Abstract
Ethoxyquin (EQ), a quinolone-based antioxidant, has demonstrated neuroprotective properties against several neurotoxic drugs in a phenotypic screening and is shown to protect axons in animal models of chemotherapy-induced peripheral neuropathy. We assessed the effects of EQ on peripheral nerve function in the db/db mouse model of type II diabetes. After a 7 week treatment period, 12-week-old db/db-vehicle, db/+ -vehicle and db/db-EQ treated animals were evaluated by nerve conduction, paw withdrawal against a hotplate, and fiber density in hindlimb footpads. We found that the EQ group had shorter paw withdrawal latency compared to vehicle db/db group. The EQ group scored higher in nerve conduction studies, compared to vehicle-treated db/db group. Morphology studies yielded similar results. To investigate the potential role of mitochondrial DNA (mtDNA) deletions in the observed effects of EQ, we measured total mtDNA deletion burden in the distal sciatic nerve. We observed an increase in total mtDNA deletion burden in vehicle-treated db/db mice compared to db/+ mice that was partially prevented in db/db-EQ treated animals. These results suggest that EQ treatment may exert a neuroprotective effect in diabetic neuropathy. The prevention of diabetes-induced mtDNA deletions may be a potential mechanism of the neuroprotective effects of EQ in diabetic neuropathy.
Highlights
Diabetic peripheral neuropathy (DPN) is a major complication of diabetes that affects predominantly sensory and autonomic axons
We previously have shown that small fiber sensory and autonomic neuropathy occurs as early as six weeks of age in db/db mice[24]
We began EQ treatment at 6 weeks because we did not see any defect in thermal sensation at 5 weeks and our prior study had shown that db/db mice develop signs of peripheral neuropathy by age 6 weeks and the defect of thermal sensation is consistent with the denervation[24]
Summary
Diabetic peripheral neuropathy (DPN) is a major complication of diabetes that affects predominantly sensory and autonomic axons. Abnormalities in mitochondrial fusion and fission has been described in animal models of DPN18 and accumulation of mtDNA deletion mutations has been shown to play a role in HIV-associated peripheral n europathy[19]. We still do not have a clear understanding of whether mtDNA mutations and subsequent mitochondrial dysfunction is involved in diabetic neuropathy. We assessed the effect of EQ in a genetic model of type II diabetes, the db/db m ouse[22,23] and assessed the role that mtDNA deletion mutation might play. We show that EQ demonstrates neuroprotective effects on several measures of both sensory and autonomic diabetic neuropathy and that this neuroprotection correlates with reduction in mtDNA deletion mutations induced by diabetes
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