Seigo Nagao

Edaravone Attenuates Brain Edema and Neurologic Deficits in a Rat Model of Acute Intracerebral Hemorrhage

Background and Purpose— Our previous studies have demonstrated that oxidative DNA injury occurs in the brain after intracerebral hemorrhage (ICH). We therefore examined whether edaravone, a free-radical scavenger, could reduce ICH-induced brain injury. Methods— These experiments used pentobarbital-anesthetized, male Sprague-Dawley rats that received an infusion of either 100 &mgr;L autologous whole blood (ICH), FeCl2, or thrombin into the right basal ganglia. The rats were humanely killed 24 hours later. There were 4 sets of experiments. In the first, the dose-dependent effects of edaravone on ICH-induced brain injury were examined by measuring brain edema and neurologic deficits. In the second set, apurinic/apyrimidinic abasic sites and 8-hydroxyl-2′-deoxyguanosine, which are hallmarks of DNA oxidation, were investigated after treatment for ICH. In the third, the effect of delayed treatment with edaravone on ICH-induced injury was determined, whereas the fourth examined the effects of edaravone on iron- and thrombin-induced brain injury. Results— Systemic administration of edaravone immediately or 2 hours after ICH reduced brain water content 24 hours after ICH compared with vehicle (P<0.05). Edaravone treatment immediately or 2 hours after ICH also ameliorated neurologic deficits (P<0.05). Edaravone also attenuated ICH-induced changes in apurinic/apyrimidinic abasic sites and 8-hydroxyl-2′-deoxyguanosine and reduced iron- and thrombin-induced brain injury. Conclusions— Edaravone attenuates ICH-induced brain edema, neurologic deficits, and oxidative injury. It also reduces iron- and thrombin-induced brain injury. These results suggest that edaravone is a potential therapeutic agent for ICH.

Hyperglycemia Induces Progressive Changes in the Cerebral Microvasculature and Blood-brain Barrier Transport During Focal Cerebral Ischemia

Hyperglycemia generally enhances cerebral ischemic injury. Most attention on a mechanism has focused on the adverse effect of increased lactate production (acidosis) leading to neuronal injury. The effects of hyperglycemia on another possible primary target, the cerebral microvasculature, is examined in this study. Focal cerebral ischemia was achieved by thread occlusion of the middle cerebral artery (MCA). Preischemic hyperglycemia was induced by intraperitoneal administration of 50% of D-glucose solution. In contrast to normoglycemic controls, glucose-injected rats showed a well demarcated pale infarct after 2 or 4 hours of ischemia reflecting a reduction in cerebral plasma volume (CPV) to 73 +/- 9 and 55 +/- 6% of contralateral by 2 and 4 hours respectively. Cerebral blood flow (CBF) measured by laser-Doppler flowmetry indicated that after the initial decline in CBF with MCA occlusion, hyperglycemia led to a further progressive reduction during ischemia. Blood-brain barrier transport measured by permeability surface area (PS) product for glutamine was reduced in both normoglycemic and hyperglycemic rats. However, the decline was greater in the hyperglycemic rats. Hyperglycemia induces progressive cerebrovascular changes and affects blood-brain barrier transport during focal cerebral ischemia. These changes may contribute to the adverse effects of hyperglycemia in stroke.

The use of mild hypothermia for patients with severe vasospasm: a preliminary report

The purpose of this study was to determine the effect of mild hypothermia on cerebral ischaemia due to severe vasospasm, which was refractory to medical and intravascular treatments and to assess the brain protection of this treatment in patients who underwent delayed aneurysm clipping after presenting with ischaemic neurological deficits. Mild hypothermia (32-34 degrees C of brain temperature) was employed in two groups: (1) Patients (Hunt and Kosnik grades I to II) who showed progressive neurological deficits due to vasospasm and did not respond to conventional therapy (Group 1) and (2) Patients who received delayed aneurysm clipping after presenting with ischaemic neurological deficits due to vasospasm (Group 2). Seven of 8 patients in both Groups showed a favorable outcome with mild hypothermia (good recovery in 5 and moderate disability in two patients). Mild hypothermia is considered to be effective on critical cerebral ischaemia due to vasospasm even after failure to response the conventional therapies and to provide brain protection in delayed aneurysm clipping.

Do rapid systemic changes of brain temperature have an influence on the brain

Summary. Background: The purpose of the present study was to examine the influence of cooling and rewarming conditions using an accurate brain temperature control system. Method: The brain temperature of animals was measured with a thermometer while feedback regulation was achieved with a cold (4°C) and hot (50°C) water on-off flow system. Brain temperature was well controlled throughout the experiment by using both cold water and hot water simultaneously. Three groups were studied, as follows: 1) the standard group (cooled to 24°C for 1 hour, kept at 24°C for 2 hours and rewarmed to 37°C for 1 hour), 2) the rapid-cooling group (cooled to 24°C for 30 min, kept at 24°C for 2 h, and rewarmed to 37°C for 1 h), 3) the rapid-rewarming group (cooled to 24°C for 1 h, kept at 24°C for 2 h, and rewarmed to 37°C for 30 min) and the normal-control group. Findings: An increase of MAP-2 immunoreactivity of the CA1 neurons in the dorsal hippocampus was observed one week but not one month after hypothermia in the rapid-rewarming group. There was also a significant increase in the glutamate and lactate value at the end of rewarming compared with the baseline in the rapid-rewarming group (p<0.01). Interpretation: Our results suggest that rapid rewarming after hypothermia triggered an uncoupling of cerebral circulation and metabolism, inducing an increase of extracellular glutamate and lactate, consequently reversible neuronal cell damage.

The chronic cell death with DNA fragmentation after post-ischaemic hypothermia in the gerbil hippocampus.

Summary The long-term effects of post-ischaemic hypothermia are controversial. The purpose of this study was to examine the long-term effects of post-ischaemic hypothermia on neuronal survival in gerbils in terms of morphology and function. Hypothermia was induced at 32° C for 4 h immediately after ischaemia. Examination was performed at 1 week and at 1 month after ischaemia. Post-ischaemic hypothermia prevented CA1 neuronal damage 1 week after ischaemia. At 1 month after ischaemic insult, however, the degree of the protective effect of post-ischaemic hypothermia was reduced in the lateral and medial CA1 areas. DNA fragmentation was also observed at 1 month. The errors in the 8-arm radial maze trial were increased at 1 month. These data may indicate that cells in the CA1 area are very vulnerable to ischaemia and die after post-ischaemic hypothermia, and that their death is associated with apoptosis.

Significance of Multimodal Cerebral Monitoring under Moderate Therapeutic Hypothermia for Severe Head Injury

The therapeutic significance of moderate hypothermia and cerebral monitorings was assessed in the 10 patients with severe head injury. Cooling was begun as soon as possible after admission, using water blankets under general anesthesia. Jugular venous or tympanic temperature of patients was maintained at 32 degrees C for 3 to 5 days, then rewarming at the rate of 1 degree C a day was started. The intracranial pressure was controllable less than 20 mmHg under hypothermia. Moderate hypothermia reduced the jugular venous lactate (33.5%) as well as the cerebral blood flow velocity at M1 portion of middle cerebral artery (CBFV-M1) measured by transcranial Doppler (7.2%), while increase of the jugular venous oxygen saturation (SjO2) (17.9%) was observed in a majority of the patients. Our results demonstrated that moderate therapeutic hypothermia significantly reduced cerebral circulation and metabolism. Measurement of SjO2 and CBFV-M1 seems to be useful for estimation of cerebral circulation and metabolism in therapeutic hypothermia.

Effects of Hypothermia on Intracranial Hemodynamics and Ischemic Brain Damage-Studies in the Rat Acute Subdural Hematoma Model

Brain ischemia is the leading pathophysiological mechanism in the development of secondary brain damage after subdural hematoma (SDH). Hypothermia has been used as the effective neuroprotective treatment in clinical and laboratory studies of ischemic brain injury. In this study, we have examined the rat acute SDH model to assess the effect of hypothermia upon intracranial hemodynamics and also upon ischemic brain injury 4 hours after the induction of hematoma. Moderate hypothermia (32 degrees C) did not affect the intracranial pressure nor cerebral perfusion pressure, and it significantly reduced cortical brain edema formation underneath the hematoma (80.88 +/- 0.17%; p < 0.01) compared with the normothermic control group (81.65 +/- 0.52%). This reduction in brain edema formation was comparable to the result of MK-801 (2 mg/kg) treatment (80.95 +/- 0.35%; p < 0.01). Ischemic brain damage detected by H-E staining was also significantly reduced in the hypothermia and MK-801 treated groups (59.1 +/- 12.3 mm3 and 66.4 +/- 13.8 mm3; p < 0.01 and p < 0.05) compared with the normothermic control group (86.6 +/- 20.7 mm3). In conclusion, the present study demonstrates that hypothermia is a potent neuroprotective method and an inhibition of the glutamate excitotoxic process may contribute the protective mechanisms of hypothermia in this rat acute SDH model.

Angiographically Occult Anomalous Ophthalmic Artery Arising from the Anterior Cerebral Artery

Cerebral angiography demonstrated an ACoA aneurysm in a 63-year-old man with subarachnoid haemorrhage (Fig. 1 a). Although the left OA was clearly seen, the right OA could not be identified. The anomalous OA, which was found later during surgery, had not been seen on the common carotid angiograms in any phases in multiple views. A right pterional craniotomy was performed. An artery 1 mm in diameter was found above the right optic nerve. This artery arose from the proximal (A1) segment of the ACA and entered the optic canal, and was identified as an anomalous OA (Fig. 1 b). Since this artery anchored the A1 segment firmly at its origin, retraction of the frontal lobe was restricted. Thus neck clipping was unavoidably performed through the space behind the right ACA with extensive resection of the gyrus rectus. Post-operative angiography confirmed completely satisfactory clipping, but the anomalous OA was not demonstrated.

Treatment of arteriovenous malformation of the brain--preliminary experience.

With the availability of new techniques, such as intravascular embolisation and radiosurgery, the therapeutic approach to arteriovenous malformations (AVMs) of the brain has recently been modified. The present study reports the authors, experiences in treating AVMs over the past 13 years. Spetzler-Martin grading of AVMs was I and II in 19 cases, III in 12, IV in 5 and V in 1 case. Four therapeutic regimens were utilised: surgical resection alone, embolisation and resection, and radiosurgery alone or after surgical resection. Generally, for low-grade AVMs (Spetzler-Martin grades I, II and III), the therapeutic choice was surgical resection in 27 cases, in combination with pre-operative embolisation in two of these patients. Two cases received radiotherapy only and one case received radiosurgery after embolisation, while one case was treated conservatively. Of the five cases of grade IV, four required surgical treatment, whereas the fifth case was treated conservatively. Favourable results (good recovery and moderate disability) were obtained in 96% of the low-grade AVMs as compared with the high-grade AVMs (66%) that had a poor outcome (due to primary brain damage resulting from haemorrhage at the onset in three cases and due to postoperative re-bleeding in one case). This report summarises preliminary experience in treating intracranial AVMs by surgical resection, intravascular embolisation and radiotherapy. Good therapeutic results can be expected by combining these therapeutic modalities.

Transplantation of neural stem cells into epileptic brain

Abstract Embryonic stem cells (ES cells) differentiate into multiple cell lineages including neurons and glia. Subsequent to the isolation of neural stem cells, they can be expanded, genetically modified and extensively characterized prior to transplantation. These neural stem cells represent an ideal cell type for transplantation purpose in the central nervous system due to their multipotency. In the present study, we optimized the effective method to induce the differentiation of GABAergic neurons from neurospheres that had been derived from ES cells. Moreover, the effect of the transplantation of these cells was investigated on morphological and functional outcome in grafted mice kindled by electrical stimulation.