Yasukazu Kajita

Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson's disease

Molecular hydrogen serves as an antioxidant that reduces hydroxyl radicals, but not the other reactive oxygen and nitrogen species. In the past year, molecular hydrogen has been reported to prevent or ameliorate eight diseases in rodents and one in human associated with oxidative stress. In Parkinsons disease, mitochondrial dysfunction and the associated oxidative stress are major causes of dopaminergic cell loss in the substantia nigra. We examined effects of approximately 50%-saturated molecular hydrogen in drinking water before or after the stereotactic surgery on 6-hydroxydopamine-induced nigrostrital degeneration in a rat model of Parkinsons disease. Methamphetamine-induced behavioral analysis showed that molecular hydrogen prevented both the development and progression of the nigrostrital degeneration. Tyrosine hydroxylase staining of the substantia nigra and striatum also demonstrated that pre- and post-treatment with hydrogen prevented the dopaminergic cell loss. Our studies suggest that hydrogen water is likely able to retard the development and progression of Parkinsons disease.

Human Gene Therapy for Malignant Gliomas (Glioblastoma Multiforme and Anaplastic Astrocytoma) by In Vivo Transduction with Human Interferon β Gene Using Cationic Liposomes

Transfer of interferon beta gene via cationic liposomes has been found to induce regression of experimental glioma. We performed a pilot clinical trial of safety and effectiveness of this interferon beta gene therapy in five patients with malignant glioma (glioblastoma multiforme or anaplastic astrocytoma). Transgene expression and antitumor activity were detected in four patients. Two patients showed a partial response (>50% tumor reduction) and two others had stable disease 10 weeks after beginning therapy. One patient could not be evaluated because of previous treatment with gamma-knife therapy. This study suggests the feasibility and safety of interferon beta gene therapy, which may become an important treatment option for patients with malignant glioma.

Long-term follow-up results of 175 patients with malignant glioma : importance of radical tumour resection and postoperative adjuvant therapy with interferon : ACNU and radiation

SummaryWe analysed long-term follow-up results of 175 patients with malignant glioma (110 glioblastoma and 65 anaplastic astrocytoma) treated under five different regimes during the past two decades. The factors of age (less than 40), histology (anaplastic astrocytoma) and type of adjuvant therapy (radiation and chemotherapy) contributed to long survival. The other important factor was the response to adjuvant therapy.Cases of gross total removal or complete response (CR) of a residual tumour to an adjuvant therapy showed a better prognosis. The three and five year survival rate was 42% and 24%, respectively. The highest CR ratio (23%) was seen in patients treated by intravenous injection of interferon and ACNU in addition to radiotherapy (IAR therapy).

Expression and Distribution of Beta Amyloid Precursor Protein and Beta Amyloid Peptide in Reactive Astrocytes After Transient Middle Cerebral Artery Occlusion

Summary Background. In the brains of Alzheimers disease patients, beta amyloid protein is the major component of senile plaque. In ischemic stress, beta amyloid precursor protein (APP) and beta amyloid peptide are reported to be upregulated. Method. Using Male Wistar-ST rats, expression and distribution of APP and beta amyloid peptide were examined immunohistochemically after transient ischemia induced by a 2-h middle cerebral artery occlusion (MCAO). After reperfusion for 3, 7, 14, 30 and 60 days, brains were removed and immunostaining was performed. Findings. The reactive astrocytes with APP were observed in the periphery of infarct from 3 days to 60 days post-occlusion. The immunoreactivity of beta amyloid peptide was also localized in the reactive astrocytes in the peripheral zone of infarct at 7, 14, and 30 days post-occlusion. However, beta amyloid expression was not identified at 3 days or 60 days post MCAO. Transient ischemia temporarily induced beta amyloid peptide expression in reactive astrocytes, but this expression peaked at 30 days and disappeared at 60 days. Interpretation. These findings suggested that beta amyloid peptide was derived from the processing of APP produced in the same reactive astrocytes and the production of the peptide stopped within 60 days after the ischemic stress.

Role of Nitric Oxide in the Cerebral Vasodilatory Responses to Vasopressin and Oxytocin in Dogs

We angiographically assessed the vasodilatory effects of vasopressin and oxytocin on the basilar arteries in dogs. Intracisternal bolus injections of vasopressin (100 pmol and 1 nmol) and oxytocin (1 and 10 nmol) produced dose-dependent increases in the internal diameter of the basilar arteries without affecting mean arterial blood pressure. The maximal dilatations of the basilar arteries induced by 1 nmol vasopressin and 10 nmol oxytocin were 142.3 ± 19.9 and 136.8 ± 25.5% of the baseline, respectively. When the same peptides were injected into the vertebral artery, the maximal dilatations were similar, but the duration of response was shorter. Pretreatment with intracisternal injection of 10 μmol NG-monomethyl-l-arginine (l-NMMA), which inhibits the synthesis of nitric oxide from l-arginine, suppressed the vasodilatory responses induced by intracisternal injection of vasopressin and oxytocin and by intraarterial injection of vasopressin. Calcitonin gene-related peptide also caused dilatation of the basilar artery when injected into the cisterna magna, but its effect was not blocked by l-NMMA. l-NMMA reduced the basal diameter of the basilar artery in a dose-dependent manner; l-arginine produced dose-dependent increases in diameter. The vasoconstriction induced by l-NMMA was reversed by high concentrations of l-arginine. These results suggest that vasopressin and oxytocin dilate the basilar arteries via the release of nitric oxide from both the intraluminal and the extraluminal sides and that synthesis and release of nitric oxide in the vascular wall contribute to maintenance of basal vascular tonus.

Triphasic response of rat intracerebral arterioles to increasing concentrations of vasopressin In vitro

To determine how vasopressin affects the vascular tone of the smaller cerebral arterioles, we carried out an in vitro study of isolated and cannulated intracerebral arterioles of rats. We found that increasing concentrations of vasopressin induced a triphasic response of vasodilation (10−12–10−11 M), vasoconstriction (10−10–10−8 M), and vasodilation stabilizing to control diameter (10−7–10−6 M) and that the maximum constriction was twice the maximum dilation in these smaller arterioles [21.2 ± 13.1% (mean ± SD) decrease in diameter vs. 11.2 ± 5.7% increase]. Pretreatment of the arterioles with NG-monomethyl-l-arginine (10−4 M), a specific inhibitor of endothelium-derived relaxing factor, abolished the vasopressin-induced vasodilation and significantly increased the vasoconstriction. These results suggest that these arterioles were maintained in a dilated state by an endothelium-derived relaxing factor activated by vasopressin. Both vasodilation and vasoconstriction were found to be mediated through vasopressin V1 receptors in a study of arterioles pretreated with d(CH2)5Tyr(Me)arginine vasopressin (10−6 M), a vasopressin V1 receptor antagonist. These results support the hypothesis that vasopressin may constrict smaller cerebral arterioles while simultaneously dilating larger cerebral arteries. Our results also suggest that vasopressin may aggravate cerebral ischemia in pathological conditions, such as subarachnoid hemorrhage, when the arteriolar response to vasopressin shifts from vasodilation to vasoconstriction due to increased vasopressin levels in plasma and CSF and impaired endothelium-derived relaxation.

Distinct phenotypes of speech and voice disorders in Parkinson's disease after subthalamic nucleus deep brain stimulation

Objectives To elucidate the phenotypes and pathophysiology of speech and voice disorders in Parkinsons disease (PD) with subthalamic nucleus deep brain stimulation (STN-DBS). Methods We conducted a cross-sectional study on 76 PD patients treated with bilateral STN-DBS (PD-DBS) and 33 medically treated PD patients (PD-Med). Speech and voice functions, electrode positions, motor function and cognitive function were comprehensively assessed. Moreover, speech and voice functions were compared between the on-stimulation and off-stimulation conditions in 42 PD-DBS patients. Results Speech and voice disorders in PD-DBS patients were significantly worse than those in PD-Med patients. Factor analysis and subsequent cluster analysis classified PD-DBS patients into five clusters: relatively good speech and voice function type, 25%; stuttering type, 24%; breathy voice type, 16%; strained voice type, 18%; and spastic dysarthria type, 17%. STN-DBS ameliorated voice tremor or low volume; however, it deteriorated the overall speech intelligibility in most patients. Breathy voice did not show significant changes and stuttering exhibited slight improvement after stopping stimulation. In contrast, patients with strained voice type or spastic dysarthria type showed a greater improvement after stopping stimulation. Spastic dysarthria type patients showed speech disorders similar to spastic dysarthria, which is associated with bilateral upper motor neuron involvement. Strained voice type and spastic dysarthria type appeared to be related to current diffusion to the corticobulbar fibres. Conclusions Stuttering and breathy voice can be aggravated by STN-DBS, but are mainly due to aging or PD itself. Strained voice and spastic dysarthria are considered corticobulbar side effects.

Vasorelaxant effect of PACAP-27 on canine cerebral arteries and rat intracerebral arterioles.

The vasorelaxant effects of pituitary adenylate cyclase activating polypeptide (PACAP)-27 were examined and compared with those of PACAP-38 and vasoactive intestinal polypeptide (VIP) on isolated canine cerebral arteries and rat intracerebral arterioles in vitro. The addition of PACAP-27, PACAP-38 or VIP resulted in similar concentration-dependent relaxations in both canine basilar arteries and rat intracerebral arterioles. There were regional differences in the PACAP-27-induced relaxations measured in canine cerebral arteries. The maximum relaxation induced by PACAP-27 was significantly lower in the basilar arteries (23.0 +/- 5.6%) than in the rostrally located arteries (proximal middle cerebral arteries: 45.4 +/- 5.7%, anterior cerebral arteries: 55.2 +/- 5.8%). The maximum relaxation induced by PACAP-27 in the basilar arteries was significantly enhanced by mechanical removal of the endothelium (16.4 +/- 4.5% vs. 32.7 +/- 5.8%) as well as by pretreatment with indomethacin or aspirin (12.9 +/- 4.1% vs. 48.7 +/- 6.1% and 46.5 +/- 9.2%, respectively). Incubation of canine cerebral arteries with PACAP-27 in vitro resulted in an increased release of prostaglandin F2 alpha in the buffer from 14.5 +/- 2.1 pg/min/1 mg vessel to 31.1 +/- 4.2 pg/min/1 mg vessel, while other cyclooxygenase cascade metabolites such as prostaglandin E2, thromboxane B2 and 6-keto prostaglandin F1 alpha did not change. These data suggest that the PACAP-27-induced relaxation of canine basilar arteries may be associated with prostaglandin F2 alpha or its precursor, prostaglandin H2.

Dysfunction of nitric oxide in the spastic basilar arteries after subarachnoid hemorrhage

The function of nitric oxide in spastic cerebral arteries after subarachnoid hemorrhage (SAH) was angiographically investigated in dogs. On days 4 and 7, after two intracisternal injections of autologous blood, higher concentrations of L-arginine than those of endogenous L-arginine in the cerebrospinal fluid produced a transient vasodilation of the spastic basilar artery, whereas NG-monomethyl-L-arginine (L-NMMA) produced no significant vasoconstriction. The vasodilator effect of L-arginine after SAH was stronger on day 4 than day 7, but less than that in intact dogs. Vasopressin, which is known to activate the endothelial L-arginine pathway, could induce a vasodilation only after the treatment with L-arginine. Intracisternal injection of superoxide dismutase (SOD), which caused no effect by itself, enhanced the duration of the vasodilator effect of L-arginine on the basilar artery on day 4 and both the magnitude and duration of that effect on day 7. Thus, the basal release of nitric oxide was impaired after SAH, but the ability to synthesize nitric oxide in the vascular wall was not abolished. Enhancement of L-arginines effect by SOD suggested that the inactivation of nitric oxide by superoxide anion contributed to the development of vasospasm.

Neurosurgical robotic system for brain tumor removal

PurposeBrain tumor (e.g., glioma) resection surgery, representing the first step for many treatments, is often difficult and time-consuming for neurosurgeons. Thus, intelligent neurosurgical instruments have been developed to improve tumor removal.MethodsThe concept and robotic structure of intelligent neurosurgical instruments were introduced. These instruments consist of a surgical robot, a master device and operating software. The robot incorporates a surgical motion base and tool manipulator, including a volume control suction tool. Open Core Control software was developed for connecting intelligent neurosurgical instruments through a network connection and integrating the instruments into a system.ResultsMechanical evaluation tests on the components and a preliminary system evaluation were performed. A phantom model was fixed on a head frame, and a tumor-removal procedure was successfully performed using prototype intelligent neurosurgical instruments.ConclusionIntelligent neurosurgical instruments are feasible and suitable for on-going evaluation in practical tasks, including in-vivo animal testing.