Neuroprotective Effect of ZnT3 Knockout on Subarachnoid Hemorrhage.

BACKGROUND: The pathophysiology of early brain injury (EBI) after subarachnoid hemorrhage (SAH) is poorly understood. The present study evaluates the influence of zinc transporter 3 (ZnT3) knockout and the depletion of vesicular zinc on EBI. METHODOLOGY: SAH was induced in ZnT3 KO mice by internal carotid artery perforation. The changes in behavior were recorded at 24 hours after SAH. Hematoxylin-eosin, Nissl and TUNEL staining were performed to evaluate neuronal apoptosis. Data from mice with a score of 8-12 in intracerebral bleeding (i.e. moderate SAH), were analyzed. RESULTS: The degree of SAH-induced neuronal injury was directly correlated to the amount of blood lost, which in turn was negatively reflected in their behavior. The Wild Type (WT)-SAH group behaved poorly when compared to the knockout (KO)-SAH mice and their poor neurological score was accompanied by an increase in the number of apoptotic neurons. Conversely, the improvement of behavior in the KO-SAH group was associated with a marked reduction in apoptotic neurons. CONCLUSIONS: These results suggest that ZnT3 knockout may have played a vital role in the attenuation of neuronal injury after SAH and that ZnT3 may prove to be a potential therapeutic target for neuroprotection in EBI.

EGF stimulates glioblastoma metastasis by induction of matrix metalloproteinase-9 in an EGFR-dependent mechanism.

Epidermal growth factor (EGF) and EGF receptor (EGFR) play prominent roles in the metastasis of glioblastoma (GBM). However, the molecular mechanisms for the function of EGF and EGFR in GBM metastasis have not been elucidated. Herein, we demonstrate that coactivation of EGF and EGFR drives tumor metastasis in a matrix metalloproteinase-9 (MMP-9)-dependent manner. Expression levels of EGF, EGFR, and MMP-9 were substantially upregulated in the GBM and edema zones of patients, compared with those of paired unaffected participants. Secretion of EGF and MMP-9 was reduced in the cerebrospinal fluid (CSF) after removing GBM for 2 weeks by operation. To the mechanism, MMP-9 was upregulated by activating EGF and EGFR via PI3K/AKT- and ERK1/2-dependent pathways. Moreover, signal transducer and activator of transcription (STAT) 3 and STAT5 mediated the activation of NF-κB by PI3K/AKT and ERK1/2 pathways. This resulted in transactivation of MMP-9 in GBM. Finally, MMP-9 induction facilitated abnormal proliferation, migration, and invasion of cells, which contributed to GBM metastasis.

Polymorphisms in DNA repair genes and susceptibility to glioma in a chinese population.

The excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1), and X-ray repair cross-complementing group 1 (XRCC1) genes appear to protect mammalian cells from the harmful effects of ionizing radiation. We conducted a large case-control study to investigate the association of polymorphisms in ERCC1 C118T, ERCC1 C8092A, XRCC1 A194T, XRCC1 A194T, and XRCC3 C241T, with glioma risk in a Chinese population. Five single nucleotide polymorphisms (SNPs) were genotyped, using the MassARRAY IPLEX platform, in 443 glioma cases and 443 controls. Association analyses based on an χ2 test and binary logistic regression were performed to determine the odds ratio (OR) and a 95% confidence interval (95% CI) for each SNP. For XRCC1 Arg194Trp, the variant genotype T/T was strongly associated with a lower risk of glioma cancer when compared with the wild type C/C (OR = 2.45, 95% CI = 1.43-4.45). Individuals carrying the XRCC1 399A allele had an increased risk of glioma (OR = 1.33, 95% CI = 1.02-1.64). The XRCC3 241T/T genotype was associated with a strong increased glioma risk (OR = 3.78, 95% CI = 1.86-9.06). Further analysis of the interactions of two susceptibility-associated SNPs, XRCC1 Arg194Trp and XRCC3 Thr241Met, showed that the combination of the XRCC1 194T and XRCC3 241T alleles brought a large increase in glioma risk (OR = 2.75, 95% CI = 1.54-4.04). XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XRCC3 C241T, appear to be associated with susceptibility to glioma in a Chinese population.

Inhibition of c-Jun N-terminal kinase prevents blood-brain barrier disruption and normalizes the expression of tight junction proteins clautin-5 and ZO-1 in a rat model of subarachnoid hemorrhage.

BACKGROUND: The c-Jun N-terminal kinase (JNK) proteins are encoded by three genes (JNK1, JNK2, and JNK3), giving rise to multiple isoforms via alternative splicing. JNK inhibition using a chemical inhibitor SP600125 confers neuroprotection in an animal model of subarachnoid hemorrhage (SAH). The aim of this study is to investigate whether the protective effects of SP600125 were associated with modulation of tight junction proteins including claudin-5 and ZO-1 and to define which JNK isoforms were involved in the early brain injury after SAH. METHODS: Seventy-five male Sprague Dawley rats (weighing 300-350 g) were randomly assigned to five groups (n = 15): (1) sham, (2) SAH, (3) SAH + DMSO (dimethyl sulfoxide), (4) SAH + 10 mg/kg SP600125, and (5) SAH + 30 mg/kg SP600125. SP600125 or DMSO was injected intraperitoneally 1 h before and 6 h after the induction of SAH. Animals from all the groups were killed 24 h after SAH, and brain tissues were dissected and subjected to electron microscopic examination, Western blot analysis, and histological evaluation. RESULTS: SP600125 pretreatment restored tight junctions and attenuated blood-brain barrier (BBB) disruption and cerebral edema after SAH, coupled with reduced apoptosis in the cerebral cortex. SP600125 exposure restored the reduced expression of both claudin-5 and ZO-1 following SAH and normalized the levels of JNK1 and JNK3. CONCLUSION: Our data demonstrate that the JNK signaling plays an important role in the regulation of tight junction proteins and BBB integrity, and thus represents a promising target against brain injuries after SAH.

Role of ERK1/2 and vascular cell proliferation in cerebral vasospasm after experimental subarachnoid hemorrhage.

BACKGROUND: Although there are still some unresolved aspects, current research has revealed that vascular cell proliferation probably plays an important part in the pathological formation process of cerebral vasospasm. Using a "two-hemorrhage" model of subarachnoid hemorrhage (SAH), this study investigated the function of ERK1/2 and vascular wall cell proliferation in pathological development of cerebral vasospasm. METHODS: Fifty rabbits were randomly divided into five groups: (1) SAH day 1, (2) SAH day 3, (3) SAH day 7, (4) SAH + DMSO (dimethyl sufoxide) solution, (5) SAH + PD98059 (a mitogen-activated protein kinase inhibitor) dissolved in DMSO solution. In the SAH + PD98059/DMSO group and SAH + DMSO control group, PD98059 in DMSO (2 mmol/l) or an equal quantity of DMSO, respectively, was injected into the cisterna magna, once a day from SAH day 1 to day 3. Western protein blotting was used to detect the expression of proliferating cell nuclear antigen (PCNA) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in each group's basilar arteries. Light microscopy and electron microscopy were used for dynamic histological detection at each observation point of the SAH vascular wall under the effects of SAH and the mitogen-activated protein kinase inhibitor. Another 18 rabbits were randomly divided into three groups: SAH, SAH + DMSO and SAH + PD98059/DMSO; cerebral angiograpathy was conducted on SAH days 1 and 7, and the progression of angiographic vasospasm evaluated. RESULTS: Compared with the control group, the extent of vasospasm after SAH increased with time. PD98059 significantly reduced angiographic and morphological vasospasm. In cerebral vasospasm, the expression of T-ERK1/2 showed no significant change. However, expression of p-ERK1/2 and PCNA began to increase significantly on day 3, and achieved a peak on day 7. PD98059 significantly inhibited the expression of p-ERK1/2 and PCNA (p < 0.05). CONCLUSIONS: Cell proliferation on the vascular wall plays an important part in the pathological formation process of cerebral vasospasm. ERK1/2 phosphorylation, as an important signaling pathway, taking part in the process of vascular-wall pathological proliferation of cerebral vasospasm.

[Gamma knife for hypersecreting pituitary adenoma: analysis of 120 cases].

OBJECTIVE: To estimate the efficacy of Gamma knife radiosurgery (GKR) especially as a primary surgical treatment for hypersecreting pituitary adenoma. METHODS: One hundred and twenty cases with hypersecreting pituitary adenoma had been treated by Gamma knife radiosurgery. The clinical date had been analysed retrospectively. The tumor margin was covered by an isodose ranging from 45% to 70%. The margin dose was 15 to 32 Gy (mean 28.5 Gy) and the maximum dose varied from 35 to 70 Gy (mean 45.5 Gy). The total number of isocenter was 165 (mean 1-3). RESULTS: One hundred and eleven cases had been followed-up by hormone level, and 104 cases had been followed-up by image of MRI. The mean follow-up duration was 12-72 months (mean 36 months). The control rate of hormone level was 48.6%, the control rate of tumor growth was 96.2%, the incidence of hypopituitarism was in 2.7% and the incidence of tumor apoplexy was in 0.9% in followed-up cases. CONCLUSIONS: As a primary surgical treatment for hypersecreting pituitary adenoma, GKR can be effective and safe in controlling tumor growth and inducing hormonal normalization.