Alzheimer disease (AD) is an age-dependent neurodegenerative disease characterized by the formation of β–amyloid (Aβ)-containing senile plaque. The disease could be induced by the administration of Aβ 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 Aβ-induced hippocampal neuron loss and memory impairment. On adult Sprague-Dawley rats, we found the injection of Aβ 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 Aβ, resveratrol was able to confer a significant improvement in spatial memory, and protect animals from Aβ-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 Aβ 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 Aβ-induced lipid peroxidation and HO-1 downregulation, and resveratrol protects animals from Aβ-induced neurotoxicity by suppressing iNOS production.

Objective: Brain edema is one of the characteristic features of patients with severe traumatic brain injury. The aim of this study was to examine the effects of Na⁺-K⁺-2Cl⁻ co-transporter on traumatic brain injury-induced brain edema and neuron damage and to elucidate the relationship between Na⁺-K⁺-2Cl⁻ co-transporter and mitogen-activated protein kinase (MAPK) cascade. Design: Laboratory investigation. Setting: University research laboratory. Subjects: Male Wistar rats weighing 350–400 g. Interventions: Anesthetized animals were subjected to a weight-drop device (450-g weight, 1.8-m height) to induce traumatic brain injury. Measurements and Main Results: The expression of Na⁺-K⁺-2Cl⁻ co-transporter and phosphorylation of MAPK cascade were determined by Western blot test. We also analyzed the degree of brain edema and neuronal damage in this study. We found that the messenger RNA and protein of Na⁺-K⁺-2Cl⁻ co-transporter were up-regulated mainly in hippocampus neurons from 2 to 24 hrs after traumatic brain injury. After traumatic brain injury, animals displayed severe brain edema and neuron damage. The phosphorylation of extracellular signal-regulated kinase, MAPK kinase, and Raf also was significantly elevated after traumatic brain injury. Bumetanide (15.2 mg/kg), a specific Na⁺-K⁺-2Cl⁻ co-transporter inhibitor, significantly attenuated the neuronal damage and brain edema after traumatic brain injury by decreasing the phosphorylation of Raf/MEK/ERK cascade proteins. Conclusions: The present study suggests that Na⁺-K⁺-2Cl⁻ co-transporter plays an important role in TBI-induced brain edema and neuronal damage via activation of MAPK cascade.

Fragile X syndrome (FXS) is the most frequent inherited form of human mental retardation. It is characterized by cognitive impairment and physical and behavioral problems and is caused by the silencing of fmr1 transcription and the absence of the fmr1 protein (FMRP). Recently, animal models of FXS have greatly facilitated the investigation of the molecular and cellular mechanisms of this loss-of-function disorder. The present study was aimed to further characterize the role of FMRP in behavior and synaptic function by using fmr1 knockout zebrafish. In adult zebrafish, we found that fmr1 knockout produces the anxiolytic-like responses of increased exploratory behavior in light/dark and open-field tests and avoidance learning impairment. Furthermore, electrophysiological recordings from telencephalic slice preparations of knockout fish displayed markedly reduced long-term potentiation and enhanced long-term depression compared to wild-type fish; however, basal glutamatergic transmission and presynaptic function at the lateral (Dl) and medial (Dm) division of the dorsal telencephalon synapse remained normal. Taken together, our study not only evaluates the mechanism of FRMP but also suggests that zebrafish have valuable potential as a complementary vertebrate model in studying the molecular pathogenesis of human fragile X syndrome.

Adult neurogenesis occurs in the subgranular zone of the hippocampal dentate gyrus, and can be modulated by physiological and pathological events. We examined the effect of vascular endothelial growth factor (VEGF), and the correlation between VEGF and the Raf/MEK/ERK cascade in neurogenesis after traumatic brain injury (TBI). The expression of VEGF and the phosphorylation level of Raf/MEK/ERK were analyzed by Western blot, and TBI-induced neurogenesis was determined by immunofluorescence labeling and confocal microscopic detection. Hippocampal VEGF began to increase after 12 h, and reached a peak at day 7. Along with the upregulation of VEGF, neurogenesis in the hippocampus also increased. Administration of the VEGF antisense oligodeoxynucleotide, or the VEGF receptor-2 antagonist SU1498 (10 μg, ICV), attenuated the phosphorylation of the MAPK cascade proteins and caused a decrease in neurogenesis in the hippocampus. Similarly, administration of the ERK inhibitor PD98059 (500 ng, ICV) also exhibited a suppressive effect on neurogenesis. Our results indicate that VEGF plays an important role in neurogenesis after TBI, and that the process involves VEGF receptor-2 and the Raf/MEK/ERK cascade.