Neuroprotective effect of angiotensin II type 2 receptor stimulation in vincristine-induced mechanical allodynia

Abstract

Peripheral neuropathy is the major dose-limiting side effect of many currently used chemotherapies, such as vincristine (VCR). We recently demonstrated that candesartan, an angiotensin II type 1 receptor antagonist, was neuroprotective against resiniferatoxin-induced sensory neuropathy, and that this effect is mediated by stimulation of the angiotensin II type 2 receptor (AT2R). Thus, we evaluated the effect of preventive treatment with candesartan and a specific AT2R agonist, C21, on a mouse model of VCR-induced neuropathy. Vincristine was administered daily for 7 days to male Swiss mice. Treatment with candesartan and C21 was started on day 1, before VCR treatment, and continued until day 7. We evaluated the development of VCR-induced neuropathy and the effect of treatment by functional tests, immunohistochemical analyses of intraepidermal nerve fibers and dorsal root ganglia neurons, and ultrastructural analysis of the sciatic nerve. Mice treated with VCR showed high mechanical allodynia but no modifications of motor performance or mechanical/thermal nociception. Treatment with candesartan and C21 completely restored normal tactile sensitivity of VCR-treated mice. Both drugs prevented VCR-induced nonpeptidergic intraepidermal nerve fiber loss. Only C21 displayed neuroprotective effects against VCR-induced loss and enlargement of myelinated nerve fibers in the sciatic nerve. Our finding that candesartan and C21 are protective against VCR-induced neuropathic pain through AT2R stimulation favors evaluation of its therapeutic potential in patients receiving chemotherapy.

Lack of association between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and pain improvement in patients with oral cancer

“…Other investigations support Shepherd's findings. For instance, ARBs showed anti-allodynic effects in animals with vincristine-and paclitaxel-induced neuropathic pain [7,25]. In our cohort of patients, the level of bioinflammatory markers, NLR and MLR did not differ significantly amongst ACEi and ARB treatment groups when compared to no treatment, again supporting the lack of efficacy of ARBs on inflammatory pain even after excluding patients taking NSAIDs.…”

Angiotensin Type 2 Receptors: Painful, or Not?

“…Moreover, the clear evidence that AT 2 R agonism suppresses oxidative stress (ROS/ RNS) in neurons and glia that can prevent TRPA1 activation, and that neither DRG-neuronal nor peripheral-macrophage AT 2 R activate TRPA1 (the mediator of mechanical and cold hypersensitivity) in these cells, questions whether AT 2 R is actually a pain inducer for neuropathic pain. This contention is supported by recent studies which demonstrate that the nonpeptide AT 2 R agonist Compound 21 is protective against vincristine-induced neuropathic pain (Bessaguet et al, 2018). The same group had earlier demonstrated that the beneficial effects afforded by the AT 1 R blocker candesartan in resiniferatoxin-induced neuropathic pain were due to generation of Ang II and stimulation of the AT 2 R (Bessaguet et al, 2017).…”

“…However, as also seen in Figure 1, with regard to pain the story is different, with literature over the past 5-6 years concluding that AT 2 R antagonists are analgesic, particularly in neuropathic pain and chronic inflammatory pain (Smith et al, 2016). On the other hand, there are also studies which indicate that AT 2 R agonists exert beneficial effects in pain (Bessaguet et al, 2018).…”

“…However, despite the fact that a large majority of studies have projected AT 2 R activation as being "good" or beneficial, studies published within the past 5-6 years conclude that blockade of AT 2 R provides relief in neuropathic pain and inflammatory pain (Chakrabarty et al, 2013;Smith et al, 2013;Muralidharan et al, 2014;Shepherd et al, 2018). In contrast to this, other studies have implied that activation of AT 2 R can produce beneficial effects in neuropathic pain (Bessaguet et al, 2018). Nonetheless, the implication that AT 2 R activation is harmful under certain circumstances, i.e., it causes pain, has severe consequences for efforts that intend to take advantage of the beneficial action of AT 2 R agonists and translate findings in animal models to novel therapeutics for human disease.…”

Blockade of bradykinin receptors or angiotensin II type 2 receptor prevents paclitaxel‐associated acute pain syndrome in mice

“…Angiotensin II is classically associated to vascular effects, which are mediated by activation of the angiotensin II type 1 receptor (AT1R). However, more recently, Ang II has been associated with pain sensitization during neuropathic pain induced by nerve injury, diabetis or herpes zoster, by an action on its receptor Ang II receptor type 2 (AT2R) (Anand et al., 2013; Bessaguet et al., 2018; Kim et al., 2019; Nemoto et al., 2015; Ogata et al., 2016; Rice et al., 2014; Shepherd, Copits, et al., 2018; Shepherd, Mickle, et al., 2018; Smith et al., 2016). AT2R antagonists have been successfully tested in pre‐clinical studies and, lately in clinical trials in patients with neuropathic pain (Ogata et al., 2016; Rice et al., 2014; Smith et al., 2016).…”