| Autor: |
Cronin, Shane J. F., Rao, Shuan, Tejada, Miguel A., Turnes, Bruna Lenfers, Licht-Mayer, Simon, Omura, Takao, Brenneis, Christian, Jacobs, Emily, Barrett, Lee, Latremoliere, Alban, Andrews, Nick, Channon, Keith M., Latini, Alexandra, Arvanites, Anthony C., Davidow, Lance S., Costigan, Michael, Rubin, Lee L., Penninger, Josef M., Woolf, Clifford J. |
| Předmět: |
|
| Zdroj: |
Science Translational Medicine; 8/31/2022, Vol. 14 Issue 660, p1-14, 14p |
| Abstrakt: |
Increased tetrahydrobiopterin (BH4) generated in injured sensory neurons contributes to increased pain sensitivity and its persistence. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the de novo BH4 synthetic pathway, and human single-nucleotide polymorphism studies, together with mouse genetic modeling, have demonstrated that decreased GCH1 leads to both reduced BH4 and pain. However, little is known about the regulation of Gch1 expression upon nerve injury and whether this could be modulated as an analgesic therapeutic intervention. We performed a phenotypic screen using about 1000 bioactive compounds, many of which are target-annotated FDA-approved drugs, for their effect on regulating Gch1 expression in rodent injured dorsal root ganglion neurons. From this approach, we uncovered relevant pathways that regulate Gch1 expression in sensory neurons. We report that EGFR/KRAS signaling triggers increased Gch1 expression and contributes to neuropathic pain; conversely, inhibiting EGFR suppressed GCH1 and BH4 and exerted analgesic effects, suggesting a molecular link between EGFR/KRAS and pain perception. We also show that GCH1/BH4 acts downstream of KRAS to drive lung cancer, identifying a potentially druggable pathway. Our screen shows that pharmacologic modulation of GCH1 expression and BH4 could be used to develop pharmacological treatments to alleviate pain and identified a critical role for EGFR-regulated GCH1/BH4 expression in neuropathic pain and cancer in rodents. A shared target between cancer and pain: Neuropathic pain is a chronic condition for which effective safe treatments are lacking. Polymorphisms in the GTP cyclohydrolase 1 (GCH1) gene have been associated with chronic pain severity; and modulation of the GCH1/BH4 pathway has been shown to affect neuropathic pain. Here, Cronin et al. screened over a thousand annotated and FDA-approved compounds and showed that the antipsychotic fluphenazine hydrochloride reduced GCH1 expression and had analgesic effects in a neuropathic pain model in rodents. Among the hits, EGFR/KRAS pathway modulators also affected GCH1 expression, and the authors identified a common signaling, downstream KRAS, involving GCH1, that affects chronic pain and lung cancer development in mice. The results suggest that targeting this signaling could alleviate neuropathic pain. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
