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

Abstract

Pristanic 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.

An in vitro approach to assess the neurotoxicity of valproic acid-induced oxidative stress in cerebellum and cerebral cortex of young rats

“…Sulfhydryl groups of proteins are oxidized by reactive free radicals giving rise to carbonyl levels. It is therefore presumed that attack of reactive species which are induced by this short branched chain fatty acid leads to the oxidative damage to proteins (Leipnitz et al, 2011). Our results corroborate this observation as PC content increased dose dependently on being exposed to VPA in cerebral cortex and cerebellum.…”

“…ROS have been associated with many pathophysiological conditions such as cancer and in various neurodegenerative diseases (Leipnitz et al, 2011). Under normal physiological conditions, a delicate balance exists between the rate of ROS formation and the rate of their neutralization.…”

Experimental evidence that pristanic acid disrupts mitochondrial homeostasis in brain of young rats

“…In line with these observations, we have recently shown that Prist markedly induces oxidative damage, reduces the antioxidant defenses (Leipnitz et al,2011), and compromises neurotransmission and the electron flow through the respiratory chain in brains of young rats (Busanello et al,2011). However, to our knowledge, nothing has been reported on the effects of Prist on other important parameters of mitochondrial energy homeostasis, such as the respiratory parameters states 3 and 4, respiratory control ratiom and ADP/O ratio determined by oxymetry, as well as on mitochondrial NAD(P)H levels, membrane potential, and swelling.…”

“…We always carried out parallel experiments with various blanks (controls) in the presence or absence of Prist (20–100 μM) or Palm (100 μM) and also with or without mitochondrial preparations in the reaction medium to detect any interference (artifacts) of these fatty acids on the techniques utilized to measure the mitochondrial parameters. The tested Prist doses were based on the concentrations of this fatty acid found in plasma of patients affected by some peroxisomal disorders and in previous reports showing cytotoxic effects of Prist on neural cells (Ferdinandusse et al,2000; McLean et al,2002; Kahlert et al,2005; Thompson et al,2008; Rönicke et al,2009; Smith et al,2010; Leipnitz et al,2011; Busanello et al,2011).…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…Note that pristanic acid apparently exerts its toxic effect mainly through its protonophoric action, at least in human skin fibroblasts (Komen et al, 2007). When given to post-nuclear supernatant fractions prepared from rat brain cortex, pristanic acid also causes ROS-generation, as evidenced by decreased GSH levels and increased levels of MDA and protein oxidation (Leipnitz et al, 2011;Busanello et al, 2014). In mitochondrial preparations of rat brain, pristanic acid decreases the m and NAD(P)H levels and causes mitochondrial swelling.…”