Abstract
Neuropathic pain is common in peripheral nerve injury and often fails to respond to ordinary medication. Here, we investigated whether the two novel epigallocatechin-3-gallate (EGCG) polyphenolic derivatives, compound 23 and 30, reduce the neuropathic pain in mice chronic constriction nerve injury (CCI). First, we performed a dose-response study to evaluate nociceptive sensation after administration of EGCG and its derivatives 23 and 30, using the Hargreaves test at 7 and 21 days after injury (dpi). We daily administered EGCG, 23 and 30 (10 to 100 mg/Kg; i.p.) during the first week post-CCI. None of the doses of compound 23 caused significant pain diminution, whereas 50mg/kg was optimal for both EGCG and 30 to delay the latency of paw withdrawal. With 50 mg/Kg, we showed that EGCC prevented the thermal hyperalgesia from 7 to 21 dpi and compound 30 from 14 to 56 dpi. To evaluate the molecular mechanisms underpinning why EGCG and compound 30 differentially prevented the thermal hyperalgesia, we studied several biochemical parameters in the dorsal horn of the spinal cord at 14 and 56 dpi. We showed that the effect observed with EGCG and compound 30 was related to the inhibition of fatty acid synthase (FASN), a known target of these polyphenolic compounds. Additionally, we observed that EGCG and compound 30 reduced the expression of CCI-mediated inflammatory proteins and the nuclear localization of nuclear factor-kappa B at 14 dpi, but not at 56 dpi. We also strongly detected a decrease of synaptic plasma membrane levels of N-methyl-D-asparte receptor 2B in CCI-mice treated with compound 30 at 56 dpi. Altogether, compound 30 reduced the chronic thermal hyperalgesia induced by CCI better than the natural compound EGCG. Thus, our findings provide a rationale for the preclinical development of compound 30 as an agent to treat neuropathic pain.
Highlights
Neuropathic pain is caused by injury or disease to the peripheral or central nervous system with no available effective treatment
In order to know whether EGCG and the two synthetic derivatives compounds 23 and 30 had the ability to prevent chronic neuropathic pain, we performed a dose-response study to test their effect on thermal sensation of forepaws in mice after chronic constriction injury (CCI)
The prevention of CCI induced-neuropathic pain by EGCG and compound 30 is associated to a reduction of FASN activity in the dorsal horn of the spinal cord. It has been well reported the role of fatty acids in neuropathic pain after peripheral nerve injuries [28,29,30]. As it has been described in non-neural cells that EGCG inhibits the fatty acid synthase activity (FASN) [24], we studied the inhibition of FASN activity in the dorsal horn of the spinal cord of CCI-mice treated with EGCG and the two polyphenolic synthetic derivatives at 14 and 56 dpi
Summary
Neuropathic pain is caused by injury or disease to the peripheral or central nervous system with no available effective treatment. It has been reported in rats that intrathecal administration of EGCG attenuates mechanical allodynia and thermal hyperalgesia after chronic constriction nerve injury [12] and reduces mechanical allodynia after spinal nerve ligation [13]. These beneficial effects have been attributed to the antioxidant activity against nitric oxide [10, 13, 14] and reduction of pro-inflammatory cytokines expression [10, 12]. Renno et al [16] have recently shown that EGCG modulated chronic injured spinal cord in rats
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