to mice increased NRF2 expression in their trigeminal ganglion neurons and also decreased their sensitivities to tactile and cold stimuli. Notably, exemestane’s analgesic effect did not work on mice lacking NRF2, confirming that this oxidative master regulator mediates the drug’s efficacy.

“Exemestane is the single most promising substance in the paper,” said Fischer. “This is a classical case of drug repurposing.” Fischer is interested in seeing how effectively exemestane treats trigeminal neuropathic pain in a clinical trial. Lim does not yet have a defined plan for a clinical trial, but he and his colleagues are contemplating it as the next stride towards translation. 

“We may have found another pathway that causes pain in trigeminal neuralgic patients, and we have the opportunity to develop new therapeutics around that to help our patients,” Lim said. “We’re excited for that opportunity.”

References

1. Vasavda, C. et al. Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain. Sci Adv  8, eabo5633 (2022).
2. Yowtak, J. et al. Reactive oxygen species contribute to neuropathic pain by reducing spinal GABA release. Pain  152, 844-852. 
3. Trevisan, G. et al. TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress. Brain  139, 1361-77 (2016). 
4. Schwarz, M.G. et al. TRPA1 and TRPV1 Antagonists Do Not Inhibit Human Acidosis-Induced Pain. J Pain  18, 526–534 (2017).