Nuclear factor erythroid-2-related factor 2 signaling in the neuropathophysiology of inherited metabolic disorders

Inherited metabolic disorders (IMDs) are rare genetic conditions that affect multiple organs, predominantly the central nervous system. Since treatment for a large number of IMDs is limited, there is an urgent need to find novel therapeutical targets. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor that has a key role in controlling the intracellular redox environment by regulating the expression of antioxidant enzymes and several important genes related to redox homeostasis. Considering that oxidative stress along with antioxidant system alterations is a mechanism involved in the neuropathophysiology of many IMDs, this review focuses on the current knowledge about Nrf2 signaling dysregulation observed in this group of disorders characterized by neurological dysfunction. We review here Nrf2 signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Additionally, beneficial effects of different Nrf2 activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf2 pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection

Why antidiabetic drugs are potentially neuroprotective during the Sars-CoV-2 pandemic: The focus on astroglial UPR and calcium-binding proteins

We are living in a terrifying pandemic caused by Sars-CoV-2, in which patients with diabetes mellitus have, from the beginning, been identified as having a high risk of hospitalization and mortality. This viral disease is not limited to the respiratory system, but also affects, among other organs, the central nervous system. Furthermore, we already know that individuals with diabetes mellitus exhibit signs of astrocyte dysfunction and are more likely to develop cognitive deficits and even dementia. It is now being realized that COVID-19 incurs long-term effects and that those infected can develop several neurological and psychiatric manifestations. As this virus seriously compromises cell metabolism by triggering several mechanisms leading to the unfolded protein response (UPR), which involves endoplasmic reticulum Ca2+ depletion, we review here the basis involved in this response that are intimately associated with the development of neurodegenerative diseases. The discussion aims to highlight two aspects—the role of calcium-binding proteins and the role of astrocytes, glial cells that integrate energy metabolism with neurotransmission and with neuroinflammation. Among the proteins discussed are calpain, calcineurin, and sorcin. These proteins are emphasized as markers of the UPR and are potential therapeutic targets. Finally, we discuss the role of drugs widely prescribed to patients with diabetes mellitus, such as statins, metformin, and calcium channel blockers. The review assesses potential neuroprotection mechanisms, focusing on the UPR and the restoration of reticular Ca2+ homeostasis, based on both clinical and experimental data

ETHE1 and MOCS1 deficiencies : disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblasts

Ethylmalonic encephalopathy protein 1 (ETHE1) and molybdenum cofactor (MoCo) defciencies are hereditary disorders that afect the catabolism of sulfur-containing amino acids. ETHE1 defciency is caused by mutations in the ETHE1 gene, while MoCo defciency is due to mutations in one of three genes involved in MoCo biosynthesis (MOCS1, MOCS2 and GPHN). Patients with both disorders exhibit abnormalities of the mitochondrial respiratory chain, among other biochemical fndings. However, the pathophysiology of the defects has not been elucidated. To characterize cellular derangements, mitochondrial bioenergetics, dynamics, endoplasmic reticulum (ER)-mitochondria communication, superoxide production and apoptosis were evaluated in fbroblasts from four patients with ETHE1 defciency and one with MOCS1 defciency. The efect of JP4-039, a promising mitochondrial-targeted antioxidant, was also tested on cells. Our data show that mitochondrial respiration was decreased in all patient cell lines. ATP depletion and increased mitochondrial mass was identifed in the same cells, while variable alterations in mitochondrial fusion and fssion were seen. High superoxide levels were found in all cells and were decreased by treatment with JP4-039, while the respiratory chain activity was increased by this antioxidant in cells in which it was impaired. The content of VDAC1 and IP3R, proteins involved in ER-mitochondria communication, was decreased, while DDIT3, a marker of ER stress, and apoptosis were increased in all cell lines. These data demonstrate that previously unrecognized broad disturbances of cellular function are involved in the pathophysiology of ETHE1 and MOCS1 defciencies, and that reduction of mitochondrial superoxide by JP4-039 is a promising strategy for adjuvant therapy of these disorders

Pristanic acid promotes oxidative stress in brain cortex of young rats: A possible pathophysiological mechanism for brain damage in peroxisomal disorders

AbstractPristanic acid (Prist) is accumulated in various peroxisomal disorders characterized by severe neurological dysfunction whose pathogenesis is poorly understood. Since oxidative damage has been demonstrated in brain of patients affected by neurodegenerative disorders, in the present work we investigated the in vitro effects of Prist on important parameters of oxidative stress in cerebral cortex from young rats. Prist significantly increased malondialdehyde levels, reflecting an increase of lipid peroxidation. This effect was totally prevented by the free radical scavenger melatonin, suggesting the involvement of reactive species. Prist also provoked protein oxidative damage, as determined by increased carbonyl formation and sulfhydryl oxidation. Otherwise, it did not alter nitric oxide production, indicating that nitrogen reactive species were not implicated in the lipid and oxidative damage provoked by Prist. Furthermore, the concentration of glutathione (GSH), the major brain non-enzymatic antioxidant defense, was significantly decreased by Prist and this decrease was fully prevented by melatonin and attenuated by α-tocopherol. It is therefore presumed that Prist elicits oxidative stress in the brain probably via reactive oxygen species formation and that this pathomechanism may possibly be involved in the brain damage found in patients affected by peroxisomal disorders where Prist accumulates

Inibição dos complexos da cadeia respiratória pelos ácidos 2-metil-3-hidroxibutírico e 2-metilacetoacético em córtex cerebral de ratos jovens

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Inhibition of cytochrome c oxidase activity in rat cerebral cortex and human skeletal muscle by d-2-hydroxyglutaric acid in vitro

Abstractl-2-Hydroxyglutaric (LGA) and d-2-hydroxyglutaric (DGA) acids are the characteristic metabolites accumulating in the neurometabolic disorders known as l-2-hydroxyglutaric aciduria and d-2-hydroxyglutaric aciduria, respectively. Although these disorders are predominantly characterized by severe neurological symptoms, the neurotoxic mechanisms of brain damage are virtually unknown. In this study we have evaluated the role of LGA and DGA at concentrations ranging from 0.01 to 5.0 mM on various parameters of energy metabolism in cerebral cortex slices and homogenates of 30-day-old Wistar rats, namely glucose uptake, CO2 production and the respiratory chain enzyme activities of complexes I to IV. DGA significantly decreased glucose utilization (2.5 and 5.0 mM) by brain homogenates and CO2 production (5 mM) by brain homogenates and slices, whereas LGA had no effect on either measurement. Furthermore, DGA significantly inhibited cytochrome c oxidase activity (complex IV) (EC 1.9.3.1) in a dose-dependent manner (35–95%) at doses as low as 0.5 mM, without compromising the other respiratory chain enzyme activities. In contrast, LGA did not interfere with these activities. Our results suggest that the strong inhibition of cytochrome c oxidase activity by increased levels of DGA could be related to the neurodegeneration of patients affected by d-2-hydroxyglutaric aciduria

Myelin disruption, neuroinflammation, and oxidative stress induced by sulfite in the striatum of rats are mitigated by the pan-PPAR agonist bezafibrate

Sulfite predominantly accumulates in the brain of patients with isolated sulfite oxidase (ISOD) and molybdenum cofactor (MoCD) deficiencies. Patients present with severe neurological symptoms and basal ganglia alterations, the pathophysiology of which is not fully established. Therapies are ineffective. To elucidate the pathomechanisms of ISOD and MoCD, we investigated the effects of intrastriatal administration of sulfite on myelin structure, neuroinflammation, and oxidative stress in rat striatum. Sulfite administration decreased FluoromyelinTM and myelin basic protein staining, suggesting myelin abnormalities. Sulfite also increased the staining of NG2, a protein marker of oligodendrocyte progenitor cells. In line with this, sulfite also reduced the viability of MO3.13 cells, which express oligodendroglial markers. Furthermore, sulfite altered the expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1), indicating neuroinflammation and redox homeostasis disturbances. Iba1 staining, another marker of neuroinflammation, was also increased by sulfite. These data suggest that myelin changes and neuroinflammation induced by sulfite contribute to the pathophysiology of ISOD and MoCD. Notably, post-treatment with bezafibrate (BEZ), a pan-PPAR agonist, mitigated alterations in myelin markers and Iba1 staining, and IL-1β, IL-6, iNOS and HO-1 expression in the striatum. MO3.13 cell viability decrease was further prevented. Moreover, pretreatment with BEZ also attenuated some effects. These findings show the modulation of PPAR as a potential opportunity for therapeutic intervention in these disorders

Inhibition of cytochrome c oxidase activity in rat cerebral cortex and human skeletal muscle by d-2-hydroxyglutaric acid in vitro

Abstractl-2-Hydroxyglutaric (LGA) and d-2-hydroxyglutaric (DGA) acids are the characteristic metabolites accumulating in the neurometabolic disorders known as l-2-hydroxyglutaric aciduria and d-2-hydroxyglutaric aciduria, respectively. Although these disorders are predominantly characterized by severe neurological symptoms, the neurotoxic mechanisms of brain damage are virtually unknown. In this study we have evaluated the role of LGA and DGA at concentrations ranging from 0.01 to 5.0 mM on various parameters of energy metabolism in cerebral cortex slices and homogenates of 30-day-old Wistar rats, namely glucose uptake, CO2 production and the respiratory chain enzyme activities of complexes I to IV. DGA significantly decreased glucose utilization (2.5 and 5.0 mM) by brain homogenates and CO2 production (5 mM) by brain homogenates and slices, whereas LGA had no effect on either measurement. Furthermore, DGA significantly inhibited cytochrome c oxidase activity (complex IV) (EC 1.9.3.1) in a dose-dependent manner (35–95%) at doses as low as 0.5 mM, without compromising the other respiratory chain enzyme activities. In contrast, LGA did not interfere with these activities. Our results suggest that the strong inhibition of cytochrome c oxidase activity by increased levels of DGA could be related to the neurodegeneration of patients affected by d-2-hydroxyglutaric aciduria

Protective effects of diet containing rutin against trichlorfon-induced muscle bioenergetics disruption and impairment on fatty acid profile of silver catfish Rhamdia quelen

Trichlorfon is an organophosphate insecticide that is widely used on fish farms to control parasitic infections. It has been detected in freshwater ecosystems as well as in fishery products. There is a growing body of evidence to suggest that certain feed additives may reduce or prevent pesticide-induced toxicity in fish. The aim of the present study was to determine whether acute exposure to trichlorfon would alter bioenergetic homeostasis and alter fatty acid profiles in muscles of silver catfish (Rhamdia quelen). We also sought to determine whether rutin prevents or reduces these effects. Cytosolic and mitochondrial creatine kinase (CK) and activities of complexes II-III and IV in muscle were significantly inhibited by exposure to 11 mg/L trichlorfon for 48 h compared to effects in the unexposed group. Total content of polyunsaturated fatty acids (omega-3 and omega-6) were significantly lower in muscle of silver catfish exposed to 11 mg/L trichlorfon for 48 h than in the unexposed group. Addition of 3 mg rutin/kg feed increased CK activity and prevented inhibition of complex IV activity, as well as preventing all alterations of muscle fatty acid profiles elicited by exposure to trichlorfon. No significant differences were observed between groups with respect to muscle adenylate kinase or pyruvate kinase activities, as well as total content of saturated and monounsaturated fatty acids. Our findings suggest that exposure (48 h) to 11 mg trichlorfon/L water inhibits cytosolic and mitochondrial CK activity in muscle. Trichlorfon also affects activities of complexes II-III and IV in respiratory chain, with important consequences for adenosine triphosphate production. The pesticide alters fatty acid profiles in the fish and endangers human consumers of the product. The most important finding of the present study is that inclusion of rutin improves bioenergetic homeostasis and muscle fatty acid profiles, suggesting that it reduces trichlorfon-induced muscle damage