Experimental Evidence that Methylmalonic Acid Provokes Oxidative Damage and Compromises Antioxidant Defenses in Nerve Terminal and Striatum of Young Rats

Abstract

Methylmalonic acidemia and propionic acidemia are organic acidemias biochemically characterized by predominant tissue accumulation of methylmalonic acid (MMA) and propionic acid (PA), respectively. Affected patients present predominantly neurological symptoms, whose pathogenesis is not yet fully established. In the present study we investigated the in vitro effects of MMA and PA on important parameters of lipid and protein oxidative damage and on the production of reactive species in synaptosomes from cerebrum of developing rats. Synaptosomes correspond to nerve terminals that have been used to investigate toxic properties of compounds on neuronal cells. The in vivo effects of intrastriatal injection of MMA and PA on the same parameters and on enzymatic antioxidant defenses, were also studied. MMA-induced in vitro and in vivo lipid peroxidation and protein oxidative damage. Furthermore, the lipid oxidative damage was attenuated or prevented, pending on the doses utilized, by the free radical scavengers α-tocopherol, melatonin and by the NMDA glutamate receptor antagonist MK-801, implying the involvement of reactive species and glutamate receptor activation in these effects. In addition, 2',7'-dichlorofluorescein diacetate oxidation was significantly increased in synaptosomes by MMA, reinforcing that reactive species generation is elicited by this organic acid. We also verified that glutathione peroxidase activity was inhibited by intrastriatal MMA injection. In contrast, PA did not induce any significant effect on all parameters examined in vitro and in vivo, implying a selective action for MMA. The present data demonstrate that oxidative stress is induced by MMA in vitro in nerve terminals and in vivo in striatum, suggesting the participation of neuronal cells in MMA-elicited oxidative damage.

Brain damage in methylmalonic aciduria: 2-methylcitrate induces cerebral ammonium accumulation and apoptosis in 3D organotypic brain cell cultures

“…The same group, however, could not find any permanent defects on mitochondrial respiration in isolated brain mitochondria after intraperitoneal injection of MMA in young rats [16]. MMA provoked oxidative damage and compromised antioxidant defenses in nerve terminals and striatum of young rats [17]. In conclusion, the mitochondrial impairment in MMAuria seems to be a combination of inhibition of specific enzymes and transporters, limitation in the availability of substrates and oxidative damage [18].…”

Expression of Proinflammatory Factors in Renal Cortex Induced by Methylmalonic Acid

“…Previous animal and human data have shown how MMA induces oxidative stress in vivo in the brain and fibroblasts. 22 In order to understand the underlying physiopathology of TI damage, we have to bear in mind that increments in interstitial volume and reported fibrosis are correlated with renal functional impairment and worse prognosis. On the contrary, the decrease in the numbers of peritubular capillaries, the morphological changes in tubular epithelia, and the intensity of inflammatory infiltration in the interstitium have also been found to be correlated with renal functional deterioration.…”

“…Rats were housed individually in metabolic cages which were placed in an air-conditioned room (18)(19)(20)(21)(22) C) with a light/dark cycle of 12 h. The study was approved by the Ethics Committee of Cruces Hospital. Animal studies were carried out in compliance with American National Institutes of Health (NIH) Principles of Laboratory Animal Care (NIH Publication 25, no.…”

Glutathione as a Redox Biomarker in Mitochondrial Disease—Implications for Therapy

“…Abnormal mitochondrial structure and function, as well as various abnormal measures of oxidative stress and redox imbalance, have been reported in animal models and patients affected by a variety of organic acidemias, including methylmalonic acidemia, cobalamin A disease, cobalamin C disease, cobalamin H/cobalamin D disease, propionic acidemia, isovaleric acidemia, 2-methyl-3-hydroxybutyric acidemia, 3-methylglutaconic acidemia types II and IV, d -2-hydroxyglutaric aciduria, l -2-hydroxyglutaric aciduria, and glutaric acidemia [42,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70]. GSH levels have been found to be low in methylmalonic acidemia (MMA), propionic acidemia (PA), and isovaleric acidemia (IVA) [25,26,71].…”