Neuroinflammation aggravated by traumatic brain injury at high altitude is reversed by L-serine via NFAT1-mediated microglial polarization.

Traumatic brain injury (TBI) is one of the main causes of disability and death, especially in plateau areas, where the degree of injury is often more serious than in plain areas. It is likely that high altitude (HA) aggravates neuroinflammation; however, prior studies are limited. This study was designed to evaluate the effects of HA on the degree of TBI and the neuroprotective effects and underlying mechanisms of L-serine against TBI at HA (HA-TBI). In in vivo experiments, wild-type mice and mice with Nfat1 (Nfat1-/- ) deficiency in the C57BL/6 background were kept in a hypobaric chamber for 3 days under simulated conditions of 4,000 m, 6,000 m and 8,000 m above sea level. After leaving the chamber, the standardized TBI model was established immediately. Mice were then intraperitoneally injected with L-serine (342 mg.kg-1) 2 h after TBI and then daily for 5 days. Behavioral tests and histological analysis were assessed at different time points post TBI induction. In vitro, we applied primary cultured microglia for hypoxia treatment (1% O2 for 24 h). The major findings include the following: (1) with increasing altitude, the neurological function of TBI mice decreased, and the damage to cerebral gray matter and white matter became more significant, (2) L-serine significantly improved the sensorimotor function of mice, reversed the increase in brain lesion volume, and promoted the renovation of brain tissue after HA-TBI, (3) L-serine significantly decreased the activation of microglia and promoted microglia polarization toward the protective M2 phenotype both in vivo and in vitro, (4) L-serine significantly suppressed the expression of NFAT1 in mice after HA-TBI and inhibited NFAT1 expression in primary microglia after hypoxia, and (5) knockout of Nfat1 inhibited the inflammatory reaction caused by excessive activation of microglia, and L-serine lost its neuroprotective effect in Nfat1 knockout mice. The present study suggests that HA aggravates brain damage after TBI and that the damage also increases with increasing altitude. As an endogenous amino acid, L-serine may be a neuroprotective agent against HA-TBI, and suppression of NFAT1 in microglia is a potential therapy for neuroinflammation in the future.

Nitrogen narcosis induced by repetitive hyperbaric nitrogen oxygen mixture exposure impairs long-term cognitive function in newborn mice.

Human beings are exposed to compressed air or a nitrogen-oxygen mixture, they will produce signs and symptoms of nitrogen narcosis such as amnesia or even loss of memory, which may be disappeared once back to the normobaric environment. This study was designed to investigate the effect of nitrogen narcosis induced by repetitive hyperbaric nitrogen-oxygen mixture exposure on long-term cognitive function in newborn mice and the underlying mechanisms. The electroencephalogram frequency was decreased while the amplitude was increased in a pressure-dependent manner during 0.6, 1.2, 1.8 MPa (million pascal) nitrogen-oxygen mixture exposures in adult mice. Nitrogen narcosis in postnatal days 7-9 mice but not in adult mice induced by repetitive hyperbaric exposure prolonged the latency to find the platform and decreased the number of platform-site crossovers during Morris water maze tests, and reduced the time in the center during the open field tests. An increase in the expression of cleaved caspase-3 in the hippocampus and cortex were observed immediately on the first day after hyperbaric exposure, and this lasted for seven days. Additionally, nitrogen narcosis induced loss of the dendritic spines but not of the neurons, which may mainly account for the cognitive dysfunction. Nitrogen narcosis induced long-term cognitive and emotional dysfunction in the postnatal mice but not in the adult mice, which may result from neuronal apoptosis and especially reduction of dendritic spines of neurons.