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

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.

Abnormal Reinnervation of Denervated Areas Following Nerve Injury Facilitates Neuropathic Pain

“…The most probable explanation for this decrease is the lesion of the axons, which prevents the transport of AF488 and AF647 dyes from the examined areas to DRG somata. However, the apoptosis of the injured and neighboring DRG neurons following SNI-type nerve injury could be another explanation for the decrease in innervating DRG neurons [21,22]. The origin of the newly labeled DRG somata is most probably the result of the dye uptake by the axons, which sprouts from the neighboring areas and not from the regrowth of injured axons [7,11,12] (see also Figure 5, here).…”

An extract of Hypericum perforatum induces wound healing through inhibitions of Ca2+ mobilizations, mitochondrial oxidative stress and cell death in epithelial cells: Involvement of TRPM2 channels

“…We used commercial H. perforatum extract (HP) from Indena Inc. (Indena Industria Derivati Naturali, S.p.A. Viale Ortles, Milan, Italy) (Özdemir et al, 2016;Uslusoy et al, 2017). Contents of total hypericin, flavonoids, and hyperforin in the extract were analyzed by the company, and their rates were 0.10-0.30, 6.0, and 6.0%, respectively.…”

“…John's wort' Hypericum perforatum is a wellknown traditional plant, and it has been used in the treatment of several diseases such as depression, inflammatory, and skin diseases (Meinke et al, 2012;Nazıroğlu, 2016). The main components of H. perforatum are hyperforin, flavonoids, hypericin, and their anti-apoptosis and antioxidant properties through inhibition of TRPM2 channel were reported in neuropathic pain, neutrophil activation and mechanical brain injury (Nazıroğlu et al, 2014a(Nazıroğlu et al, , 2014b(Nazıroğlu et al, , 2014cUslusoy et al, 2017). In addition, involvements of HP through inhibition of TRPM2 channels in the mechanical sciatic nerve and spinal cord injuries were recently reported (Pogatzki-Zahn et al, 2005;Özdemir et al, 2016;Uslusoy et al, 2017;Uslusoy et al, 2019).…”

“…The main components of H. perforatum are hyperforin, flavonoids, hypericin, and their anti-apoptosis and antioxidant properties through inhibition of TRPM2 channel were reported in neuropathic pain, neutrophil activation and mechanical brain injury (Nazıroğlu et al, 2014a(Nazıroğlu et al, , 2014b(Nazıroğlu et al, , 2014cUslusoy et al, 2017). In addition, involvements of HP through inhibition of TRPM2 channels in the mechanical sciatic nerve and spinal cord injuries were recently reported (Pogatzki-Zahn et al, 2005;Özdemir et al, 2016;Uslusoy et al, 2017;Uslusoy et al, 2019). Involvement of HP through inhibition of TRPM2 channel in the recovering skin injury has not been clarified yet, although results of recent studies indicated protective roles of HP treatments through inhibition of oxidative stress on diabetic surgical wound (Altıparmak and Eskitaşçıoğlu, 2018) and burn wound healing (Vafi et al, 2016) in rats.…”

Spinal α2‐adrenoceptors and neuropathic pain modulation; therapeutic target

“…Matsushita et al (2018) concluded that delivery of NA reduces the activity of transient receptor potential vanilloid type 1 (TRPV1) channels in dorsal sensory neurons. TRPV1 is a well-known nociceptionmediating ion channel and is mainly expressed in peripheral Aδ-and C-fibres as well as throughout the CNS, which overloads Ca 2+ entry through the channels involved in neuropathic pain (Chen et al, 2015;Ren et al, 2015;Uslusoy, Nazıroğlu, & Çiğ, 2017). The contribution of TRPV1 has also been evaluated in several rodent models of neuropathic pain.…”