**Background**
Spasticity is a condition characterized by increased muscle tone and stiffness, often resulting from upper motor neuron lesions. It is a common complication in patients suffering from multiple sclerosis (MS), stroke, and spinal cord injury (SCI), significantly impairing mobility and quality of life. Beyond its application in neurology, recent research has explored the potential of certain muscle relaxants in oncology. Specifically, the inhibition of signaling pathways such as AKT and Wnt3a/$\beta$-catenin has emerged as a strategy to suppress the proliferation and metastasis of lung cancer cells. In this context, we will introduce a centrally acting $\alpha_2$-adrenoceptor agonist – Tizanidine.
**Definition**
Tizanidine hydrochloride is an orally effective skeletal muscle relaxant and $\alpha_2$-adrenoceptor agonist with an $\text{IC}_{50}$ value of 6.9 nmol.
**In Vitro and In Vivo Studies**
The Tizanidine description highlights its primary mechanism as the inhibition of excitatory amino acid release (glutamate and aspartate) from presynaptic terminals of spinal cord interneurons. Regarding Tizanidine in vitro activity, the compound is mainly metabolized by cytochrome CYP1A2, exhibiting a half-life of 50 min in human liver microsomes. In lung cancer research, Tizanidine (20 $\mu$M; 0-72 h) inhibits the proliferation, migration, and invasion of A549 cells. This effect is mediated by the upregulation of Nischarin, which leads to the inactivation of the Wnt3a/$\beta$-catenin pathway and the inhibition of AKT and mTOR phosphorylation. Furthermore, treatment of A549 cells with 20 $\mu$M Tizanidine for 48 h significantly increases the apoptosis rate, characterized by decreased Bcl-2 expression and increased Bax and Caspase-3 expression.
Tizanidine in vivo studies have demonstrated its efficacy in managing neuropathic pain. In a spinal nerve ligation (SNL) model using Wistar rats, oral administration of Tizanidine (0.02, 0.2, 2, and 20 mg/kg) for 14 days produced a dose-dependent analgesic effect. Notably, this effect was significantly stronger in female rats than in males, with estrogen identified as a key contributing factor. In ovarian removal (OVX) female rats, the TZN AUC decreased to 90 g·h (a 50% reduction compared to intact females), a result that was reversed following E2 replacement therapy. In conclusion, Tizanidine is a versatile $\alpha_2$-adrenoceptor agonist with potent muscle relaxant, analgesic, and antitumor properties.
Keywords
Tizanidine, 64461-82-1, Adrenergic Receptor, Apoptosis, Akt, Wnt, β-catenin, Beta Receptor, PKB, Protein kinase B, Beta catenin, Adrenergic receptors, Allodynia, Neuropathic pain, Sex-dependent
References
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[3] Zhao L, Zhao G, Xue Q. Tizanidine (Hydrochloride) Inhibits A549 Lung Cancer Cell Proliferation and Motility Through Regulating Nischarin. Onco Targets Ther. 2020 Jan 10;13:291-298.
[4] Rodríguez-Palma EJ, et al. Sex-dependent antiallodynic effect of α2 adrenergic receptor agonist tizanidine in rats with experimental neuropathic pain. Eur J Pharmacol. 2022 Apr 5;920:174855.