Chemotherapy-induced
peripheral neuropathy (CIPN) accompanied by chronic
neuropathic pain is a major dose-limiting side effect of a large number of antitumoral agents including
paclitaxel (
Taxol). Thus, CIPN is one of most common causes of
dose reduction and discontinuation of what is otherwise a life-saving
therapy. Neuropathological changes in spinal cord are linked to CIPN, but the causative mediators and mechanisms remain poorly understood. We report that formation of
peroxynitrite (PN) in response to activation of
nitric oxide synthases and
NADPH oxidase in spinal cord contributes to neuropathological changes through two mechanisms. The first involves modulation of neuroexcitatory and proinflammatory (TNF-α and IL-1β) and anti-inflammatory (IL-10 and IL-4)
cytokines in favor of the former. The second involves post-translational nitration and modification of glia-derived
proteins known to be involved in glutamatergic neurotransmission (astrocyte-restricted
glutamate transporters and
glutamine synthetase). Targeting PN with PN decomposition catalysts (PNDCs) not only blocked the development of
paclitaxel-induced
neuropathic pain without interfering with antitumor effects, but also reversed it once established. Herein, we describe our mechanistic study on the role(s) of PN and the prevention of
neuropathic pain in rats using known PNDCs (FeTMPyP(5+) and MnTE-2-PyP(5+)). We also demonstrate the prevention of CIPN with our two new orally active PNDCs, SRI6 and SRI110. The improved chemical design of SRI6 and SRI110 also affords selectivity for PN over other
reactive oxygen species (such as
superoxide). Our findings identify PN as a critical determinant of CIPN, while providing the rationale toward development of
superoxide-sparing and "PN-targeted"
therapeutics.