Brain and Muscle Redox Imbalance Elicited by Acute Ethylmalonic Acid Administration

Abstract

Ethylmalonic acid (EMA) accumulates in tissues and biological fluids of patients affected by short-chain acyl-CoA dehydrogenase deficiency (SCADD) and ethylmalonic encephalopathy, illnesses characterized by neurological and muscular symptoms. Considering that the mechanisms responsible for the brain and skeletal muscle damage in these diseases are poorly known, in the present work we investigated the effects of acute EMA administration on redox status parameters in cerebral cortex and skeletal muscle from 30-day-old rats. Animals received three subcutaneous injections of EMA (6 μmol/g; 90 min interval between injections) and were killed 1 h after the last administration. Control animals received saline in the same volumes. EMA administration significantly increased thiobarbituric acid-reactive substances levels in cerebral cortex and skeletal muscle, indicating increased lipid peroxidation. In addition, carbonyl content was increased in EMA-treated animal skeletal muscle when compared to the saline group. EMA administration also significantly increased 2’,7’-dihydrodichlorofluorescein oxidation and superoxide production (reactive species markers), and decreased glutathione peroxidase activity in cerebral cortex, while glutathione levels were decreased only in skeletal muscle. On the other hand, respiratory chain complex I-III activity was altered by acute EMA administration neither in cerebral cortex nor in skeletal muscle. The present results show that acute EMA administration elicits oxidative stress in rat brain and skeletal muscle, suggesting that oxidative damage may be involved in the pathophysiology of the brain and muscle symptoms found in patients affected by SCADD and ethylmalonic encephalopathy.

Poor geotaxis correlated with haematoporphyrin‐induced peroxidation of brain lipids as a predictor of medfly longevity reduction

“…The increased lipid peroxidation observed in the head of 10-day-old flies indicated that HP IX crossed the gut and affected the head more strongly than the thorax. Similar results were reported by Schuck et al (2015) who found that ethylmalonic acid-injected rats presented a marked increase in TBARS levels in both the cerebral cortex and muscle, and the registered levels in the former tissue were higher than in the latter tissue. As indicated by Rao & Balachandran (2002), the brain is particularly vulnerable to free radical damage because membrane lipids contain high levels of polyunsaturated fatty acid side chains, and consume large quantities of oxygen.…”

SHR/NCrl rats as a model of ADHD can be discriminated from controls based on their brain, blood, or urine metabolomes

“…In addition, elevated succinate levels and mitochondrial dysfunctions have been associated to an increased oxidative stress, which has been extensively described in the brain of this animal model 34 , 35 , and in ADHD patients 36 – 39 . The higher brain levels of 2-ethylmalonate also observed in SHR/NCrl rats are consistent with an increased oxidative stress as it is a reliable lipid peroxidation biomarker 40 . Thus, the higher brain levels of glucuronate detected could reflect an elevated activity of the pentose phosphate pathway due to the increased oxidative stress, as the pentose phosphate pathway is used by neurons to regenerate glutathione 41 .…”

Silencing of ECHDC1 inhibits growth of gemcitabine‑resistant bladder cancer cells

“…In human cells, silencing of ECHDC1 decreased ethylmalonyl-CoA decarboxylase activity and increased the formation of ethylmalonic acid (EMA) (11). EMA induces oxidative stress in skeletal muscle and in the cerebral cortex (18,19). Human cancer cells are more sensitive to oxidative stress, which inhibits cell proliferation (20).…”