Indomethacin protects rats from neuronal damage induced by traumatic brain injury and suppresses hippocampal IL-1ß release through the inhibition of Nogo-A expression.

BACKGROUND: Nogo-A is a member of the reticulon family of membrane-associated proteins and plays an important role in axonal remodeling. The present study aimed to investigate alterations in Nogo-A expression following traumatic brain injury (TBI)-induced inflammation and neuronal damage. METHODS: A weight-drop device was used to deliver a standard traumatic impact to rats. Western blot, RT-PCR and ELISA were used to analyze the expression of Nogo-A and IL-1ß. Nogo-A antisense, and an irrelevant control oligonucleotide was intracerebroventricularly infused. We also performed H & E staining and luxol fast blue staining to evaluate the neuronal damage and demyelination resulting from TBI and various treatments. RESULTS: Based on RT-PCR and western blot analyses, the expression of Nogo-A was found to be significantly upregulated in the hippocampus beginning eight hours after TBI. In addition, TBI caused an apparent elevation in IL-1ß levels and severe neuronal damage and demyelination in the tested animals. All of the TBI-associated molecular and cellular consequences could be effectively reversed by treating the animals with the anti-inflammatory drug indomethacin. More importantly, the TBI-associated stimulation in the levels of both Nogo-A and IL-1ß could be effectively inhibited by a specific Nogo-A antisense oligonucleotide. CONCLUSIONS: Our findings suggest that the suppression of Nogo-A expression appears to be an early response conferred by indomethacin, which then leads to decreases in the levels of IL-1ß and TBI-induced neuron damage.

Resveratrol protects rats from Aß-induced neurotoxicity by the reduction of iNOS expression and lipid peroxidation.

Alzheimer disease (AD) is an age-dependent neurodegenerative disease characterized by the formation of ß-amyloid (Aß)-containing senile plaque. The disease could be induced by the administration of Aß peptide, which was also known to upregulate inducible nitric oxide synthase (iNOS) and stimulate neuronal apoptosis. The present study is aimed to elucidate the cellular effect of resveratrol, a natural phytoestrogen with neuroprotective activities, on Aß-induced hippocampal neuron loss and memory impairment. On adult Sprague-Dawley rats, we found the injection of Aß could result in a significant impairment in spatial memory, a marked increase in the cellular level of iNOS and lipid peroxidation, and an apparent decrease in the expression of heme oxygenase-1 (HO-1). By combining the treatment with Aß, resveratrol was able to confer a significant improvement in spatial memory, and protect animals from Aß-induced neurotoxicity. These neurological protection effects of resveratrol were associated with a reduction in the cellular levels of iNOS and lipid peroxidation and an increase in the production of HO-1. Moreover, the similar neurological and cellular response were also observed when Aß treatment was combined with the administration of a NOS inhibitor, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME). These findings strongly implicate that iNOS is involved in the Aß-induced lipid peroxidation and HO-1 downregulation, and resveratrol protects animals from Aß-induced neurotoxicity by suppressing iNOS production.

Inhibition of the Na+ -K+ -2Cl- -cotransporter in choroid plexus attenuates traumatic brain injury-induced brain edema and neuronal damage.

The present study was aimed to elucidate the possible role of Na+ -K+ -2Cl- -cotransporter (NKCC1) on traumatic brain injury-induced brain edema, cerebral contusion and neuronal death by using traumatic brain injury animal model. Contusion volume was verified by 2,3,5,-triphenyltetrazolium chloride monohydrate staining. NKCC1 mRNA expression was detected by RT-PCR and the protein expression of NKCC1 was measured by Western blot. We found that the expression of NKCC1 RNA and protein were up-regulated in choroid plexus apical membrane from 2 h after traumatic brain injury, peaked at 8 h, and lasted for 24 h. Rats in the experimental group displayed severe brain edema (water content: 81.45 +/- 0.32% compared with 78.38 +/- 0.62% of sham group) and contusion volume significantly increased 8 h after traumatic brain injury (864.14 +/- 28.07 mm3). Administration of the NKCC1 inhibitor bumetanide (15 mg/kg, I.V.) significantly attenuated the contusion volume (464.03 +/- 23.62 mm3) and brain edema (water content: 79.12 +/- 0.28%) after traumatic brain injury. Our study demonstrates that NKCC1 contributes to traumatic brain injury-induced brain edema and neuronal damage.