Long-term Outcomes after Microsurgical Decompression of Lumbar Foraminal Stenosis and Adverse Effects of Preoperative Scoliosis: A Prospective Cohort Study.

Lumbar foraminal stenosis is a common disorder, with surgical treatment varying from simple decompression to interbody fusion. It is often associated with degenerative lumbar scoliosis, but the effects of scoliosis on outcomes are unclear. The objectives of this study were to clarify long-term outcomes after microsurgical decompression of lumbar foraminal stenosis through Wiltse's approach and to determine the effects of scoliosis on these outcomes. A total of 86 consecutive patients with lumbar foraminal stenosis were prospectively followed after microsurgical decompression. They were categorized in multiple subcohorts with follow-up durations ranging from 6 months to 5 years. Outcomes were assessed using the Short Form 36 questionnaire (average physical scores and bodily pain scores). Local Cobb angle of the operative segment was measured preoperatively, and its effects on outcomes were analyzed. Average physical scores improved significantly from 33.8 (95% confidence interval [CI]: 29.1-38.5) preoperatively to 59.5 (95% CI: 54.6-64.3) at 6 months postoperatively and remained improved for 5 years. Bodily pain scores improved significantly from 23.7 (95% CI: 18.7-28.6) preoperatively to 56.3 (95% CI: 51.2-61.6) at 6 months postoperatively and remained improved for 5 years. Patients with preoperative scoliosis (local Cobb angle >10 degrees) had poorer outcomes: average physical scores were worse by 9.6 points (p = 0.07) and bodily pain scores were worse by 12.1 points (p = 0.02), compared with patients without scoliosis (local Cobb angle ≤10 degrees). Microsurgical foraminal decompression produced overall excellent outcomes in patients with lumbar foraminal stenosis. Preoperative scoliosis attenuated these beneficial effects.

A case of insulinoma effectively treated with low-dose diazoxide.

Diazoxide is a benzothiadiazine that can be effective in managing hypoglycemia in frail patients with surgical risk. We report here a case of insulinoma effectively treated with diazoxide, as our report will be helpful for similar cases.

Severe Spinal Cord Compression by Anomalous Vertebral Arteries Treated with Gore-Tex Tape Transposition Technique.

Rare anomalous courses of vertebral arteries in the craniovertebral junction may compress the spinal cord causing myelopathy. We report here the severest form of this pathologic condition successfully treated with transposition of bilateral vertebral artery using Gore-Tex tapes. A 73-year-old man presented with progressive tetraparesis and gait disturbance. Imaging studies showed bilateral atresia of the C1 transverse foramina and the both vertebral arteries penetrating the dura below the C1 lamina. Pinched by the vertebral artery loops on both sides, the spinal cord was severely deformed. Through the standard midline approach, we carefully transposed both vertebral arteries off the spinal cord, placing them at the optimal position using Tanaka et al's Gore-Tex tape technique originally reported for microvascular decompression. The Gore-Tex tape transposition technique proved to be versatile and useful for safe transposition of the vertebral artery in this challenging case.

Neuroendoscopic Evacuation for Spontaneous Cerebellar Hemorrhage Is a Safe and Secure Approach and May Become a Mainstream Technique.

Patients with spontaneous cerebellar hemorrhage present with rapidly deteriorating neurological symptoms due to a hematoma-induced mass effect in the brainstem. We compared the standard surgical approach of a suboccipital craniectomy with neuroendoscopic surgery for treating spontaneous cerebellar hemorrhage. We performed a retrospective analysis of 41 patients indicated for surgery to treat spontaneous cerebellar hemorrhage. At our hospital, craniectomy was performed until 2010, and neuroendoscopic surgery was performed thereafter when a qualified surgeon was available. Duration of surgery and intraoperative blood loss were lower in the neuroendoscopic surgery group. The extent of hematoma removal and the percentage of patients requiring shunting were similar between groups. The mass effect was resolved in all patients in both groups, and no substantial re-bleeding was observed in either group. The outcomes at discharge were comparable between the two groups. Our surgeons used the supine lateral position, which involves fewer burdens to the patient than the prone position. Selection of the site of the burr hole is important to avoid the midline and to avoid the area exactly above the transverse and sigmoid sinus. Our results suggest that minimally invasive neuroendoscopic surgery is safe and superior to craniectomy due to shortened duration of surgery and decreased intraoperative bleeding.

Radical Intracapsular Dissection Technique for Dumbbell-Shaped Spinal Schwannoma with Intradural and Extradural Components.

BACKGROUND: Dumbbell-shaped spinal schwannomas with intradural and extradural components are associated with higher complication rates. This may be in part due to epineurial dissection of the extradural component, which inevitably damages the functioning nerve fibers beneath the epineurium and may lead to dural defects that are often difficult to repair. OBJECTIVE: The objective was to describe a radical intracapsular dissection technique that provides a simpler operative field with no need for dural repair and a better chance of preserving functioning nerve fibers. METHODS: The technique comprised the following: 1) exposure of the tumor while preserving spinal stability; 2) a single incision encompassing the dura and epineurium; 3) microsurgical dissection of the tumor just beneath the epineurium, preserving the viable nerve fibers; and 4) primary closure of the duroepineurial incision. We describe a case series of 7 patients in whom this type of tumor was excised using this technique. RESULTS: Gross total excision was achieved in 5 patients. In 1 patient with a large paravertebral component, the remaining tumor was removed with an additional anterior approach. No cerebrospinal fluid leak was noted, and no recurrence was observed in the median follow-up period of 36 months. CONCLUSIONS: The radical intracapsular dissection technique described herein represents an alternative technique for the removal of dumbbell-shaped spinal schwannomas with intradural and extradural components.

Chronic Subdural Hematomas Associated with Arachnoid Cysts: Significance in Young Patients with Chronic Subdural Hematomas.

Although arachnoid cysts (ACs) are associated with chronic subdural hematomas (CSDHs), especially in young patients, the detailed features of CSDHs associated with ACs remain poorly understood. The objective of this study was to clarify the relationship between the location of CSDHs and ACs and the significance of ACs in young patients with CSDHs. We retrospectively assessed 605 consecutive patients 7 years of age and older who were diagnosed with a CSDH between 2002 and 2014. Twelve patients (2%) had ACs, and 10 of the 12 patients were 7-40 years of age. Patients with ACs as a complication of CSDHs were significantly younger than those without ACs (p < 0.05). Three different relationships between the location of CSDHs and ACs were found: a CSDH contacting an AC, an ipsilateral CSDH apart from an AC, and a CSDH contralateral to an AC. In 21 patients with CSDHs who were 7-40 years of age, 10 (47.6%) had ACs (AC group) and 7 (33.3%) had no associated illnesses (non-AC group). All 10 young patients with ACs showed ipsilateral CSDHs including a CSDH apart from an AC. All 17 patients in both the AC and non-AC groups showed headache but no paresis at admission. The pathogenesis of CSDHs associated with ACs may be different among the three types of locations. The clinical characteristics of patients with a combination of a CSDH and an AC including headache as a major symptom may be attributed to young age in the majority of patients with ACs.

A Case of a TSH-secreting Pituitary Adenoma Associated with Evans' Syndrome.

We present a case of a TSH-secreting pituitary adenoma (TSHoma) associated with Evans' syndrome. A 30-year-old woman was referred to our hospital due to purpura and ecchymoses on her limb and body and epistaxis. Evans' syndrome was diagnosed based on idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia. She had a history of malocclusion and thyroid gland enlargement 4 years prior to admission. Endocrinological tests and magnetic resonance imaging also revealed that this patient had hyperthyroidism due to the TSHoma and that this adenoma concomitantly secreted GH. Recently, several cases of Evans' syndrome were associated with hyperthyroidism caused by autoimmune thyroid disease, such as Graves' disease, suggesting that these 2 conditions may have a common immunological basis. To the best of our knowledge, there is no case report of Evans' syndrome associated with hyperthyroidism due to TSHoma. Our report suggests that the excess of thyroid hormone itself promotes autoimmunity in Evans' syndrome. Thus, early treatment for hyperthyroidism is necessary in TSHomas because of the possibility that thyroid hormone normalization may prevent the development of Evans' syndrome.

Risks and benefits of CT angiography in spontaneous intracerebral hemorrhage.

BACKGROUND: Few studies have examined the risk of computed tomography angiography (CTA) during the acute phase of spontaneous intracerebral hemorrhage (ICH), while the benefits of CTA in ICH have been well-documented. The present study investigated both the benefits of identifying spot signs, which are supposed to indicate hematoma enlargement after admission, and risks of CTA performed during the acute phase of ICH. METHODS: We retrospectively assessed 323 consecutive patients with spontaneous ICHs admitted to our hospital between April 2009 and March 2012 and who underwent CTA on admission. RESULTS: In 80 patients (24.7 %), spot signs were demonstrated on CTA source images. Multivariate analysis revealed two independent factors correlated with presence of the spot sign: age and hematoma volume (p < 0.05 each). The presence of spot sign was associated with unfavorable outcomes at discharge and hematoma growth after admission (p < 0.05 each). Adverse events related to CTA occurred in 17 patients (5.2 %), including transient renal dysfunction in 16 patients and allergy to contrast medium in one patient. All adverse events completely resolved within 1 week. CONCLUSIONS: Presence of the spot sign indicated the possibility of hematoma growth and unfavorable outcomes. A small number of adverse events occurred in association with CTA, but without any permanent deficits. Given the potential benefits and risks, we believe that CTA performed at admission in all patients with ICH is beneficial to improve the outcomes.

Neuroprotective effects of liraglutide for stroke model of rats.

The number of diabetes mellitus (DM) patients is increasing, and stroke is deeply associated with DM. Recently, neuroprotective effects of glucagon-like peptide-1 (GLP-1) are reported. In this study, we explored whether liraglutide, a GLP-1 analogue exerts therapeutic effects on a rat stroke model. Wistar rats received occlusion of the middle cerebral artery for 90 min. At one hour after reperfusion, liraglutide or saline was administered intraperitoneally. Modified Bederson's test was performed at 1 and 24 h and, subsequently, rats were euthanized for histological investigation. Peripheral blood was obtained for measurement of blood glucose level and evaluation of oxidative stress. Brain tissues were collected to evaluate the level of vascular endothelial growth factor (VEGF). The behavioral scores of liraglutide-treated rats were significantly better than those of control rats. Infarct volumes of liraglutide-treated rats at were reduced, compared with those of control rats. The level of derivatives of reactive oxygen metabolite was lower in liraglutide-treated rats. VEGF level of liraglutide-treated rats in the cortex, but not in the striatum significantly increased, compared to that of control rats. In conclusion, this is the first study to demonstrate neuroprotective effects of liraglutide on cerebral ischemia through anti-oxidative effects and VEGF upregulation.

The striate artery, hematoma, and spot sign on coronal images of computed tomography angiography in putaminal intracerebral hemorrhage.

BACKGROUND AND PURPOSE: A spot sign is a bright spot on computed tomography angiography source images, which is predictive of hematoma growth in spontaneous intracerebral hemorrhage, although the cause of the spot sign is unclear. Our aim was to investigate the spot sign seen on computed tomography angiography and a striate artery, which is a presumed site of intracerebral hemorrhage bleeding origin in the putamen. METHODS: In consecutive cases of spontaneous intracerebral hemorrhage in the putamen, spot signs and striate arteries were evaluated. Coronal reformat images of computed tomography angiography were created to visualize the striate arteries. Acute deterioration, defined as hematoma enlargement, emergency hematoma removal, or death within the day of admission, was reviewed. RESULTS: Of the 141 patients undergoing computed tomography angiography, 15 of the 30 patients (50%) who had spot signs showed an intrahematoma striate artery (termed spot and tail sign), which was a linear density extending from the middle cerebral artery toward the spot sign. Acute deterioration occurred more frequently in patients who had a spot and tail sign compared with patients who had spot signs without intrahematoma striate arteries (P<0.05). Multivariate analysis revealed that hematoma volume, spot signs, and intrahematoma striate arteries were independent predictors of acute deterioration (P<0.05). CONCLUSIONS: The presence of a spot and tail sign, assumed to indicate active bleeding from the striate artery, could be a more sensitive predictor of acute deterioration than the presence of a simple spot sign.

Impact of the combination of 5-aminolevulinic acid-induced fluorescence with intraoperative magnetic resonance imaging-guided surgery for glioma.

OBJECTIVE: To compare intraoperative magnetic resonance imaging (MRI)-guided resection with resection guided by 5-aminolevulinic acid (5-ALA)-induced fluorescence in patients with gliomas and to evaluate the impact of intraoperative MRI in glioma surgery. METHODS: From January 2005 to February 2009, 33 patients with gliomas (6 with World Health Organization [WHO] grade II, 7 with WHO grade III, 20 with WHO grade IV) who underwent craniotomy with neuronavigation and received 5-ALA by the same neurosurgeon were investigated retrospectively. In 19 patients, operations were performed using a combination of 5-ALA with intraoperative 1.5-T MRI. All patients were subjected to postoperative 1.5-T MRI to confirm the extent of resection. RESULTS: Of 33 patients with gliomas, 21 (4 with WHO grade III and 17 with WHO grade IV) were 5-ALA-induced fluorescence-positive (5-ALA (+)). Surgery with intraoperative MRI was performed in 10 of the 21 patients, and the average resection rate was 92.6%. The average resection rate of patients who underwent surgery without intraoperative MRI was 91.8%. 5-ALA-induced fluorescence was not detected in 12 patients (6 with WHO grade II, 3 with WHO grade III, and 3 with WHO grade IV) with gliomas. Surgery with intraoperative MRI was performed in 9 of 12 patients, and the average resection rate was 89.2%. The average resection rate of patients who underwent surgery without intraoperative MRI was 68.7%. Intraoperative MRI-guided tumor resection resulted in a better resection rate in patients with 5-ALA-induced fluorescence-negative (5-ALA (-)) gliomas than in patients with 5-ALA (+) gliomas (20.5% vs 0.8%). CONCLUSIONS: Intraoperative MRI-guided resection is a powerful tool to treat 5-ALA (-) gliomas (mostly low grade), and 5-ALA is useful for high-grade gliomas. The combination of intraoperative MRI and 5-ALA has a synergistic effect in glioma surgery. Additionally, precise tumor grading in preoperative imaging studies can be difficult. Surgery for gliomas should be performed using both 5-ALA-induced fluorescence and intraoperative MRI-guided resection.

Urinary 8-OHdG elevations in a partial lesion rat model of Parkinson's disease correlate with behavioral symptoms and nigrostriatal dopaminergic depletion.

Increased oxidative stress contributes to pathogenesis of Parkinson's disease (PD). 8-hydroxy-2'-deoxyguanosine (8-OHdG) is the oxidation product most frequently measured as an indicator of oxidative DNA damage. Several studies have shown increased 8-OHdG in PD patients. There are few basic laboratory data examining 8-OHdG levels in animal models of PD. In this study, we utilized hemiparkinsonian model of rats induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA). The urinary 8-OHdG level was measured in relation to behavioral and pathological deficits arising from 6-OHDA-induced neurotoxic effects on the nigrostriatal dopaminergic pathway. All rats were subjected to a series of behavioral tests for 42 days after 6-OHDA injection. We collected urine samples with subsequent measurement of 8-OHdG level using ELISA kits. For immunohistochemical evaluation, tyrosine hydroxylase (TH) staining was performed. Significant increments in urinary 8-OHdG level were observed continuously from day 7 until day 35 compared to control group, which showed a trend of elevation as early as day 3. Such elevated urinary 8-OHdG level significantly correlated with all of the behavioral deficits measured here, suggesting that urinary 8-OHdG level provides a good index of severity of parkinsonism. Urinary 8-OHdG level also had a significant positive correlation with the survival rate of dopaminergic fibers or neurons, advancing the concept that oxidative stress during the early phase of 6-OHDA neurotoxicity may correspond to disease progression closely approximating neuronal degeneration in the nigrostriatal dopaminergic system. The present results demonstrate that alterations in urinary 8-OHdG level closely approximate onset and disease progression in PD.

Striatal stimulation nurtures endogenous neurogenesis and angiogenesis in chronic-phase ischemic stroke rats.

Deep brain stimulation (DBS) is used to treat a variety of neurological disorders including Parkinson's disease. In this study, we explored the effects of striatal stimulation (SS) in a rat model of chronic-phase ischemic stroke. The stimulation electrode was implanted into the ischemic penumbra at 1 month after middle cerebral artery occlusion (MCAO) and thereafter continuously delivered SS over a period of 1 week. Rats were evaluated behaviorally coupled with neuroradiological assessment of the infarct volumes using magnetic resonance imaging (MRI) at pre- and post-SS. The rats with SS showed significant behavioral recovery in the spontaneous activity and limb placement test compared to those without SS. MRI visualized that SS also significantly reduced the infarct volumes compared to that at pre-SS or without SS. Immunohistochemical analyses revealed a robust neurogenic response in rats that received SS characterized by a stream of proliferating cells from the subventricular zone migrating to and subsequently differentiating into neurons in the ischemic penumbra, which exhibited a significant GDNF upregulation. In tandem with this SS-mediated neurogenesis, enhanced angiogenesis was also recognized as revealed by a significant increase in VEGF levels in the penumbra. These results provide evidence that SS affords neurorestoration at the chronic phase of stroke by stimulating endogenous neurogenesis and angiogenesis.

Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell-derived factor-1alpha.

BACKGROUND: Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from bone marrow with secretory functions of various neurotrophic factors. Stromal cell-derived factor-1alpha (SDF-1alpha) is also reported as one of chemokines released from MSCs. In this research, the therapeutic effects of MSCs through SDF-1alpha were explored. 6-hydroxydopamine (6-OHDA, 20 microg) was injected into the right striatum of female SD rats with subsequent administration of GFP-labeled MSCs, fibroblasts, (i.v., 1 x 107 cells, respectively) or PBS at 2 hours after 6-OHDA injection. All rats were evaluated behaviorally with cylinder test and amphetamine-induced rotation test for 1 month with consequent euthanasia for immunohistochemical evaluations. Additionally, to explore the underlying mechanisms, neuroprotective effects of SDF-1alpha were explored using 6-OHDA-exposed PC12 cells by using dopamine (DA) assay and TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining. RESULTS: Rats receiving MSC transplantation significantly ameliorated behaviorally both in cylinder test and amphetamine-induced rotation test compared with the control groups. Correspondingly, rats with MSCs displayed significant preservation in the density of tyrosine hydroxylase (TH)-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra pars compacta (SNc) compared to that of control rats. In the in vitro study, SDF-1alpha treatment increased DA release and suppressed cell death induced by 6-OHDA administration compared with the control groups. CONCLUSIONS: Consequently, MSC transplantation might exert neuroprotection on 6-OHDA-exposed dopaminergic neurons at least partly through anti-apoptotic effects of SDF-1alpha. The results demonstrate the potentials of intravenous MSC administration for clinical applications, although further explorations are required.

Exercise exerts neuroprotective effects on Parkinson's disease model of rats.

Recent studies demonstrate that rehabilitation ameliorates physical and cognitive impairments of patients with stroke, spinal cord injury, and other neurological diseases and that rehabilitation also has potencies to modulate brain plasticity. Here we examined the effects of compulsive exercise on Parkinson's disease model of rats. Before 6-hydroxydopamine (6-OHDA, 20 microg) lesion into the right striatum of female SD rats, bromodeoxyuridine (BrdU) was injected to label the proliferating cells. Subsequently, at 24 h after the lesion, the rats were forced to run on the treadmill (5 days/week, 30 min/day, 11 m/min). As behavioral evaluations, cylinder test was performed at 1, 2, 3, and 4 weeks and amphetamine-induced rotational test was performed at 2 and 4 weeks with consequent euthanasia for immunohistochemical investigations. The exercise group showed better behavioral recovery in cylinder test and significant decrease in the number of amphetamine-induced rotations, compared to the non-exercise group. Correspondingly, significant preservation of tyrosine hydroxylase (TH)-positive fibers in the striatum and TH-positive neurons in the substantia nigra pars compacta (SNc) was demonstrated, compared to the non-exercise group. Additionally, the number of migrated BrdU- and Doublecortin-positive cells toward the lesioned striatum was increased in the exercise group. Furthermore, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor increased in the striatum by exercise. The results suggest that exercise exerts neuroprotective effects or enhances the neuronal differentiation in Parkinson's disease model of rats with subsequent improvement in deteriorated motor function.

Electrical stimulation of the cerebral cortex exerts antiapoptotic, angiogenic, and anti-inflammatory effects in ischemic stroke rats through phosphoinositide 3-kinase/Akt signaling pathway.

BACKGROUND AND PURPOSE: Neuroprotective effects of electric stimulation have been recently shown in ischemic stroke, but the underlying mechanisms remain poorly understood. METHODS: Adult Wistar rats weighing 200 to 250 g received occlusion of the right middle cerebral artery for 90 minutes. At 1 hour after reperfusion, electrodes were implanted to rats on the right frontal epidural space. Electric stimulation, at preset current (0 to 200 microA) and frequency (0 to 50 Hz), was performed for 1 week. Stroke animals were subjected to behavioral tests at 3 days and 1 week postmiddle cerebral artery and then immediately euthanized for protein and immunohistochemical assays. After demonstration of behavioral and histological benefits, subsequent experiments pursued the mechanistic hypothesis that electric stimulation exerted antiapoptotic effects through the phosphoinositide 3-kinase-dependent pathway; thus, cortical stimulation was performed in the presence or absence of specific inhibitors of phosphoinositide 3-kinase (LY294002) in stroke rats. RESULTS: Cortical stimulation abrogated the ischemia-associated increase in apoptotic cells in the injured cortex by activating antiapoptotic cascades, which was reversed by the phosphoinositide 3-kinase inhibitor LY294002 as reflected behaviorally and immunohistochemically. Furthermore, brain levels of neurotrophic factors (glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor) were upregulated, which coincided with enhanced angiogenesis and suppressed proliferation of inflammatory cells in the ischemic cortex. CONCLUSIONS: These results suggest that electric stimulation prevents apoptosis through the phosphoinositide 3-kinase pathway. Consequently, the ischemic brain might have been rendered as a nurturing microenvironment characterized by robust angiogenesis and diminished microglial/astrocytic proliferation, resulting in the reduction of infarct volumes and behavioral recovery. Electric stimulation is a novel and potent therapeutic tool for cerebral ischemia.

The combined therapy of intrahippocampal transplantation of adult neural stem cells and intraventricular erythropoietin-infusion ameliorates spontaneous recurrent seizures by suppression of abnormal mossy fiber sprouting.

Adult neural stem cells (NSCs) possess the potentials to self-renew and exert neuroprotection. In this study, we examined whether adult NSCs had anti-epileptic effects in rats with status epilepticus (SE) induced by kainic acid (KA) and whether co-administration of erythropoietin (EPO) enhanced anti-epileptic effects or cell survival. Adult NSCs were transplanted into KA-lesioned hippocampus with or without intracerebroventricular EPO infusion. Electronic encephalography (EEG) was recorded for 3 weeks after transplantation. The frequency of abnormal spikes in rats with NSC transplantation decreased significantly compared to those of rats without NSC transplantation. Most of the transplanted NSCs differentiated into GFAP-positive astrocytes. EPO infusion significantly enhanced the survival of NSCs, but not neuronal differentiation or migration. NSC transplantation increased the number of neuropeptide Y (NPY) and glutamic acid decarboxylase 67 (GAD67)-positive interneurons. NSC transplantation also suppressed mossy fiber sprouting into the inner molecular layer with subsequent reduction of hippocampal excitability, which finally prevented the development of spontaneous recurrent seizures in adult rats after KA-induced SE. This study might shed light on the cytoarchitectural mechanisms of temporal lobe epilepsy as well as clarify the effect of adult NSC transplantation with intracerebroventricular EPO infusion for temporal lobe epilepsy.

Continuous intraventricular infusion of erythropoietin exerts neuroprotective/rescue effects upon Parkinson's disease model of rats with enhanced neurogenesis.

Parkinson's disease (PD) is characterized by degeneration of nigrostriatal dopaminergic neuronal systems. Several therapeutic tools for PD include medication using L-DOPA and surgeries such as deep brain stimulation are established. However, the therapies are considered as symptomatic therapy, but not basic remedy for PD and a new regenerative therapy would be desired to explore. In this study, the neuroprotective/rescue effects of erythropoietin (EPO), a well known hematopoietic hormone, on dopaminergic neurons were explored with neurogeneic potencies of EPO. EPO (100 IU/day) was continuously administered with micro-osmotic pump for a week to PD model of rats induced by intrastriatal 6-hydroxydopamine (6-OHDA) injection with subsequent behavioral and immunohistochemical investigations. The number of amphetamine-induced rotations of EPO-treated rats significantly decreased, compared to the control rats. The preservation of dopaminergic neurons of EPO-treated rats were confirmed by tyrosine hydroxylase staining and Fluoro-Gold staining. The number of bromodeoxyuridine (BrdU)/polysialic acid-neural cell adhesion molecule (PSA-NCAM) double positive cells in the subventricular zone of EPO treated rats significantly increased with migratory potencies to the damaged striatum,compared to the control rats. Furthermore, TUNEL staining and phosphorylated Akt staining revealed that the neuroprotective/rescue effects of EPO might be mediated by anti-apoptotic effects through the increase of phosphorylated Akt. These results suggest that continuous low dose infusion of EPO exerts neuroprotective/rescue effects with neurogeneic potentials. EPO might be a strong tool for PD therapy, although the further experiments should be added.

Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons.

BACKGROUND: Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of nigrostriatal dopaminergic systems. Free radicals induced by oxidative stress are involved in the mechanisms of cell death in PD. This study clarifies the neuroprotective effects of edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one), which has already been used for the treatment of cerebral ischemia in Japan, on TH-positive dopaminergic neurons using PD model both in vitro and in vivo. 6-hydroxydopamine (6-OHDA), a neurotoxin for dopaminergic neurons, was added to cultured dopaminergic neurons derived from murine embryonal ventral mesencephalon with subsequet administration of edaravone or saline. The number of surviving TH-positive neurons and the degree of cell damage induced by free radicals were analyzed. In parallel, edaravone or saline was intravenously administered for PD model of rats receiving intrastriatal 6-OHDA lesion with subsequent behavioral and histological analyses. RESULTS: In vitro study showed that edaravone significantly ameliorated the survival of TH-positive neurons in a dose-responsive manner. The number of apoptotic cells and HEt-positive cells significantly decreased, thus indicating that the neuroprotective effects of edaravone might be mediated by anti-apoptotic effects through the suppression of free radicals by edaravone. In vivo study demonstrated that edaravone-administration at 30 minutes after 6-OHDA lesion reduced the number of amphetamine-induced rotations significantly than edaravone-administration at 24 hours. Tyrosine hydroxylase (TH) staining of the striatum and substantia nigra pars compacta revealed that edaravone might exert neuroprotective effects on nigrostriatal dopaminergic systems. The neuroprotective effects were prominent when edaravone was administered early and in high concentration. TUNEL, HEt and Iba-1 staining in vivo might demonstrate the involvement of anti-apoptotic, anti-oxidative and anti-inflammatory effects of edaravone-administration. CONCLUSION: Edaravone exerts neuroprotective effects on PD model both in vitro and in vivo. The underlying mechanisms might be involved in the anti-apoptotic effects, anti-oxidative effects, and/or anti-inflammatory effects of edaravone. Edaravone might be a hopeful therapeutic option for PD, although the high therapeutic dosage remains to be solved for the clinical application.

Mechanism of injury to the corpus callosum, with particular reference to the anatomical relationship between site of injury and adjacent brain structures.

The location of corpus callosum injury was investigated using magnetic resonance imaging in 92 patients. The anatomical relationships in the region around the corpus callosum were also evaluated to clarify involvement in the mechanism of corpus callosum injury in 20 normal volunteers. Lesions in the posterior half of the corpus callosum accounted for 80% of corpus callosum injuries. The falx was increasingly elongated toward the posterior portion of the corpus callosum and the corpus callosum was thinnest at the body-splenium junction in the normal volunteers. The mechanism of corpus callosum injury apparently involves the following factors. The posterior half of the falx is closer to the corpus callosum than the anterior half. Therefore, the anterior part of the corpus callosum easily moves with lateral movement of the cerebral hemispheres, and the strain is likely to be concentrated in the posterior half of the corpus callosum, because the falx greatly limits lateral movement of the hemisphere in the posterior region. The corpus callosum is easily distorted at the thinnest part of the body-splenium junction. Therefore, corpus callosum injury predominantly occurs in the posterior half of the corpus callosum.