Preclinical evidence, accumulated over the past decade, indicates that the angiotensin II type 2 receptor (AT2R) stimulation exerts significant neuroprotective effects in various animal models of neuronal injury, notably in the central nervous system. While the atypical G protein-coupled receptor superfamily nature of AT2R and its related signaling are still under investigation, pharmacological studies have shown that stimulation of AT2R leads to neuritogenesis in vitro and in vivo. In this review, we focus on the potential neuroprotective and neuroregenerative roles of AT2R specifically in the peripheral nervous system (PNS). The first section describes the evidence for AT2R expression in the PNS and highlights current controversies concerning the cellular distribution of the receptor. The second section focuses on AT2R signaling implicated in neuronal survival and in neurite outgrowth. The following sections review the relatively few preclinical studies highlighting the putative neuroprotective and neuroregenerative effects of AT2R stimulation in the context of peripheral neuropathy.

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.