Abstract
Background and AimsGlutaric aciduria type I (GA-I) is characterized by accumulation of glutaric acid (GA) and neurological symptoms, such as cognitive impairment. Although this disease is related to oxidative stress and inflammation, it is not known whether these processes facilitate the memory impairment. Our objective was to investigate the performance of rat pups chronically injected with GA and lipopolysaccharide (LPS) in spatial memory test, antioxidant defenses, cytokines levels, Na+, K+-ATPase activity, and hippocampal volume. We also evaluated the effect of N-acetylcysteine (NAC) on theses markers.MethodsRat pups were injected with GA (5umol g of body weight-1, subcutaneously; twice per day; from 5th to 28th day of life), and were supplemented with NAC (150mg/kg/day; intragastric gavage; for the same period). LPS (2mg/kg; E.coli 055 B5) or vehicle (saline 0.9%) was injected intraperitoneally, once per day, from 25th to 28th day of life. Oxidative stress and inflammatory biomarkers as well as hippocampal volume were assessed.ResultsGA caused spatial learning deficit in the Barnes maze and LPS potentiated this effect. GA and LPS increased TNF-α and IL-1β levels. The co-administration of these compounds potentiated the increase of IL-1β levels but not TNF-α levels in the hippocampus. GA and LPS increased TBARS (thiobarbituric acid-reactive substance) content, reduced antioxidant defenses and inhibited Na+, K+-ATPase activity. GA and LPS co-administration did not have additive effect on oxidative stress markers and Na+, K+ pump. The hippocampal volume did not change after GA or LPS administration. NAC protected against impairment of spatial learning and increase of cytokines levels. NAC Also protected against inhibition of Na+,K+-ATPase activity and oxidative markers.ConclusionsThese results suggest that inflammatory and oxidative markers may underlie at least in part of the neuropathology of GA-I in this model. Thus, NAC could represent a possible adjuvant therapy in treatment of children with GA-I.
Highlights
Glutaric aciduria type I (GA-I) is an inherited neurometabolic disease caused by a deficiency of mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH; EC 1.3.99.7) involved in the metabolism of L-lysine, L-hydroxylysine and L-tryptophan
Studies have reported that patients with glutaric acid (GA)-I present cognitive deficit [5,6,7] mainly after encephalopathic crises precipitated by a non-specific illness or infection [10], which suggests a close association between inflammation and the occurrence of cognitive disorder in GA-I children
Since there is clinical evidence that infection and/or inflammation mediators facilitate metabolic crises and neurologic dysfunction in patients with GA-I, in this study we investigated the performance of rat pups chronically injected with GA and LPS in spatial memory test, antioxidant defenses, cytokines levels, NA+,K+-ATPase activity, and hippocampal volume
Summary
GA-I is an inherited neurometabolic disease caused by a deficiency of mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH; EC 1.3.99.7) involved in the metabolism of L-lysine, L-hydroxylysine and L-tryptophan. Glutaric aciduria type I (GA-I) is characterized by accumulation of glutaric acid (GA) and neurological symptoms, such as cognitive impairment. This disease is related to oxidative stress and inflammation, it is not known whether these processes facilitate the memory impairment. Our objective was to investigate the performance of rat pups chronically injected with GA and lipopolysaccharide (LPS) in spatial memory test, antioxidant defenses, cytokines levels, Na+, K+-ATPase activity, and hippocampal volume. GA and LPS co-administration did not have additive effect on oxidative stress markers and Na+, K+ pump. NAC protected against impairment of spatial learning and increase of cytokines levels. NAC protected against inhibition of Na+,K+-ATPase activity and oxidative markers. NAC could represent a possible adjuvant therapy in treatment of children with GA-I
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