Alpha7 nAChR: pathogenesis and treatment of chemotherapy-induced neuropathy

Oxaliplatin, unlike other platinum chemotherapic agents, does not result in significant renal impairment or ototoxicity, and it has only mild hematological and gastrointestinal toxicity. On the other hand, the limiting side effect is its neurotoxicity that may evolve to neuropathic syndrome. In a rat model of painful oxaliplatin-induced neuropathy, we are describing a pattern of molecular and morphological alterations of both the peripheral and the central nervous system (CNS). Among them an important activation of the glial component has been evidenced. Alpha7 nicotinic acetylcholine receptor (AChR) is widely expressed throughout the CNS. It has been described in neurons, microglia and astrocytes, where it seems to play a modulatory role. Moreover, alpha7 nAChR stimulation induces antihyperalgesic and neuroprotective effects in trauma-induced neuropathy. Aimed to study the pathophysiological mechanism of the chemotherapy-dependent neuropathy, the role of the alpha7 was investigated in a rat model of oxaliplatin-induced neuropathy (2.4 mgkg-1 intraperitoneally, daily injected for 21 days). At day 21th, when neuropathic pain is well established, alpha7 protein level expression was dramatically decreased both in the peripheral and in the central nervous system. The repeated treatment with two alpha7 agonists PNU-282987 and the novel (R)-(-)-3-methoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene [(R)-ICH3] (30 mgkg-1 p. os, daily administered for 21 days, starting from the first oxaliplatin injection) was able to prevent mechanical hyperalgesia. Moreover, mechanical and thermal allodynia were significantly reduced whereas motor coordination was improved. Western blot analysis revealed that the repeated treatment with the agonists prevented the decrease of alpha7 protein level in a significant manner. Further ex vivo analysis of the nervous system showed an alpha7-dependent neuroprotective effect: in morphological terms, in the dorsal root ganglia, and in the peripheral nerve and in the spinal cord as indicated by molecular parameters. These results strongly suggest the pivotal role of alpha7 nAChR in neuroprotection during neuropathy.