The role of oxidative damage in the neuropathology of organic acidurias: Insights from animal studies

Abstract

Organic acidurias represent a group of inherited disorders resulting from deficient activity of specific enzymes of the catabolism of amino acids, carbohydrates or lipids, leading to tissue accumulation of one or more carboxylic (organic) acids. Patients affected by organic acidurias predominantly present neurological symptoms and structural brain abnormalities, of which the aetiopathogenesis is poorly understood. However, in recent years increasing evidence has emerged suggesting that oxidative stress is possibly involved in the pathology of some organic acidurias and other inborn errors of metabolism. This review addresses some of the recent developments obtained mainly from animal studies indicating oxidative damage as an important determinant of the neuropathophysiology of some organic acidurias. Recent data showing that various organic acids are capable of inducing free radical generation and decreasing brain antioxidant defences is presented. The discussion focuses on the relatively low antioxidant defences of the brain and the vulnerability of this tissue to reactive species. This offers new perspectives for potential therapeutic strategies for these disorders, which may include the early use of appropriate antioxidants as a novel adjuvant therapy, besides the usual treatment based on removing toxic compounds and using special diets and pharmacological agents, such as cofactors and L-carnitine.

Lipid peroxidation in rats treated with vincristine sulphate and nandrolone decanoate

“…Total blood was homogenized in PBS 0.1M (pH 7.4) containing Triton X -100 (0.03%) and stocked at -20°C for further enzymatic assays. TBARS reactions were determined by the method previously described (Jentzsch et al, 1996) The increased TBARS values may be due in part to not only the aerobic metabolism of the CNS, but also to high levels of polyunsaturated fatty acids and low levels of antioxidant defenses (Wajner et al, 2004). The results in striatum demonstrate that the separate use of the two drugs increased free radical production at that site.…”

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

“…One factor that is considered to play a role in the neuropathogenesis of the disease is oxidative stress. The role of oxidative damage in the neuropathology of organic acidurias is presented in a review by Wajner et al (2004) who discusses considerable evidence in which organic acid accumulation associated with various metabolic disorders will induce free radical and reactive species (RS) generation and will also decrease antioxidant defenses in tissues. These reactive species can inhibit various complexes of the respiratory chain and critical enzymes necessary for energy production resulting in metabolic failure, cell injury and cell death (Castro et al, 1994(Castro et al, ,1998Radi et al, 2002;Wyse et al, 2001).…”

Biochemical Characterisation and Whole Genome Expression Profiling of Cultured Skin Fibroblasts from Two South African Adults with Urinary 3-Hydroxyisovaleric Acid and 3-Methylcrotonylglycine

“…In addition to the index patient and his brother another thirteen family members over three generations (Figure 1), ten females (aged, 83,80,56,53,33,7, and twins of 2 years) and three males (aged 31, 6 and 4 years), participated in a voluntarily metabolic screen. From the thirteen family members that were screened another two males in the family, the grandsons of NWU002 (NWU003, male, aged 6 years and NWU004, male, aged 4 years) also presented with a similar urinary organic acid profile as that of NWU001 and NWU002 (Supplementary Table 1).…”

“…Since oxidative stress and unregulated reactive oxygen species (ROS) were reported to contribute to MCC deficiency related neurological symptoms [55][56][57], the knowledge-based ROS interactome of marginal MCC deficiency was compiled and inspected. Secondary signalling responses and the associated impact on target transcripts of the interactome were identified with IPA software (Figure 3).…”