title: Hypericum perforatum Attenuates Spinal Cord Injury-Induced Oxidative Stress and Apoptosis in the Dorsal Root Ganglion of Rats: Involvement of TRPM2 and TRPV1 Channels.
abstract: Oxidative stress and cytosolic Ca(2+) overload have important roles on apoptosis in dorsal root ganglion (DRG) neurons after spinal cord injury (SCI). Hypericum perforatum (HP) has an antioxidant property in the DRGs due to its ability to modulate NADPH oxidase and protein kinase C pathways. We aimed to investigate the protective property of HP on oxidative stress, apoptosis, and Ca(2+) entry through transient receptor potential melastatin 2 (TRPM2) and transient receptor potential vanilloid 1 (TRPV1) channels in SCI-induced DRG neurons of rats. Rats were divided into four groups as control, HP, SCI, and SCI + HP. The HP groups received 30 mg/kg HP for three concessive days after SCI induction. The SCI-induced TRPM2 and TRPV1 currents and cytosolic free Ca(2+) concentration were reduced by HP. The SCI-induced decrease in glutathione peroxidase and cell viability values were ameliorated by HP treatment, and the SCI-induced increase in apoptosis, caspase 3, caspase 9, cytosolic reactive oxygen species (ROS) production, and mitochondrial membrane depolarization values in DRG of SCI group were overcome by HP treatment. In conclusion, we observed a protective role of HP on SCI-induced oxidative stress, apoptosis, and Ca(2+) entry through TRPM2 and TRPV1 in the DRG neurons. Our findings may be relevant to the etiology and treatment of SCI by HP. Graphical Abstract Possible molecular pathways of involvement of Hypericum perforatum (HP) on apoptosis, oxidative stress, and calcium accumulation through TRPM2 and TRPV1 channels in DRG neurons of SCI-induced rats. The TRPM2 channel is activated by ADP-ribose and oxidative stress through activation of ADP-ribose pyrophosphate although it was inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and 2-aminoethyl diphenylborinate (2APB). The TRPV1 channel is activated by oxidative stress and capsaicin and it is blocked by capsazepine. Injury in the DRG can result in augmented ROS release, leading to Ca(2+) uptake through TRPM2 and TRPV1 channels. Mitochondria were reported to accumulate Ca(2+), provided intracellular Ca(2+) rises, thereby leading to depolarization of mitochondrial membranes and release of apoptosis-inducing factors such as caspase 3 and caspase 9. HP via regulation of NADPH oxidase and PKC inhibits TRPM2 and TRPV1 channels. The molecular pathway may be a cause of SCI-induced pain and neuronal death, and the subject should be urgently investigated.
authors.affiliation: Department of Neurosurgery, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey.
authors.forename: Ümit Sinan
authors.initials: ÜS
authors.lastname: Özdemir
authors.affiliation: Neuroscience Research Center, Suleyman Demirel University, TR-32260, Isparta, Turkey. mustafanaziroglu@sdu.edu.tr.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Nazıroğlu
authors.affiliation: Department of Neurosurgery, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey.
authors.forename: Nilgün
authors.initials: N
authors.lastname: Şenol
authors.affiliation: Neuroscience Research Center, Suleyman Demirel University, TR-32260, Isparta, Turkey.
authors.forename: Vahid
authors.initials: V
authors.lastname: Ghazizadeh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006861:Hydrogen Peroxide; D020902:Hypericum / Q000737:chemistry*; D015640:Ion Channel Gating / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology; D050053:TRPM Cation Channels / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D010936:Plant Extracts; D017382:Reactive Oxygen Species; D050053:TRPM Cation Channels; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C557080:Trpm2 protein, rat; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D020169:Caspases; D005978:Glutathione; C071423:capsazepine; D002211:Capsaicin; D002118:Calcium
keywords: Apoptosis; Hypericum perforatum; Oxidative stress; Spinal cord injury; TRPM2; TRPV1