7.4 The NRF2 Network: A Potential Therapeutic Target for Trigeminal Neuralgia
By Risheng Xu, MD, PhD; Collin B. Kilgore, MD; and Michael Lim, MD (USA)
Editor’s Note: In 1756, Nicolaus Andre, a French physician, in his text, maladies de l’urethre et sur plusies fait, convulsitts, 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 ensure that no blood clots formed that might put pressure on the offending nerve, a hypothesized cause of nerve injury. It was not until 1962, 2 centuries later, that an oral anticonvulsant medication, carbamazepine (Tegretol), was discovered to be an effective therapy for trigeminal pain. This study, summarized so well by Xu, 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 currently compose our mainstay medical therapy.
Typical trigeminal neuralgia (TN) is thought to result from pulsatile vascular compression of the trigeminal nerve, the principal sensory nerve of the face. This compression can injure the nerve, leaving it prone to sending painful signals to the brain. The only drug approved by the U.S. Food and Drug Administration (FDA) for managing TN is carbamazepine (Tegretol), an anticonvulsant, which reduces signaling throughout the nervous system. In Australia the Pharmaceutical Benefits Scheme (PBS) also approves Pregabalin (Lyrica), Gabapentin (Neurontin) and Oxcarbazepine (Trileptal).
Patients who do not find relief from medication may undergo surgery, in which microsurgical dissection frees the nerve from the offending blood vessel. Microvascular decompression (MVD) is 90% effective, with a recurrence rate averaging 15% after 15 years.
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. People with multiple sclerosis, 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. A common consequence of nerve injury and inflammation is the generation of reactive oxygen species (ROS). ROS are unstable molecules that, when uncontrolled, can damage signaling proteins through a process of oxidative stress. Several studies have found that ROS may contribute to neuropathic pain signaling. In animal models of sciatica, it has been found that pain relief can occur by blocking ROS with antioxidants. However, the sciatic and trigeminal nerves are very different, and it was necessary to do more work to investigate what these results could mean for TN.
We first collected cerebrospinal fluid (CSF) from patients with TN when they were undergoing an MVD procedure. We discovered that most of these patients had elevated CSF markers of oxidative stress. To validate these findings, we worked with an animal model for TN and found the same elevated markers for oxidative stress as we saw in humans.
After we had established that oxidative stress occurs in TN, we wanted to know which pain pathway is activated. We hypothesized that TRPA1, a well-known pain-producing channel located in both pain- and itch-encoding sensory neurons, was activated in TN. To confirm our hypothesis that the channel was activated by ROS, 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 reduce their pain.
Now that we knew that blocking TRPA1 had pain-reducing effects, we believed that this could be a promising therapeutic strategy in managing TN. However, current approaches to block TRPA1 in diabetic neuropathy and postoperative pain have been disappointing. This pushed us to try a new approach, namely, to go back to the cause of the pain, namely, the oxidative stress, and to reduce it. For this, we turned to NRF2, a known transcription 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 the level of 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 (which are also being used for cancer, diabetes, and inflammatory bowel disease, for example), we focused our efforts on two compounds with a high likelihood of activating the NRF2 antioxidant network: exemestane and JQ-1. When we applied the two 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 the mice experienced much less pain, suggesting that 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. Figure 7-2 presents schematics illustrating the roles of TRPA1 and ROS in generating TN pain, as well as the potential effects of the candidate drugs exemestane and JQ-1 in blocking TRPA1 and reducing the level of ROS.
Figure 7-2. Schematics depicting (A) the involvement of TRPA1 and ROS in the generation of TN pain and (B) proposed mechanism by which the candidate drugs exemestane and JQ-1 could reduce TN pain by blocking TRPA1 and activating the NRF2 antioxidant network to reduce the level of ROS. Abbreviations: NRF2, nuclear factor erythroid 2-related factor 2 (used by the body to create natural antioxidants); TN, trigeminal neuralgia; TRPA1, transient receptor potential ankyrin 1 (channel located in pain-encoding sensory neurons); ROS, reactive oxygen species.
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, which mask pain by blunting nerve firing, increasing the NRF2 transcriptional network may provide a therapeutic approach that improves 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.
