7-Chloro-4-(Phenylselanyl) Quinoline Is a Novel Multitarget Therapy to Combat Peripheral Neuropathy and Comorbidities Induced by Paclitaxel in Mice

Abstract

Paclitaxel-induced peripheral neuropathy (PIPN) is a very common and complex painful condition related to paclitaxel (PTX) exposure, severely impacting patients' quality of life, and contributing to the emergence of clinical signs of anxiety and cognitive loss. At present, no sufficient treatment options are available for PIPN and its exact pathophysiology remains unclear. Based on the therapeutic potential of the 7-chloro-4-(phenylselanyl) quinoline (4-PSQ), we assessed its ability to reverse PIPN and its comorbities induced by PTX. The effect of 4-PSQ was evaluated on pathophysiological processes involved in PIPN, such as oxidative stress (oxidative damage and antioxidant enzymes), neuroinflammation (mRNA expression levels of nuclear factor-kappa B, interleukin-1beta, tumor necrosis factor-alpha, and inducible nitric oxide synthase), and calcium homeostasis (Ca²⁺ATPase activity) in the spinal cord, cerebral cortex, and hippocampus of mice. Male Swiss mice received PTX (2 mg/kg) or vehicle by intraperitoneal route (days 1, 2, and 3). Oral administration of 4-PSQ (1 mg/kg) or vehicle was performed on days 3 to 14. It was observed that 4-PSQ reduced the mechanical and thermal hypersensitivities induced by PTX. Likewise, 4-PSQ reduced both anxious behavior and cognitive impairment in mice with PIPN. We believe that effects of 4-PSQ may be associated, at least in part, with the modulation of oxidative stress, reduction of neuroinflammation, and normalizing Ca²⁺ATPase activity in the spinal cord, cerebral cortex, and hippocampus of mice with PIPN. Taken together, the 4-PSQ might be a good prototype for the development of a more effective drug for the treatment of PIPN and its comorbities.

Keywords: Anxiety; Inflammation; Memory; Neurotoxicity; Paclitaxel; Peripheral neuropathy.