The NRF2 Network: A potential therapeutic target for trigeminal neuralgia

By Collin B. Kilgore, BS, Michael Lim, MD, Risheng Xu, MD, PhD

Typical trigeminal neuralgia (TN) is thought to result from vascular compression of the trigeminal nerve, the principal sensory nerve of the face. This compression can injure the nerve, rendering it more prone to sending painful signals back to the brain. The only U.S. Food and Drug Administration (FDA)-approved drug for managing TN is carbamazepine, an anti-convulsant, which broadly reduces brain signaling. Patients who do not find relief from medication may resort to surgery, in which microsurgical dissection frees the nerve from the offending blood vessel. Microvascular decompression (MVD) is often effective, with most patients reporting sustained pain relief years after surgery. However, this procedure still leaves some patients with persistent or recurrent pain.

To date, we still have an incomplete understanding of the molecular mechanisms behind TN. Not all patients with TN have an identifiable vascular etiology causing the short circuits felt as stabbing pain. Multiple sclerosis patients, for example, most often do not have one because the disease can cause sclerotic plaques in the trigeminal white matter that jumble normal neural transmission.* Regardless, all these potential causes for TN converge upon orofacial pain. A common consequence of nerve injury and inflammation is the generation of reactive oxygen species (ROS). ROS are unstable molecules and when uncontrolled, can wreak havoc in our body’s cells by damaging signaling proteins through a process called oxidative stress. Several studies have found that ROS may contribute to neuropathic pain signaling. In animal models of sciatica, blocking ROS using antioxidants offered some pain relief. However, the sciatic and trigeminal nerves are very different, and we needed to do more work to investigate what these results could mean for TN.

To start, we collected cerebrospinal fluid (CSF) from patients with TN during their MVD procedure. We found that most of these patients had elevated markers of oxidative stress in their CSF. To validate these findings, we turned to an animal model for TN, and found the same elevated markers for oxidative stress that we saw in patients.

After establishing that oxidative stress is occurring in trigeminal neuralgia, we wanted to know which pain pathway was activated. We hypothesized that TRPA1 – a well-known pain producing channel located in both pain – and itch-encoding sensory neurons – was being activated in TN (by building on the works of others). To confirm our hypothesis that the channel was activated by ROS seen in our TN patients, we first created a line of cells containing TRPA1. We then introduced patient CSF samples from our TN patients to the TRPA1 cell line. To our surprise, we found that TRPA1 was activated by our patients’ CSF! Furthering this hypothesis, we treated our TN mice with compounds blocking TRPA1, and found that we could improve their pain.

Now that we knew that blocking TRPA1 had pain-reducing effects, we believed it could be a promising therapeutic strategy in managing TN. However, current approaches to block TRPA1 in diabetic neuropathy and postoperative pain were disappointing. This pushed us to try a new approach – to go back to the cause of the pain, which was to try and reduce the oxidative stress. For this, we turned to NRF2 – a known factor that the body uses to create natural antioxidants. As TRPA1 seems central to pain in the mouse model of TN, we hypothesized that activating the NRF2 antioxidant network may lessen pain by reducing ROS.

We now had a goal. If we could somehow find a drug that could turn on the NRF2 antioxidant network, perhaps we could have a new treatment for TN. Using complex state of the art drug screening tools (that are being used in cancer, diabetes, and inflammatory bowel disease), we identified and focused our efforts on two compounds with a high likelihood of activating the NRF2 antioxidant network – exemestane and JQ-1. When we applied both drugs to our TN cells, we observed that exemestane elevated NRF2 activity better than JQ-1, but both still reduced oxidative stress. When we applied either exemestane or JQ-1 to our TN mice, we were excited to see that mice experienced much less pain, suggesting these drugs have promising potential. We even found that applying exemestane directly to branches of the trigeminal nerve lessened pain – a technique that could potentially be harnessed by surgeons as a more targeted form of therapy.

By leveraging a combined clinical, molecular, and computational approach, our study identified the NRF2 antioxidant network as a potential therapeutic target for TN pain. Using a transcriptome-guided drug discovery approach, we identified exemestane and JQ-1 as two candidate NRF2 network modulators for treating TN pain. In contrast to current pharmacologic agents that mask pain by blunting nerve firing, increasing the NRF2 transcriptional network may be a therapeutic approach that seeks to improve pain through oxidative control. These drugs are still in the very early stages of investigation, but we hope that they represent a promising new direction for TN therapy. Should they succeed in future clinical trials, the compounds we found could represent a new line of medications that patients and providers could use in TN management.

The FPA does not endorse any product, doctor, procedure, medical institution, or its staff.

Note From Medical Editor, Dr. Jeffrey Brown:
In 1756 Nicolaus Andre, a French physician, in his book on maladies of the urethra coined the term tic douloureux when commenting on other convulsive movements he observed in the body. His proposed treatment for this “Maladie cruelle and obscure” was to gradually drip mercury water and apply cauterizing stones over the face at the site of pain. It was an innovative form of nerve ablation. The cauterizing stones were added to assure that no blood clots formed that might put pressure on the offending nerve-an hypothesized cause of nerve injury. It was not until 1962, two centuries later, that an oral anticonvulsant medication, carbamazepine (Tegretol) was discovered to be an effective therapy for trigeminal pain. The drug was approved by the FDA. Since then, no further drugs have been approved because so little effort has been made to investigate any. This study summarized so well by Risheng, Kilgore and Lim is remarkable because it represents the first modern laboratory investigative leap into the medical treatment of trigeminal neuropathic pain. Bravo to the authors for this work and cross our fingers that it will lead to an effective alternative to the seizure medications that compose our mainstay medical therapy.

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