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.

The neuroprotective action of dexmedetomidine on apoptosis, calcium entry and oxidative stress in cerebral ischemia-induced rats: Contribution of TRPM2 and TRPV1 channels

“…Excessive production of mitochondrial ROS and an overload of Ca 2+ through increased TRPM2 and TRPV1 channel activity are two of the main causes of neurodegenerative diseases in hippocampus and induction of peripheral pain in DRG (Fig. 8)51017. The aim of the study was to evaluate whether DEX functionally interacts with TRPM2 and TRPV1 in the HIPPO and DRG neurons of rats with cerebral ischemia.…”

“…Mounting evidence indicates that production of free oxygen radicals and stimulation of apoptotic caspase 3 and 9 pathways are increased in the hippocampus and DRG by increased mitochondrial membrane depolarization (Fig. 8)517. This is because the neurons have poor antioxidant content but high oxygen consumption and polyunsaturated fatty acid content.…”

“…Prevention of apoptotic cascades through inhibition of the TRPM2 and TRPV1 in the hippocampal (HIPPO) and DRG neurons of rats were more recently reported517. These later results raised the possibility that HIPPO and DRG neuron apoptosis mediated by the TRPM2 and TRPV1 channels could also contribute to cerebral ischemia injuries, as accumulating evidence suggests their involvement in cerebral ischemia and SCI, including oxidative stress induced by the TRPM2 and TRPV1 channels25.…”

“…An accumulating body of evidence indicates that abnormalities of Ca 2+ homeostasis is caused by excessive levels of free oxygen radicals in rats with cerebral ischemia23. In other words, there is mounting evidence to suggest that cell death after cerebral ischemia and spinal cord injury (SCI) is predominantly mediated by high amount of reactive oxygen species (ROS) and the subsequent over-production of poly (ADP-ribose [ADPR]) polymerase-1 (PARP-1), ultimately leading to mitochondrial dysfunction, release of apoptosis-inducing factors, and cell death456. Calcium ion (Ca 2+ ) plays a crucial role in physiological activities, including apoptosis and mitochondrial functions78.…”

“…Accumulating reports in the drug discovery potential of TRP channels provides continual interest for the hypothesis that block of TRP channel inhibition underlies many of the treatments related with SCI and cerebral ischemia-induced brain injuries523. However, there have been no reports on overload Ca 2+ entry via activations of TRPM2 and TRPV1 in rats with cerebral ischemia.…”