Does thioredoxin-1 prevent mitochondria- and endoplasmic reticulum-mediated neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine?

We show that 1-methyl-4-phenylpyridinium ion (MPP(+)), an active metabolite of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), induces cytotoxicity via endoplasmic reticulum (ER)- and mitochondria-mediated pathways, and thioredoxin-1 (TRX-1), a redox-active protein, prevents MPTP-induced neurotoxicity. TRX-1 overexpression suppressed reactive oxygen species and the ATP decline caused by MPP(+) in HepG2 cells. MPP(+) activated caspase-12 in PC12 cells and induced cytotoxicity in HeLa-rho(0) cells lacking mitochondrial DNA, as well as in the parental HeLa-S3 cells. TRX-1-transgenic mice demonstrated significant resistance to caspase-12 activation and the apoptotic decrease of dopaminergic neurons after MPTP administration, compared with wild-type C57BL/6 mice.

The role of alternative anastomosis sites in occipital artery-posterior inferior cerebellar artery bypass in the absence of the caudal loop using the far-lateral approach.

OBJECTIVE Occipital artery-posterior inferior cerebellar artery (OA-PICA) bypass is a technically challenging procedure for posterior fossa revascularization. The caudal loop of the PICA is considered the optimal site for OA-PICA anastomosis, however its absence can increase the technical difficulty associated with this procedure. The use of the far-lateral approach for accessing alternative anastomosis sites in OA-PICA bypass in patients with absent or unavailable caudal loops of PICA is evaluated. METHODS A morphometric analysis of OA-PICA bypass with anastomosis on each segment of the PICA was performed on 5 cadaveric specimens through the conventional midline foramen magnum and far-lateral approaches. The difficulty level associated with anastomoses at each segment was qualitatively assessed in each approach for exposure and maneuverability by multiple surgeons. A series of 8 patients who underwent OA-PICA bypass for hemodynamic ischemia or ruptured dissecting posterior fossa aneurysms are additionally reviewed and described, and the clinical significance of the caudal loop of PICA is discussed. RESULTS Anastomosis on the caudal loop could be performed more superficially than on any other segment (p < 0.001). A far-lateral approach up to the medial border of the posterior condylar canal provided a 13.5 ± 2.2-mm wider corridor than the conventional midline foramen magnum approach, facilitating access to alternative anastomosis sites. The far-lateral approach was successfully used for OA-PICA bypass in 3 clinical cases whose caudal loops were absent, whereas the midline foramen magnum approach provided sufficient exposure for caudal loop bypass in the remaining 5 cases. CONCLUSIONS The absence of the caudal loop of the PICA is a major contributing factor to the technical difficulty of OA-PICA bypass. The far-lateral approach is a useful surgical option for OA-PICA bypass when the caudal loop of the PICA is unavailable.

[A case of bow hunter's stroke treated with endovascular surgery].

Bow hunter's stroke results from vertebrobasilar insufficiency due to a mechanical occlusion or stenosis of the vertebral artery caused by head rotation. We report here a case of bow hunter's stroke that was successfully treated with endovascular surgery. A 69-year-old male complained of intractable vertigo when he rotated his head to the right side. Neuroradiological studies proved that the symptom was attributed to the mechanical severe stenosis of the left vertebral artery at the C1-C2 level on head rotation, in addition to the atherosclerotic stenosis at the origin of the right vertebral artery. Two different treatments were considered, including direct surgeries to prevent the mechanical stenosis of the left vertebral artery, and an endovascular dilatation of the atherosclerotic stenosis of the right vertebral artery. Endovascular surgery with a stenting technique, which was thought to be less invasive, was undertaken and resulted in a complete relief of the patient's symptom. To our knowledge, this is the first report to have shown the efficacy of endovascular surgery on this uncommon disease.

[Treatment of a ruptured giant internal carotid artery pseudoaneurysm following transsphenoidal surgery: case report and literature review].

We report here a case of giant internal carotid artery (ICA) pseudoaneurysm as a complication of transsphenoidal surgery. This 50-year-old acromegalic male presented to our clinic with a status of hypovolemic shock due to serious epistaxis. Neuroradiological examinations at his admission revealed a giant aneurysm in the right cavernous portion projecting into the sphenoid sinus. Eight years before this presentation, he had undergone a transsphenoidal surgery for growth hormone producing pituitary tumor at the other clinic. Then intraoperative arterial bleeding was reported, probably as a result of carotid injury. His medical history and radiological findings suggested that his epistaxis resulted from a rupture of the iatrogenic pseudoaneurysm which had gradually grown after the ICA injury at the previous surgery over 8 years. Emergent coil embolization using Guglielmi detachable coils (GDCs) resulted in a successful homeostasis. Major part of the aneurysm dome was obliterated via the intervention, however small part of the aneurysm neck was unable to be obliterated due to a technical difficulty. His postoperative course was favorable, but he suffered from a recurrence of serious epitaxis 4 weeks after the embolization. Emergent angiography suggested a rupture of the un-obliterated aneurysm neck remnant. Thus, trapping of the aneurysm combined with high flow bypass was necessitated. Relevant literatures are reviewed, and possible therapeutic strategies for this rare lesion are discussed.

Critical roles of thioredoxin in nerve growth factor-mediated signal transduction and neurite outgrowth in PC12 cells.

Thioredoxin (TRX) has a role in a variety of biological processes, including cytoprotection and the activation of transcription factors. Nerve growth factor (NGF) is a major survival factor of sympathetic neurons and promotes neurite outgrowth in rat pheochromocytoma PC12 cells. In this study, we showed that NGF induces TRX expression at protein and mRNA levels. NGF activated the TRX gene through a regulatory region positioned from -263 to -217 bp, containing the cAMP-responsive element (CRE). Insertion of a mutation in the CRE in this region abolished the response to NGF. NGF induced binding of CRE-binding protein to the CRE of the TRX promoter in an electrophoretic mobility shift assay. NGF also induced nuclear translocation of TRX. 2'-Amino-3'-methoxyflavone, an inhibitor of mitogen-activated protein kinase kinase, which is a known inhibitor of NGF-dependent differentiation in PC12 cells, suppressed the NGF-dependent expression and nuclear translocation of TRX. Overexpression of mutant TRX (32S/35S) or TRX antisense vector blocked the neurite outgrowth of PC12 cells by NGF. Overexpression of mutant TRX (C32S/C35S) suppressed the NGF-dependent activation of the CRE-mediated c-fos reporter gene. These results suggest that TRX plays a critical regulatory role in NGF-mediated signal transduction and outgrowth in PC12 cells.

Stent-assisted coil embolization for anterior cerebral artery dissection presented with cerebral infarction.

BACKGROUND: Compared to those found in the vertebrobasilar system, intracranial dissection in the anterior circulation is relatively rare, especially in the anterior cerebral artery (ACA). Moreover, only several cases of ACA dissection that underwent endovascular treatment have been reported. Here we present a rare case of gradually developing ACA dissecting aneurysm causing cerebral infarction, successfully treated by stent-assisted coil embolization. CASE DESCRIPTION: A 36-year-old man was admitted with sudden right hemiparesis. Diffusion-weighted magnetic resonance (MR) imaging showed cerebral infarction in the left ACA territory, and MR angiography showed segmental stenosis at the A2 portion of the left ACA. Three-dimensional digital subtraction angiogram showed segmental dilatation and stenosis at the left A2 portion. We diagnosed ACA dissection causing acute cerebral infarction and treated the patient conservatively. Five months after the onset, the dissecting artery at the left A2 portion formed a gradually dilating aneurysm, suggesting increased risk for aneurysmal rupture. We attempted endovascular treatment entailing coil embolization of an aneurysm while preserving the left A2 with stent assistance. The patient remained neurologically stable 6 months after the procedure. CONCLUSIONS: Although there are few reported cases of ACA dissection where endovascular treatment was attempted, we consider stent-assisted embolization for gradually developing ACA dissecting aneurysm as an alternative method to prevent bleeding and recurrent infarction.

Activation of p38 kinase in the gerbil hippocampus showing ischemic tolerance.

Ischemic tolerance is a phenomenon in which brief episodes of ischemia protect against the lethal effects of subsequent periods of prolonged ischemia. The authors investigated the activation of p38 mitogen-activated protein kinase (p38) in the gerbil hippocampus by Western blotting and immunohistochemistry to clarify the role of p38 kinase in ischemic tolerance. After the 2-minute global ischemia, immunoreactivity indicating active p38 was enhanced at 6 hours of reperfusion and continuously demonstrated 72 hours after ischemia in CA1 and CA3 neurons. Pretreatment with SB203580, an inhibitor of active p38 (0-30 micromol/l), 30 minutes before the 2-minute ischemia reduced the ischemic tolerance effect in a dose-dependent manner. Immunoblot analysis indicated that alteration of the phosphorylation pattern of p38 kinase in the hippocampus after subsequent lethal ischemia was induced by the preconditioning. These findings suggest that lasting activation of p38 may contribute to ischemic tolerance in CA1 neurons of the hippocampus and that components of the p38 cascade can be target molecules to modify neuronal survival after ischemia.

Intravenous administration of thioredoxin decreases brain damage following transient focal cerebral ischemia in mice.

Thioredoxin (TRX) is induced by a variety of oxidative stimuli and shows cytoprotective roles against oxidative stress. To clarify the possibility of clinical application, we examined the effects of intravenously administered TRX in a model of transient focal cerebral ischemia in this study. Mature male C57BL/6j mice received either continuous intravenous infusion of recombinant human TRX (rhTRX) over a range of 1-10 mg/kg, bovine serum albumin, or vehicle alone for 2 h after 90-min transient middle cerebral artery occlusion (MCAO). Twenty-four hours after the transient MCAO, the animals were evaluated neurologically and the infarct volumes were assessed. Infarct volume, neurological deficit, and protein carbonyl contents, a marker of protein oxidation, in the brain were significantly ameliorated in rhTRX-treated mice at the dose of 3 and 10 mg/kg versus these parameters in control animals. Moreover, activation of p38 mitogen-activated protein kinase, whose pathway is involved in ischemic neuronal death, was suppressed in the rhTRX-treated mice. Further, rhTRX was detected in the ischemic hemisphere by western blot analysis, suggesting that rhTRX was able to permeate the blood-brain barrier in the ischemic hemisphere. These data indicate that exogenous TRX exerts distinct cytoprotective effects on cerebral ischemia/reperfusion injury in mice by means of its redox-regulating activity.

Thioredoxin suppresses 1-methyl-4-phenylpyridinium-induced neurotoxicity in rat PC12 cells.

Thioredoxin (TRX) is a redox-active protein which plays a cytoprotective role against oxidative stress. Geranylgeranylacetone (GGA), used widely as an anti-ulcer drug, has been reported to induce TRX as well as heat shock protein 70 (HSP70) in hepatocytes and other cells. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causes dopaminergic denervation and Parkinsonism in humans. The 1-methyl-4-phenylpyridinium ion (MPP(+)), an active metabolite of MPTP, induces cell death in a rat pheochromocytoma cell line (PC12 cells). We found that MPP(+) suppresses TRX expression in PC12 cells. Overexpression or administration of TRX attenuates MPP(+)-induced neurotoxicity on PC12 cells. Moreover, GGA induces expression of TRX and HSP70 and attenuates MPP(+)-induced toxicity in PC12 cells. These results indicate that TRX and GGA have a possible potential as new therapeutic agents for Parkinson disease.

Hypoxia-ischemia induces thioredoxin expression and nitrotyrosine formation in new-born rat brain.

Thioredoxin (TRX) is a 13 kDa protein with antioxidant effect and redox regulating functions. Peroxynitrite is a strong oxidizing and nitrating agent which can react with all classes of biomolecules. In the present study, we focused on the association between TRX and nitrotyrosine, which served as a marker of peroxynitrite formation, in the neonatal hypoxia-ischemia (HI) rat brain. At 4-16 h after HI, the immunoreactivity for TRX was diminished in the injured region in the cortex and striatum, whereas nitrotyrosine immunoreactivity was enhanced. In contrast, around the injured region, TRX immunoreactivity was enhanced in survival neurons at 4-24 h after HI, while the immunoreactivity for nitrotyrosine was mostly not detected. Northern blot analysis showed increased TRX mRNA induction in the cerebral hemisphere ipsilateral to the carotid ligation from 4-24 h after HI but not in the contralateral hypoxic hemisphere. These findings suggest that production of peroxynitrite is involved in HI brain injury, and that induced TRX plays a neuroprotective role against oxidative stress resulting from HI.

Stent-supported coil embolization for carotid artery pseudoaneurysm as a complication of endovascular surgery--case report.

A 57-year-old male presented with right amaurosis fugax and left transient ischemic attack caused by stenosis of the intracranial segment of the right internal carotid artery (ICA). Percutaneous transluminal angioplasty with stenting was successfully performed to dilate the stenosis. However, serial angiography revealed the development of a large pseudoaneurysm in the cervical ICA, probably as a result of carotid wall injury caused by the guiding catheter during the procedures. The patient underwent a second endovascular angioplasty. A Palmaz stent was placed across the aneurysm neck to stabilize the carotid wall. Guglielmi detachable coils were then inserted into the aneurysm cavity through the stent struts to successfully obliterate the aneurysm. Both the angiographical results and the patient's outcome were favorable. Stent-supported coil embolization is an effective and safe technique for medically refractory pseudoaneurysms, and may be a useful alternative to direct surgery.