Pristanic Acid Provokes Lipid, Protein, and DNA Oxidative Damage and Reduces the Antioxidant Defenses in Cerebellum of Young Rats

Abstract

Zellweger syndrome (ZS) and some peroxisomal diseases are severe inherited disorders mainly characterized by neurological symptoms and cerebellum abnormalities, whose pathogenesis is poorly understood. Biochemically, these diseases are mainly characterized by accumulation of pristanic acid (Prist) and other fatty acids in the brain and other tissues. In this work, we evaluated the in vitro influence of Prist on redox homeostasis by measuring lipid, protein, and DNA damage, as well as the antioxidant defenses and the activities of aconitase and α-ketoglutarate dehydrogenase in cerebellum of 30-day-old rats. The effect of Prist on DNA damage was also evaluated in blood of these animals. Some parameters were also evaluated in cerebellum from neonatal rats and in cerebellum neuronal cultures. Prist significantly increased malondialdehyde (MDA) levels and carbonyl formation and reduced sulfhydryl content and glutathione (GSH) concentrations in cerebellum of young rats. It also caused DNA strand damage in cerebellum and induced a high micronuclei frequency in blood. On the other hand, this fatty acid significantly reduced α-ketoglutarate dehydrogenase and aconitase activities in rat cerebellum. We also verified that Prist-induced increase of MDA levels was totally prevented by melatonin and attenuated by α-tocopherol but not by the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester, indicating the involvement of reactive oxygen species in this effect. Cerebellum from neonate rats also showed marked alterations of redox homeostasis, including an increase of MDA levels and a decrease of sulfhydryl content and GSH concentrations elicited by Prist. Finally, Prist provoked an increase of dichlorofluorescein (DCFH) oxidation in cerebellum-cultivated neurons. Our present data indicate that Prist compromises redox homeostasis in rat cerebellum and blood and inhibits critical enzymes of the citric acid cycle that are susceptible to free radical attack. The present findings may contribute to clarify the pathogenesis of the cerebellar alterations observed in patients affected by ZS and some peroxisomal disorders in which Prist is accumulated.

High‐Cholesterol Diet Disrupts the Levels of Hormones Derived from Anterior Pituitary Basophilic Cells

“…Busanello et al . found that the accumulation of pristanic acid and other fatty acids in the brain could induce Zellweger syndrome. A high‐fat diet could induce pituitary function change .…”

Redox interplay between mitochondria and peroxisomes

“…As such, many studies on the toxicity of pristanic acid focus on neurons. Rat astrocytes, oligodendrocytes, and neurons of the hippocampus and cerebellar granule cell layer have been reported to generate more ROS upon exposure to pristanic acid (50–200 μM) (Rönicke et al, 2009 ; Busanello et al, 2014 ). Compared to phytanic acid, pristanic acid has a stronger cytotoxic effect on the hippocampal cells: it causes a more profound mitochondrial depolarisation and induces a stronger ROS production (Rönicke et al, 2009 ).…”

“…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 ΔΨm and NAD(P)H levels and causes mitochondrial swelling.…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…As such, many studies on the toxicity of pristanic acid focus on neurons. Rat astrocytes, oligodendrocytes, and neurons of the hippocampus and cerebellar granule cell layer have been reported to generate more ROS upon exposure to pristanic acid (50-200 µM) (Rönicke et al, 2009;Busanello et al, 2014). Compared to phytanic acid, pristanic acid has a stronger cytotoxic effect on the hippocampal cells: it causes a more profound mitochondrial depolarisation and induces a stronger ROS production (Rönicke et al, 2009).…”

“…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.…”