Hydrogen exerts neuroprotective effects by inhibiting oxidative stress in experimental diabetic peripheral neuropathy rats

Abstract

Diabetic peripheral neuropathy (DPN) is a complex disorder caused by long-standing diabetes. Oxidative stress was considered the critical creed in this DPN pathophysiology. Hydrogen has antioxidative effects on diabetes mellitus and related complications. However, there is still no concern on the beneficial effects of hydrogen in DPN. This paper aimed to evaluate the effects of exogenous hydrogen to reduce the severity of DPN in streptozotocin-induced diabetic rats. Compared with hydrogen-rich saline treatment, hydrogen inhalation significantly reduced blood glucose levels in diabetic rats in the 4 th and 8 th weeks. With regard to nerve function, hydrogen administration significantly attenuated the decrease in the velocity of motor nerve conduction in diabetic animals. In addition, hydrogen significantly attenuated oxidative stress by reducing the level of malondialdehyde, reactive oxygen species, and 8-hydroxy-2-deoxyguanosine and meaningfully enhanced the antioxidant capability by partially restoring the activities of superoxide dismutase. Further studies showed that hydrogen significantly upregulated the expression of nuclear factor erythroid-2-related factor 2 and downstream proteins such as catalase and hemeoxygenase-1 in the nerves of diabetic animals. Our paper showed that hydrogen exerts significant protective effects in DPN by downregulating oxidative stress via the pathway of nuclear factor erythroid-2-related factor 2, which suggests its potential value in clinical applications.

Compound Qiying Granules alleviates diabetic peripheral neuropathy by inhibiting endoplasmic reticulum stress and apoptosis

“…Oxidative stress damages the peripheral nervous system, such as Schwann cells, myelinated axons, and sensory neurons, among others (Chandrasekaran et al 2019 ; Fernyhough 2015 ). ROS can lead to oxidative damage in dorsal root ganglion neurons and is considered a major mechanism in the pathogenesis of DPN (Han et al 2023 ). Insufficient mitochondrial energy production can lose the ability to transport axons, further contributing to axonal injury (Rumora et al 2018 ).…”

Mitochondria: one of the vital hubs for molecular hydrogen’s biological functions

“…It has been reported that H 2 could increase antioxidant enzymes, including SOD, CAT, Gpx, heme oxygenase-1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1) (Liu et al, 2016;Li et al, 2019). The activation of Nrf2-mediated antioxidant signaling pathway by H 2 may be responsible for the increased expression of the antioxidant enzymes (Li et al, 2019;Zheng et al, 2021;Han et al, 2023). In conclusion, available evidence indicates the inhibitory effect of H 2 on mtROS, which may be mediated by directly scavenging free radicals, inhibiting free radical production or enhancing cellular antioxidant capacity, although the detailed mechanism needs to be further investigated.…”

Therapeutic Potential of Molecular Hydrogen in Metabolic Diseases from Bench to Bedside

“…The protective effects of H 2 against the diabetic complications, including peripheral neuropathy [25][26][27][28][29], retinopathy [30,31], cardiomyopathy [32,33], wound healing [34][35][36], bone loss [37], and erectile dysfunction [38], have been extensively reported. STZ-induced mice or rats models were used in the above in vivo studies for diabetic complications.…”

“…In addition to conventional hydrogen delivery routes, some novel administration methods, such as photo-driven nanoreactor, microneedle patch, and algae-bacteria gel patch, were used, which allowed in situ continuous hydrogen production to treat chronic diabetic wounds. The inhibition of oxidative stress, inflammation, endoplasmic reticulum stress, apoptosis, and pyroptosis, as well as parthanatos (a particular type of programmed cell death that is different from the common apoptosis, necrosis, and autophagy) and activation of the mitochondrial ATP-sensitive potassium (Mito-K-ATP) pathway may be involved in the protective effects of H 2 on diabetic complications [25][26][27][28][29][30][31][32][33][34][35][36][37][38].…”

“…In addition to directly reducing ROS, H 2 could also indirectly suppress oxidative stress by increasing antioxidant capacity via regulating anti-oxidative signal transduction. H 2 has been reported to activate the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated anti-oxidative pathway, leading to an increased expression of downstream target enzymes, including heme oxygenase-1 (HO-1), catalase (CAT), SOD, and GSH-Px [29,34,67]. Although H 2 has been reported to ameliorate lipid accumulation by regulating the miR-136/MEG3/Nrf2 pathway in NAFLD [58], it is unclear whether H 2 could also regulate Nrf2 activity through the canonical Keap1-Nrf2-ARE pathway or other non-canonical pathways in metabolic diseases [85].…”