Neuroprotective Effect of Ramipril Is Mediated by AT2 in a Mouse MODEL of Paclitaxel-Induced Peripheral Neuropathy

• Published in: Pharmaceutics Vol. 14; no. 4; p. 848
• Main Authors: Bouchenaki, Hichem, Bernard, Amandine, Bessaguet, Flavien, Frachet, Simon, Richard, Laurence, Sturtz, Franck, Magy, Laurent, Bourthoumieu, Sylvie, Demiot, Claire, Danigo, Aurore
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12-04-2022; MDPI
• Subjects: angiotensin converting enzyme inhibitor; Animals; Cancer therapies; Chemotherapy; Life Sciences; Morphology; Motor ability; mouse model; Neurons; neuropathic pain; Neurotoxicity; paclitaxel-induced peripheral neuropathy; Peripheral neuropathy; Physiology; Quality of life; Ramipril; France; Ramipril; neuropathic pain; mouse model; paclitaxel-induced peripheral neuropathy; angiotensin converting enzyme inhibitor; Mouse model; Angiotensin converting enzyme inhibitor; Neuropathic pain
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics14040848

Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) induces numerous symptoms affecting patient quality of life, leading to decreased doses or even to cessation of anticancer therapy. Previous studies have reported that a widely used drug, ramipril, improves neuroprotection in several rodent models of peripheral neuropathy. The protective role of the angiotensin II type 2 receptor (AT2) in the central and peripheral nervous systems is well-established. Here, we evaluate the effects of ramipril in the prevention of PIPN and the involvement of AT2 in this effect. Paclitaxel was administered in wild type or AT2-deficient mice on alternate days for 8 days, at a cumulative dose of 8 mg/kg (2 mg/kg per injection). Ramipril, PD123319 (an AT2 antagonist), or a combination of both were administered one day before PTX administration, and daily for the next twenty days. PTX-administered mice developed mechanical allodynia and showed a loss of sensory nerve fibers. Ramipril prevented the functional and morphological alterations in PTX mice. The preventive effect of ramipril against tactile allodynia was completely absent in AT2-deficient mice and was counteracted by PD123319 administration in wild type mice. Our work highlights the potential of ramipril as a novel preventive treatment for PIPN, and points to the involvement of AT2 in the neuroprotective role of ramipril in PIPN.