Bumetanide administration attenuated traumatic brain injury through IL-1 overexpression.

OBJECTIVE: To examine the effects of administration of bumetanide, a specific NKCC1 inhibitor, on traumatic brain injury (TBI)-induced interleukin-1 (IL-1) expression. METHODS: TBI model was induced by the calibrated weight drop device (450 g in weight, 2.0 m in height) in adult rats based on procedures previously reported. One hundred and sixty Wistar rats were divided into sham-control group and experimental group for time course works of TBI. The expression of IL-1beta brain edema and neuronal damage were determined in these animals after TBI. RESULTS: We found that both mRNA and protein of IL-1beta were up-regulated in the hippocampus 3-24 hours after TBI. Animals displayed severe brain edema and neuron damage after TBI. Bumetanide (15 mg/kg), a specific Na(+) -K(+) -2Cl(-) cotransporter inhibitor, significantly attenuated the TBI-induced neuronal damage by IL-1beta overexpression. The present study suggests that administration of bumetanide could significantly decreased TBI-induced inflammatory response and neuronal damage.

Increased ALZ-50 immunoreactivity in CSF of pseudotumor cerebri patients.

Pseudotumor cerebri (PTC) is characterized by increased intracranial pressure and papilledema without a mass lesion. PTC predominantly affects obese women. Currently, the pathogenesis of PTC is obscure. Since cytoskeletal abnormalities are found in many neurodegenerative diseases, we hypothesized that some cytoskeletal protein might be involved in the pathophysiology of PTC. Western blotting with specific antibody probes was employed to evaluate ALZ-50 immunoreactive protein, cytoskeletal microtubule-associated protein (MAP), and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) samples from 8 PTC patients and 6 controls. Immunoblotting of ALZ-50 in CSF revealed intense staining of 50 kDa protein bands in 7 of 8 PTC patients, while weak staining was found in 4 of 6 controls. Moderate staining of ALZ-50 was seen in 1 of 8 PTC patients and in 2 of 6 controls. CSF blots with anti-ALZ-50 antibody also showed intense staining of a 65 kDa protein band in 3 of the 8 patients but in none of the controls. In anti-MAP CSF blots of the PTC patients and controls, weak staining of the MAP 60 kDa and 50 kDa protein bands was observed. Weak staining of 60 kDa bands was also observed in anti-GFAP CSF blots of all PTC patients and controls. In CSF blots reacted with anti-GFAP antibody, 65 kDa and 32 kDa bands were evident in some PTC patients, but in none of the controls. This study indicates that ALZ-50 immunoreactivity is elevated in CSF of PTC patients. The ALZ-50 immunoreactive protein, either normal tau protein or its phosphorylated variant, may be useful as a biomarker for the diagnosis of PTC. Since the ALZ-50 monoclonal antibody was generated against brain homogenate from Alzheimer's disease (AD) patients, this study suggests a possible link between PTC and AD.

Apoptosis and necrosis in developing cerebellum and brainstem induced after focal cerebral hypoxic-ischemic injury.

Focal cerebral hypoxia-ischemia due to isolated vascular insufficiency is well known to cause ipsilateral, but not contralateral, cerebral apoptosis. Hypoxic-ischemic damage to the cerebellum and brainstem in such a model has not been established. This experimental rodent study demonstrates, through deoxyribonucleic acid fragmentation and terminal deoxynucleotidyl transferase-mediated deoxyuridine 5'-triphosphate-digoxigenin nick end labeling analysis, that neuronal cells in these infratentorial regions also suffer mild apoptosis and necrosis after focal cerebral hypoxic-ischemic injury in the newborn rat. These data provide additional insight into the mechanisms of neurological injury in the cerebellum and brainstem areas resulting from a focal cerebral hypoxic-ischemic insult and demonstrate that future therapeutic interventions for hypoxic-ischemic encephalopathy system should deal with the entire central nervous system.

Down-regulation of phospholipase D2 mRNA in neonatal rat brainstem and cerebellum after hypoxia-ischemia.

Phospholipase D (PLD) and phosphatidylcholine (PC) were implicated in apoptosis and cancer. However, direct evidence on the role of PLD in the cause of apoptosis remains obscure. It was recently reported that apoptosis and necrosis could be induced in the cerebellum and brainstem after focal cerebral hypoxic-ischemic (HI) injury. It was found that apoptosis could be enhanced by farnesol inhibition of PLD signal transduction. Whereas it was shown that highly invasive cancer cell line depends on PLD activity for survival when deprived of serum growth factors. Based on these reports, it is postulated that apoptosis in the cerebellum and brainstem induced after focal cerebral HI treatment may be caused by faulty PLD expression. This is consistent with a report that PLD1 activity and mRNA levels were down-regulated during apoptosis. To test this hypothesis, Northern blotting was used to examine PLD2 mRNA expression after focal cerebral HI. The results show that both PLD2 mRNA 10.8 and 3.9 kb transcripts were significantly decreased by as much as 37% in the brainstem and cerebellum areas 3 h after HI compared to the control, concur with previous report of decreasing PLD activity after ischemia. These PLD2 transcripts, however, were not significantly different from the control 3 days after HI, indicating that the decrease in PLD2 transcription after HI maybe a transient phenomenon. This is the first report to show that the loss of membrane integrity resulting from deprivation of energy and growth factors after HI could cause decrease in PLD2 transcription that promotes apoptosis. The hypothetic role of PLD2 and the mechanism leading to apoptosis remains to be further elucidated.