Here comes the therapeutic target for trigeminal neuralgia

The primary symptom of trigeminal neuralgia, the most prevalent neurological condition of the brain, is recurrent, severe pain that comes and goes on one side of the face. Patients' daily activities, such as eating, drinking, talking, washing face, and brushing teeth, can cause severe pain. In some cases, even the slightest breeze can be intolerably painful. Trigeminal neuralgia is consequently referred to as the "number one pain in the world," and some sufferers may even decide to end their lives in an effort to relieve their suffering. People who endure the pain also tend to suffer from low quality of life, anxiety, and depression.

To date, the molecular mechanisms underlying the pathophysiology of trigeminal neuralgia are still poorly understood, which has led to a serious lack of therapeutic agents. Only carbamazepine has been FDA-approved for the treatment of trigeminal neuralgia, which is primarily used for seizure control and suppresses neural activity broadly and non-specifically, but it also has serious side effects. In addition, some patients also opt for surgical treatment. However, long-term follow-up has revealed that many patients with trigeminal neuralgia experience pain recurrence even after maximum pharmacological and surgical treatment.

August 3, 2022—Johns Hopkins researchers published a research paper in Science Advances titled "Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain".

The study shows that reactive oxygen species (ROS) accumulate in the cerebrospinal fluid of patients with trigeminal neuralgia and that they directly activate the pain ion channel TRPA1, which further identifies the NRF2 transcriptional network as a potential therapeutic target. Activation of the NRF2 antioxidant transcriptional network has the same analgesic effect as inhibition of TRPA1. The study used a transcriptome-based guided drug discovery strategy to identify two NRF2 network modulators as potential therapeutic approaches. One of the drug candidates, exemestane, has been approved by the FDA for the treatment of breast cancer, so this may be a promising alternative therapy for trigeminal neuralgia.

In this most recent research, the team discovered proof that elevated oxidative stress triggers trigeminal neuropathic pain. Reactive oxygen species (ROS), some of which directly activate the pain ion channel TRPA1, build up in mouse models of trigeminal neuralgia just like they do in human patients.

The team further found that inhibition of TRPA1, either pharmacologically or at the genetic level, could relieve pain. However, attempts to directly inhibit TRPA1 have been difficult to translate clinically, and previous studies have failed.

In this study, the team discovered that activating the NRF2 antioxidant transcriptional network reversed underlying oxidative stress and had an analgesic effect that was just as potent as direct TRPA1 inhibition.

Exemestane and JQ-1, two NRF2 network modulators, of which Exemestane has been approved by the FDA for the treatment of estrogen receptor-positive breast cancer, were found by the team using a transcriptome-based guided drug discovery strategy. This means that the drug is easily adaptable for the treatment of trigeminal neuralgia and may represent a promising alternative therapy for the management of trigeminal neuropathic pain.

Overall, the study identifies the NRF2 transcriptional network as a potential therapeutic target for trigeminal neuralgia by combining a clinical, molecular, and computational approach.

A fan of biotechnology who likes to post articles in relevant fields regularly