**Background**
Neurodegenerative diseases, such as Alzheimer’s disease (AD), are characterized by progressive neuronal loss and cognitive decline, often involving complex pathological changes including amyloid plaque accumulation. Research into therapeutic targets has highlighted the role of SARM1, a key mediator of axonal degeneration, and the TRPM8 channel, which is involved in sensory perception and pain. Additionally, the promotion of neuronal differentiation from stem cells remains a critical area of study for regenerative medicine and the treatment of traumatic brain injury or peripheral neuropathy. Understanding the Phenazopyridine biological activity in these contexts provides valuable insights into protecting neurons and alleviating associated symptoms. In this context, we will introduce a versatile inhibitor and analgesic – Phenazopyridine.
**Definition**
Phenazopyridine hydrochloride is a competitive SARM1 inhibitor with an $\text{IC}_{50}$ of 145 $\mu\text{M}$ and also serves as a TRPM8 antagonist.
**In Vitro and In Vivo Studies**
According to the Phenazopyridine technical information, this compound exhibits diverse pharmacological effects across various models. Phenazopyridine in vitro studies demonstrate that concentrations of 10-30 $\mu\text{M}$ for 12 hours increase the mRNA expression of RPS23RG1 in both human SHSY5Y and mouse N2a cells. In HEK293 cells, Phenazopyridine (5-50 $\mu\text{M}$; 2 min) inhibits menthol-induced TRPM8 responses in a dose-dependent and reversible manner with an $\text{IC}_{50}$ of 9.6 $\mu\text{M}$. Furthermore, treatment with 3 $\mu\text{M}$ Phenazopyridine hydrochloride for 6 weeks promotes neuronal differentiation in human embryonic stem cells, accelerating the emergence of early neuronal markers and forming a neural network after 10 weeks.
Phenazopyridine In Vivo research has shown significant potential in treating cognitive impairment. In APP/PS1 mice models of Alzheimer’s disease, intracerebroventricular injection (15 mg/kg; once daily for 2 weeks) significantly reduced amyloid plaques and increased protein levels of RPS23RG1, PSD-95, and phosphorylated/inactivated GSK-3$\beta$. Additionally, in Sprague-Dawley rats, a single intravenous dose (0.1-3 mg/kg) was found to inhibit mechanosensitive A$\delta$-fibers without affecting C-fibers. In conclusion, Phenazopyridine is a multi-target compound that acts as a SARM1 inhibitor and TRPM8 antagonist with potential applications in neuroprotection and analgesia.
Keywords
Phenazopyridine, 136-40-3, TRP Channel, Transient receptor potential channels, SHSY5Y, N2a, Cystitis, Urethritis, Urinary bladder, Analgesia, Alzheimer’s disease, Traumatic brain injury, Peripheral neuropathy, Neurodegenerative diseases, HEK293
References
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