Lipopolysaccharide impairs neurodevelopment and induces changes in astroglial reactivity, antioxidant defenses and bioenergetics in the cerebral cortex of neonatal rats.

Neonates have an immature immune system, which increases their vulnerability to infectious agents and inflammatory insults. The administration of the immunostimulatory agent lipopolysaccharide (LPS) has been shown to induce the expression of pro-inflammatory cytokines and cause behavior alterations in rodents at different ages. However, the effects of LPS administration during the neonatal period and its consequences during immune system maturation remain to be elucidated. We showed here that a single intraperitoneal administration of LPS in rats on postnatal day (PND) 7 caused early and variable alterations in TNF-α, S100B and GFAP levels in the cerebral cortex, CSF and serum of the animals, indicating long-term induction of neuroinflammation and astroglial reactivity. However, on PND 21, only GFAP levels were increased by LPS. Additionally, LPS induced oxidative stress and altered energy metabolism enzymes in the cerebral cortex on PND 21, and caused neurodevelopment impairment over time. These data suggest that neuroinflammation induction during the neonatal period induces glial reactivity, oxidative stress and bioenergetic disruption that may lead to neurodevelopment impairment and cognitive deficit in adult life.

A Possible Anti-Inflammatory Effect of Proline in the Brain Cortex and Cerebellum of Rats.

Although many studies show the toxic effects of proline, recently it has been reported some anti-inflammatory effect of this amino acid. Our principal objective was to investigate the effects of proline on the alterations caused by LPS (lipopolysaccharide) administration in the cerebral cortex and cerebellum of young Wistar rats. The animals were divided into four groups: control (0.85% saline); proline, (12.8 µmol of proline/g body weight from day 7 to 13; 14.6 µmol of proline/g body weight from day 14 to 17 and 16.4 µmol of proline/g body weight from day 18 to 21); LPS (1 mg/g body weight); LPS plus proline. The animals were killed at 22 days of age, 12 h after the last injection, by decapitation without anesthesia. The brain cortex and cerebellum were separated for chemical determinations. The effects of proline and LPS in the cerebral cortex and cerebellum on the expression of S100B and GFAP, oxidative stress parameters, enzymes of phosphoryl transfer network activity, and mitochondrial respiration chain complexes were investigated. Two-way ANOVA showed that the administration of proline did not alter the analyzed parameter in cerebral cortex and cerebellum. On the other hand, LPS administration caused a change in these parameters. Besides, the co-administration of proline and LPS showed the ability of Pro in preventing the effects of LPS. These results indicated that LPS induces inflammation, oxidative stress, and alters energy parameters in cerebral cortex and cerebellum of the rats. Moreover, co-administration of Pro was able to prevent these harmful effects of LPS.

Evaluation of Oxidative Stress Parameters and Energy Metabolism in Cerebral Cortex of Rats Subjected to Sarcosine Administration.

Sarcosine is an N-methyl derivative of the amino acid glycine, and its elevation in tissues and physiological fluids of patients with sarcosinemia could reflect a deficient pool size of activated 1-carbon units. Sarcosinemia is a rare inherited metabolic condition associated with mental retardation. In the present study, we investigated the acute effect of sarcosine and/or creatine plus pyruvate on some parameters of oxidative stress and energy metabolism in cerebral cortex homogenates of 21-day-old Wistar rats. Acute administration of sarcosine induced oxidative stress and diminished the activities of adenylate kinase, GAPDH, complex IV, and mitochondrial and cytosolic creatine kinase. On the other hand, succinate dehydrogenase activity was enhanced in cerebral cortex of rats. Moreover, total sulfhydryl content was significantly diminished, while DCFH oxidation, TBARS content, and activities of SOD and GPx were significantly enhanced by acute administration of sarcosine. Co-administration of creatine plus pyruvate was effective in the prevention of alterations provoked by sarcosine administration on the oxidative stress and the enzymes of phosphoryltransfer network. These results indicate that acute administration of sarcosine may stimulate oxidative stress and alter the energy metabolism in cerebral cortex of rats. In case these effects also occur in humans, they may contribute, along with other mechanisms, to the neurological dysfunction of sarcosinemia, and creatine and pyruvate supplementation could be beneficial to the patients.