Inhibition of the TRPM2 and TRPV1 Channels through Hypericum perforatum in Sciatic Nerve Injury-induced Rats Demonstrates their Key Role in Apoptosis and Mitochondrial Oxidative Stress of Sciatic Nerve and Dorsal Root Ganglion.

Fuat Uslusoy

doi:10.3389/fphys.2017.00335

Abstract

Sciatic nerve injury (SNI) results in neuropathic pain, which is characterized by the excessive Ca2+ entry, reactive oxygen species (ROS) and apoptosis processes although involvement of antioxidant Hypericum perforatum (HP) through TRPM2 and TRPV1 activation has not been clarified on the processes in SNI-induced rat, yet. We investigated the protective property of HP on the processes in the sciatic nerve and dorsal root ganglion neuron (DRGN) of SNI-induced rats. The rats were divided into five groups as control, sham, sham+HP, SNI, and SNI+HP. The HP groups received 30 mg/kg HP for 4 weeks after SNI induction. TRPM2 and TRPV1 channels were activated in the neurons by ADP-ribose or cumene peroxide and capsaicin, respectively. The SNI-induced TRPM2 and TRPV1 currents and intracellular free Ca2+ and ROS concentrations were reduced by HP, N-(p-amylcinnamoyl) anthranilic acid (ACA), and capsazepine (CapZ). SNI-induced increase in apoptosis and mitochondrial depolarization in sciatic nerve and DRGN of SNI group were decreased by HP, ACA, and CapZ treatments. PARP-1, caspase 3 and 9 expressions in the sciatic nerve, DRGN, skin, and musculus piriformis of SNI group were also attenuated by HP treatment. In conclusion, increase of mitochondrial ROS, apoptosis, and Ca2+ entry through inhibition of TRPM2 and TRPV1 in the sciatic nerve and DRGN neurons were decreased by HP treatment. The results may be relevant to the etiology and treatment of SNI by HP.

Highlights

Calcium ion (Ca2+) is an important messenger in neurons of the body (Kumar et al, 2014)
Addition of cumene hyroperoxide (CPx) caused a significant rise in [intracellular free calcium ion (Ca2+]i) concentration of sciatic nerve and dorsal root ganglion neuron (DRGN) of sciatic nerve injury (SNI) group which is attributed to activation of Ca2+-permeable TRP melastatin 2 (TRPM2) channels
The current results implied that Hypericum perforatum (HP) treatments might decrease the levels of SNI-induced [Ca2+]i accumulation, mitochondrial reactive oxygen species (ROS), apoptosis levels, and Poly-ADPR polymerase 1 (PARP-1), caspase 3, 9 activities and expressions in the sciatic nerve and DRGNs by inhibiting TRPM2 and TRP vanilloid 1 (TRPV1)

Summary

Introduction

Calcium ion (Ca2+) is an important messenger in neurons of the body (Kumar et al, 2014). Involvement of oxidative stress on activation of the TRPV1 channel through activation of NADPH oxidase pathway was indicated by a cell line study (Susankova et al, 2006) and DRGN (Ding et al, 2016) studies. Accumulating evidence indicated that importance of oxidative stress, the TRPM2 and TRPV1 channels in DRGN and sciatic nerve injuries has been increasing in experimental animal and human (Facer et al, 2007; Frederick et al, 2007; Haraguchi et al, 2012). It was reported that expression levels of TRPM2 and TRPV1 are increased in sciatic nerve and DRGN by spinal cord injury (SCI) and SNI (Frederick et al, 2007; Szigeti et al, 2012; Matsumoto et al, 2016)

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