Monocarboxylic acid transporter 1 (MCT1) maintains axonal function by transferring lactic acid from oligodendrocytes to axons. Subarachnoid hemorrhage (SAH) induces white matter injury, but the involvement of MCT1 is unclear. In this study, the SAH model of adult male Sprague-Dawley rats was used to explore the role of MCT1 in white matter injury after SAH. At 48 h after SAH, oligodendrocyte MCT1 was significantly reduced, and the exogenous overexpression of MCT1 significantly improved white matter integrity and long-term cognitive function. Motor training after SAH significantly increased the number of ITPR2
Animals ; Male ; MicroRNAs/genetics* ; Monocarboxylic Acid Transporters/genetics* ; Rats ; Rats, Sprague-Dawley ; Subarachnoid Hemorrhage ; Symporters/genetics* ; White Matter/injuries*

We aimed to elucidate whether the eNOS T-786C mutant allele is implicated in subarachnoid hemorrhage (SAH) susceptibility or vasospasm after SAH, and whether the mutant allele is differentially expressed in those with small and large ruptured aneurysms in Korean population. 136 consecutive patients diagnosed with aneurismal SAH and 113 controls were recruited. Polymerase chain reaction and direct sequencing of both strands were performed to determine genotypes with respect to the eNOS T-786C mutation. No significant difference was found between cases and controls with respect to the distributions of the two eNOS T-786C single nucleotide polymorphism (SNP) genotypes. No significant differences in the distributions of the eNOS T-786C SNP genotypes were found with regard to the sizes of ruptured aneurysms or the occurrence of vasospasm after SAH. Multiple logistic regression analysis after controlling for age and sex showed the eNOS T-786C SNP T/C geno-type was independently associated with an unfavorable outcome (GOS grade 3-5) of SAH (Exp (beta)=4.27, 95% CI 1.131-16.108, p=0.032). In conclusion, the eNOS T-786C mutation was not found to be associated with either a susceptibility to SAH or vasospasm after SAH, or with aneurysm size in Korean population. The eNOS T-786C SNP T/C genotype could be used as a prognostic marker in individuals with SAH.
Subarachnoid Hemorrhage/*genetics ; *Polymorphism, Single Nucleotide ; Nitric Oxide Synthase Type III/*genetics ; Middle Aged ; Male ; Logistic Models ; Humans ; Genetic Predisposition to Disease ; Female ; Aged ; Adult

Early brain injury (EBI) plays a key role in the pathogenesis of subarachnoid hemorrhage (SAH). This study investigated the role of glucose-regulated protein 78 (GRP78) in EBI after SAH. Male Sprague-Dawley rats (n=108) weighing 260±40 g were divided into control, sham-operated, and operated groups. Blood was injected into the prechiasmatic cistern of rats in the operated group. Neurological scores, ultrastructures of neurons, apoptosis, and GRP78 expression in the hippocampus were examined using Garcia scoring system, transmission electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling, and Western blotting at 1, 6, 12, 24, 48, and 72 h after SAH, respectively. The results showed that neurological scores were significantly decreased in the operated group as compared with those in control and sham-operated groups at 12, 24, 48, and 72 h. Metachromatin, chromatin pyknosis at the edge, endoplasmic reticulum swelling, and invagination of nuclear membrane were observed at 24 h in the operated group, indicating the early morphological changes of apoptosis. The number of apoptotic cells was significantly increased in the operated group as compared with that in control and sham-operated groups at 6, 12, 24, 48, and 72 h. The GRP78 protein expression levels in the operated group were significantly elevated at all time points and reached the peak at 12 h. GRP78 expression was positively associated with apoptosis cells and negatively with neurological scores. In conclusion, EBI was demonstrated to occur after SAH and GRP78 was involved in the development of EBI after SAH.
Animals ; Apoptosis ; Brain Injuries ; complications ; metabolism ; pathology ; Chromatin ; pathology ; Endoplasmic Reticulum Stress ; Heat-Shock Proteins ; genetics ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Subarachnoid Hemorrhage ; etiology ; metabolism ; pathology

OBJECTIVETo study whether endothelial nitric oxide synthase gene (eNOS) polymorphisms is implicated in the development of cerebral vasospasm following subarachnoid hemorrhage.

METHODSThree groups of patients with subarachnoid hemorrhage were selected to test this hypothesis, including 98 patients with cerebral vasospasm following aneurysmal subarachnoid hemorrhage (ASAH), 96 with cerebral vasospasm following traumatic subarachnoid hemorrhage (TSAH), and 195 patients without cerebral vasospasm following aneurysmal or traumatic subarachnoid hemorrhage. The parents of 194 patients and 100 control subjects were also examined for transmission disequilibrium test according to a family-based study design to test the associations.

RESULTSWe examined four eNOS gene polymorphisms, and two of these polymorphisms, the T to C substitution in the promoter at position -786 and the a-deletion/b-insertion in intron 4, were found to associate with cerebral vasospasm in subarachnoid hemorrhage in the case-control comparisons. For the former polymorphism, the risk of cerebral vasospasm was higher in C allele homozygotes than in the other two genotypes (odds ratio: 2.8, 95% CI: 1.4 to 5.6); for the latter polymorphism, the a-deletion carriers were exposed to a increased risk (odds ratio: 2.3, 95% CI: 1.3 to 4.0) in comparison with the noncarriers. The two polymorphisms were analyzed together as haplotypes in a family-based study using the transmission disequilibrium test. The C/a-deletion haplotype was transmitted from the heterozygous parents to cases of cerebral vasospasm in subarachnoid hemorrhage with a significantly higher frequency than expected (P=0.005).

CONCLUSIONThe findings of the case-control and family-based studies clearly demonstrate that DNA sequence differences in eNOS gene influence the risk of cerebral vasospasm in subarachnoid hemorrhage.

Adolescent ; Adult ; Case-Control Studies ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Nitric Oxide Synthase Type III ; genetics ; Polymorphism, Genetic ; Risk Factors ; Subarachnoid Hemorrhage ; complications ; enzymology ; genetics ; Vasospasm, Intracranial ; enzymology ; etiology ; Young Adult

OBJECTIVETo study the expression change of interleukin-8 (IL-8) gene in the basilar artery of rabbit and the effect of IL-8 on the development of cerebral vasospasm induced by experimental subarachnoid hemorrhage (SAH).

METHODSThirty five healthy Japanese White Rabbits were randomly divided into saline-control group and experimental group. The experimental group was subdivided into four groups, representing day 1, 4, 7 and 14 after the first blood injection of SAH. The delayed cerebral vasospasm (DCVS) model was established by double injection of autologous blood into the cisterna magna. The expression change of cytokine IL-8 mRNA in the basilar artery was analyzed by RTPCR.

RESULTSThe expression of IL-8 gene increased on day 4-7 after the first blood injection of SAH compared with control (P< 0.001), and decreased to normal on day 14. The expression of IL-8 gene in the SAH groups were positively correlated with the degree of basilar artery stenosis (r = 0.642, P< 0.01).

CONCLUSIONThe expression level of IL-8 gene in basilar arteries was intimately associated with the degree of cerebral vasospasm, suggesting that IL-8 may play an important role in the DCVS after SAH as an immunological inflammatory factor.

Animals ; Basilar Artery ; metabolism ; Disease Models, Animal ; Gene Expression Regulation ; physiology ; Interleukin-8 ; genetics ; metabolism ; RNA, Messenger ; biosynthesis ; Rabbits ; Reverse Transcriptase Polymerase Chain Reaction ; methods ; Subarachnoid Hemorrhage ; metabolism ; pathology ; Time Factors

BACKGROUNDInflammation and immunity play a vital role in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH). Nuclear factor-kappa B (NF-kappaB) regulates many genes essential for inflammation and immunity and is activated by toll-like receptor (TLR). This study aimed to detect the expression of the toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-kappaB) signaling in the rat brain after early SAH.

METHODSThe rats were decapitated and their brains were removed at 0, 2, 4, 6, 12, 24 and 48 hours after a single injection of blood into the prechiasmatic cistern. mRNA expression of TLR4 was measured by Taqman real-time RT-PCR, and protein expression by immunohistochemistry and Western blotting. NF-kappaB activity and concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA).

RESULTSTaqMan real-time RT-PCR and Western blotting identified a biphasic change in TLR4 expression in both mRNA and protein: an initial peak (2 - 6 hours) and a sustained elevation (12 - 48 hours). Immunohistochemical staining showed the inducible expression of TLR4-like immunoreactions predominantly in glial cells and vascular endothelium. A similar biphasic change in the activation of NF-kappaB subunit p65 as well as the production of NF-kappaB-regulated proinflammatory cytokines (TNF-alpha, IL-1beta and IL-6) were detected by ELISA.

CONCLUSIONSThese data suggest that experimental SAH induces significant up-regulation of TLR4 expression and the NF-kappaB signaling in early brain injury. Activation of the TLR4/NF-kappaB signaling may regulate the inflammatory responses after SAH.

Animals ; Brain ; metabolism ; Cytokines ; analysis ; Male ; NF-kappa B ; physiology ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; physiology ; Subarachnoid Hemorrhage ; immunology ; metabolism ; Toll-Like Receptor 4 ; analysis ; genetics ; physiology

Fluoxetine, an anti-depressant drug, has recently been shown to provide neuroprotection in central nervous system injury, but its roles in subarachnoid hemorrhage (SAH) remain unclear. In this study, we aimed to evaluate whether fluoxetine attenuates early brain injury (EBI) after SAH. We demonstrated that intraperitoneal injection of fluoxetine (10 mg/kg per day) significantly attenuated brain edema and blood-brain barrier (BBB) disruption, microglial activation, and neuronal apoptosis in EBI after experimental SAH, as evidenced by the reduction of brain water content and Evans blue dye extravasation, prevention of disruption of the tight junction proteins zonula occludens-1, claudin-5, and occludin, a decrease of cells staining positive for Iba-1, ED-1, and TUNEL and a decline in IL-1β, IL-6, TNF-α, MDA, 3-nitrotyrosine, and 8-OHDG levels. Moreover, fluoxetine significantly improved the neurological deficits of EBI and long-term sensorimotor behavioral deficits following SAH in a rat model. These results indicated that fluoxetine has a neuroprotective effect after experimental SAH.
Animals ; Apoptosis ; drug effects ; Blood-Brain Barrier ; drug effects ; Brain Edema ; drug therapy ; etiology ; Cytokines ; genetics ; metabolism ; Disease Models, Animal ; Fluoxetine ; pharmacology ; therapeutic use ; In Situ Nick-End Labeling ; Male ; Neuroprotective Agents ; pharmacology ; therapeutic use ; Pain Measurement ; Psychomotor Performance ; drug effects ; RNA, Messenger ; metabolism ; Rats ; Rats, Sprague-Dawley ; Subarachnoid Hemorrhage ; complications ; drug therapy ; pathology ; Time Factors ; Vasospasm, Intracranial ; drug therapy ; etiology