Abstract
Neurotoxicity is a main side effect of the anticancer drug oxaliplatin. The development of a neuropathic syndrome impairs quality of life and potentially results in chemotherapy dose reductions and/or early discontinuation. In the complex pattern of molecular and morphological alterations induced by oxaliplatin in the nervous system, an important activation of glia has been preclinically evidenced. N-Palmitoylethanolamine (PEA) modulates glial cells and exerts antinociceptive effects in several animal models. In order to improve the therapeutic chances for chemotherapy-dependent neuropathy management, the role of PEA was investigated in a rat model of oxaliplatin-induced neuropathy (2.4 mg kg-1 daily, intraperitoneally). On day 21, a single administration of PEA (30 mg kg-1 i.p.) was able to reduce oxaliplatin-dependent pain induced by mechanical and thermal stimuli. The repeated treatment with PEA (30 mg kg-1 daily i.p. for 21 days, from the first oxaliplatin injection) prevented lowering of pain threshold as well as increased pain on suprathreshold stimulation. Ex vivo histological and molecular analysis of dorsal root ganglia, peripheral nerves and spinal cord highlighted neuroprotective effects and glia-activation prevention induced by PEA repeated administration. The protective effect of PEA resulted in the normalization of the electrophysiological activity of the spinal nociceptive neurons. Finally, PEA did not alter the oxaliplatin-induced mortality of the human colon cancer cell line HT-29. The efficacy of PEA in neuropathic pain control and in preventing nervous tissue alteration candidates this endogenous compound as disease modifying agent. These characteristics, joined to the safety profile, suggest the usefulness of PEA in chemotherapy-induced neuropathy.
Highlights
Oxaliplatin is a chemotherapeutic agent effective in various solid tumours [1], [2], in particular, it was introduced for the management of the advanced stages of colorectal cancer
On day 21, oxaliplatin caused a lowering of the threshold to cold stimuli which do not normally provoke pain (Cold plate test)
The pain reliever effect of PEA (30 mg kg-1) was evaluated after a daily repeated treatment starting from day 1 to day 20 of the oxaliplatin protocol
Summary
Oxaliplatin is a chemotherapeutic agent effective in various solid tumours [1], [2], in particular, it was introduced for the management of the advanced stages of colorectal cancer. Oxaliplatin is the regimen of choice for the adjuvant treatment of patients with curative resection of node-positive colon cancer [3], [4], [5]. The dose-limiting toxicity of this compound is the development of peripheral neuropathy with glove-and-stocking distribution sensory loss, combined with paresthesia, dysesthesia, and pain [6], [7]. There is no currently univocally-accepted proven therapy for oxaliplatin-induced neuropathy [11], [14]. Like duloxetine, demonstrated clinical benefit [18]. Neuroprotective, safe, preventive agents as adjuvant to chemotherapy are a therapeutic need
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