Aldose reductase inhibitor ranirestat significantly improves nerve conduction velocity in diabetic polyneuropathy: A randomized double‐blind placebo‐controlled study in Japan

Sekiguchi, Kenji; Kohara, Nobuo; Baba, Masayuki; Komori, Tetsuo; Naito, Yutaka; Imai, Tomihiro; Satoh, Jo; Yamaguchi, Yasutaka; Hamatani, Tatsuto

doi:10.1111/jdi.12890

Cited by 38 publications

(27 citation statements)

References 34 publications

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“…Accordingly, we have demonstrated in preclinical studies the beneficial effects of substrate reduction via ARI application in human derived cells and Drosophila models. Epalrestat is currently marketed in few countries for the treatment of diabetic complications (20) while Ranirestat has been advanced into late stages of clinical trials (22,23).…”

Section: Discussionmentioning

confidence: 99%

“…We investigated the possibility that SORD-associated hereditary neuropathy could be treated. Pharmacological inhibition of aldose reductase, the enzyme upstream of SORD, has been shown to reduce detrimental sorbitol accumulation in cellular and animal model of diabetes (16)(17)(18)(19)(20), and in humans (21)(22)(23). We thus tested the effect of two commercially available aldose reductase inhibitors (ARI), Epalrestat and Ranirestat, on intracellular sorbitol accumulation in patient fibroblasts lacking functional SORD.…”

Section: Treatment With Aldose Reductase Inhibitors Normalizes Intracmentioning

confidence: 99%

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Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes

Cortese¹,

Zhu²,

Züchner³

et al. 2020

Nat Genet

107

109

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Here we demonstrate biallelic mutations in sorbitol dehydrogenase (SORD) as the most frequent recessive form of hereditary neuropathies. We identified 45 cases from 38 families across multiple ethnicities, carrying a particular nonsense mutation in SORD, c.753delG; p.Ala253GlnfsTer27, either in homozygous or compound heterozygous state with a second variant. With an allele frequency of 0.004 in healthy controls, the p.Ala253GlnfsTer27 variant represents one of the most common pathogenic alleles in humans. SORD is an enzyme that converts sorbitol into fructose, in the two-step polyol pathway that has been implicated in diabetic neuropathy. In patient-derived fibroblasts, we find a complete loss of SORD protein as well as increased intracellular sorbitol. Also, serum fasting sorbitol level was over 100 times higher in patients homozygous for the p.Ala253GlnfsTer27 mutation compared to healthy individuals. In Drosophila, we show that loss of SORD orthologues causes synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a potentially treatable cause in a significant fraction of patients with inherited neuropathies and may contribute to a better understanding of the pathophysiology of diabetic neuropathy.

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Section: Discussionmentioning

confidence: 99%

Section: Treatment With Aldose Reductase Inhibitors Normalizes Intracmentioning

confidence: 99%

Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes

Cortese¹,

Zhu²,

Züchner³

et al. 2020

Nat Genet

107

109

View full text Add to dashboard Cite

show abstract

“…Most importantly, the proposed molecular events leading to neuronal oxidative stress in hyperglycemia, explicitly via increased superoxide anion generation (Ziegler et al, 2015), mitochondrial dysfunction (Patti and Corvera, 2010), PARP1 activation (Obrosova et al, 2005), impairment of the PPP (Ziegler et al, 2017), glycation (Aubert et al, 2014) and glutathione system deficits (Kasznicki et al, 2012; Mendez et al, 2015), are all cogently established in diabetic patients with neuronal pathology. Remarkably, clinical trials employing pharmacological agents to target some of these pathways, including aldose reductase inhibitors to diminish polyol pathway influx (Greene et al, 1999; Obrosova et al, 2002; Kawai et al, 2010; Sekiguchi et al, 2019) or exogenous superoxide dismutase (SOD) to quench superoxide anion (Bertolotto and Massone, 2012), have been demonstrated to improve diabetic peripheral nerve damage and oxidative status, further solidifying the importance of oxidative stress in neuronal affections arising from hyperglycemia in humans. Unquestionably, though, glycemic control remains the most accessible means to preclude oxidative stress-induced diabetic complications in the brain and in peripheral nerves.…”

Section: Cellular Evidence: Neuronal Oxidative Stress In Hyperglycemiamentioning

confidence: 99%

Diabetes, a Contemporary Risk for Parkinson’s Disease: Epidemiological and Cellular Evidences

Sergi

Renaud

Simola

et al. 2019

Front. Aging Neurosci.

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Diabetes mellitus (DM), a group of diseases characterized by defective glucose metabolism, is the most widespread metabolic disorder affecting over 400 million adults worldwide. This pathological condition has been implicated in the pathogenesis of a number of central encephalopathies and peripheral neuropathies. In further support of this notion, recent epidemiological evidence suggests a link between DM and Parkinson’s disease (PD), with hyperglycemia emerging as one of the culprits in neurodegeneration involving the nigrostriatal pathway, the neuroanatomical substrate of the motor symptoms affecting parkinsonian patients. Indeed, dopaminergic neurons located in the mesencephalic substantia nigra appear to be particularly vulnerable to oxidative stress and degeneration, likely because of their intrinsic susceptibility to mitochondrial dysfunction, which may represent a direct consequence of hyperglycemia and hyperglycemia-induced oxidative stress. Other pathological pathways induced by increased intracellular glucose levels, including the polyol and the hexosamine pathway as well as the formation of advanced glycation end-products, may all play a pivotal role in mediating the detrimental effects of hyperglycemia on nigral dopaminergic neurons. In this review article, we will examine the epidemiological as well as the molecular and cellular clues supporting the potential susceptibility of nigrostriatal dopaminergic neurons to hyperglycemia.

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“…ranirestat, zopolrestat and epalrestat). Ranirestat and zopolrestat are already tested in clinical phases and have been shown to improve sensory nerve conduction velocity in both Type 1 and Type 2 diabetic patients (Sekiguchi et al, 2019) and to stabilize or partially reverse left ventricular abnormalities in cardiovascular autonomic neuropathy patients (Fisher & Tahrani, 2017). Moreover, non‐selective inhibition of aldose reductase by suldinac has been shown to reduce myocardial infarct size in normal and also in STZ‐induced diabetic rats (Annapurna, Challa, Prakash, & Viswanath, 2008).…”

Section: Simultaneous Therapeutic Options For the Ischaemic Heart In mentioning

confidence: 99%

Myocardial ischaemia reperfusion injury and cardioprotection in the presence of sensory neuropathy: Therapeutic options

Bencsik

Gömöri

Szabados

et al. 2020

British J Pharmacology

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During the last decades, mortality from acute myocardial infarction has been dramatically reduced. However, the incidence of post-infarction heart failure is still increasing. Cardioprotection by ischaemic conditioning had been discovered more than three decades ago. Its clinical translation, however, is still an unmet need. This is mainly due to the disrupted cardioprotective signalling pathways in the presence of different cardiovascular risk factors, co-morbidities and the medication being taken. Sensory neuropathy is one of the co-morbidities that has been shown to interfere with cardioprotection. In the present review, we summarize the diverse aetiology of sensory neuropathies and the mechanisms by which these neuropathies may interfere with ischaemic heart disease and cardioprotective signalling. Finally, we suggest future therapeutic options targeting both ischaemic heart and sensory neuropathy simultaneously.

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Aldose reductase inhibitor ranirestat significantly improves nerve conduction velocity in diabetic polyneuropathy: A randomized double‐blind placebo‐controlled study in Japan

Abstract: Ranirestat (40 mg/day) was well tolerated and improved nerve conduction velocity. Regarding symptoms and signs, no detectable benefits over the placebo were observed in the ranirestat group during the 52 weeks of treatment.

Cited by 38 publications

References 34 publications

Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes

Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes

Diabetes, a Contemporary Risk for Parkinson’s Disease: Epidemiological and Cellular Evidences

Myocardial ischaemia reperfusion injury and cardioprotection in the presence of sensory neuropathy: Therapeutic options

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