Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

Abstract

Heme oxygenase (HO)-1 has potent antioxidant and anti-inflammatory functions. Recent studies have shown that the upregulation of HO-1 is beneficial to counteract neuroinflammation, making HO-1 a new therapeutic target for neurological diseases. We have reported that epalrestat (EPS), which is currently used for the treatment of diabetic neuropathy, increases HO-1 levels through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in bovine aortic endothelial cells. In this study, we tested the hypothesis that EPS upregulates HO-1 via Nrf2 activation in the component cells of the nervous system, by using rat Schwann cells and human SH-SY5Y cells. Treatment of Schwann cells with EPS at near-plasma concentration led to a dramatic increase in HO-1 levels. Nrf2 knockdown by small interfering RNA (siRNA) suppressed the EPS-induced HO-1 expression. EPS did not promote the intracellular accumulation of free ferrous ion and reactive oxygen species, by increasing ferritin via Nrf2 during HO-1 induction. Moreover, EPS stimulated the expression of superoxide dismutase 1 and catalase, which also are Nrf2 target gene products. It also markedly increased HO-1 levels in SH-SY5Y cells through the activation of Nrf2. We demonstrated for the first time that EPS upregulates HO-1, superoxide dismutase, and catalase by activating Nrf2. We suggest that EPS has the potential to prevent several neurological diseases. Key words epalrestat; heme oxygenase (HO)-1; superoxide dismutase (SOD); catalaseHeme oxygenase (HO)-1 is a stress-responsive enzyme that has anti-inflammatory, antioxidant, and cytoprotective functions. Expectations are high that the regulation and amplification of HO-1 by pharmacological approaches would lead to the discovery of novel drugs for the treatment of a variety of diseases.1) HO-1 has emerged as an anti-inflammatory therapeutic target.2) In particular, targeting HO-1 in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, has been reported.3) As HO-1 expression is involved in neuropathological changes, its regulation is essential for the development of new therapeutic approaches.3) However, such metalloporphyrins as cobalt protoporphyrin IX, which are prototypical inducers of HO-1 and commonly used in experimental cell culture and animal models, are not applicable to clinical interventions because of their high toxicity.2) It is expected that the upregulation of HO-1 by currently available pharmacological agents, whose safety and pharmacokinetics have already been confirmed clinically, would be useful for the treatment of a variety of diseases.The biochemical activities of heme degradation products and their metabolic derivatives contribute to the cytoprotective function of HO-1. HO-1 catalyzes the degradation of heme to produce ferrous iron, carbon monoxide, and biliverdin, the latter of which is subsequently converted into bilirubin. Carbon monoxide is involved in inflammation regulation.4) Bilirubin and biliverdin, which can scavenge peroxyl radicals, are cytoprotec...

Vein wrapping facilitates basic fibroblast growth factor‐induced heme oxygenase‐1 expression following chronic nerve constriction injury

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“…39 Upregulation of HO-1 in Schwann cells may also enhance neuroprotection. 40 Here, bFGF stimulated HO-1 expression in sciatic nerve cells, as was previously reported in spinal astrocyte culture. 31 We also demonstrated that vein wrapping further stimulated HO-1 expression in sciatic nerve tissue.…”

Wrapping With Basic Fibroblast Growth Factor‐Impregnated Collagen Sheet Reduces Rat Sciatic Nerve Allodynia

“…Consistent with previous studies on the effects of vein wrapping, we found that bFGF/CS stimulates Hmox1 mRNA and HO‐1 protein expression, while PBS/CS does not. Previous studies have shown that HO‐1 induction results in anti‐nociceptive effects and alleviation of neuropathic pain . Our results suggest that bFGF/CS‐mediated HO‐1 expression may contribute to pain relief.…”

Neuroprotective Effect of Epalrestat on Memory Impairment in Streptozotocin-Induced Type-2 Diabetic Rats Using Different Behavioral Models.

“…According to the previous findings, heme oxygenase (HO)-1 has potent antioxidant and anti-inflammatory functions; however, EPS upregulates HO-1, dismutase, and catalase by activating Nrf2 and suggests that EPS has the beneficial effect on improvement of several neurological disorders [12].…”

“…It is reported for anti-inflammatory and antioxidant effects using rat Schwann cell and human neuroblastoma cell line [12][13][14]. Therefore, the antiinflammatory and anti-oxidant properties of EPS can be beneficial in the management of neurodegenerative disease by improving the memory and learning in an animal model.…”