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.

Creatine and pyruvate prevent behavioral and oxidative stress alterations caused by hypertryptophanemia in rats.

It is known that the accumulation of tryptophan and its metabolites is related to brain damage associated with both hypertryptophanemia and neurodegenerative diseases. In this study, we investigated the effect of tryptophan administration on various parameters of behavior in the open-field task and oxidative stress, and the effects of creatine and pyruvate, on the effect of tryptophan. Forty, 60-day-old male Wistar rats, were randomly divided into four groups: saline, tryptophan, pyruvate + creatine, tryptophan + pyruvate + creatine. Animals received three subcutaneous injections of tryptophan (2 µmol/g body weight each one at 3 h of intervals) and/or pyruvate (200 µg/g body weight 1 h before tryptophan), and/or creatine (400 µg/g body weight twice a day for 5 days before tryptophan twice a day for 5 days before training); controls received saline solution (NaCl 0.85%) at the same volumes (30 µl/g body weight) than the other substances. Results showed that tryptophan increased the activity of the animals, suggesting a reduction in the ability of habituation to the environment. Tryptophan induced increase of TBA-RS and total sulfhydryls. The effects of tryptophan in the open field, and in oxidative stress were fully prevented by the combination of creatine plus pyruvate. In case these findings also occur in humans affected by hypertryptophanemia or other neurodegenerative disease in which tryptophan accumulates, it is feasible that oxidative stress may be involved in the mechanisms leading to the brain injury, suggesting that creatine and pyruvate supplementation could benefit patients affected by these disorders.