Takahito Miyazawa

Cerebral cavernomas in the adult. Review of the literature and analysis of 72 surgically treated patients.

Abstract. The authors review the pertinent literature dealing with all aspects of cerebral cavernous malformations in the adult. Clinical, neuroradiological, pathological, and epidemiological aspects are presented. The clinical significance of bleeding from cavernous malformations and various hemorrhage patterns are discussed in relation to the factors that influence hemorrhage rates. Recent reports describing the genetic mechanisms of inheritance, de novo formation, and angiogenesis of cavernomas are reviewed as well. Brainstem cavernomas have received special attention, since their clinical management is controversial in the literature. Presently, microsurgical removal is favored by the majority of authors and stereotactic radiosurgery appears to be inappropriate for prevention of bleeding from a cavernoma. Our own case material consists of data of 72 patients operated upon during the past 5 years. Twenty-four patients harbored the lesion within the brainstem, 18 within the deep white matter of the hemispheres, 12 in the basal ganglia or thalamus, 11 in superficial areas of the hemisphere, and seven within the cerebellum. The perioperative morbidity rate was 29.2% (21/72) while the rate of long-term morbidity was 5.5% (4/72), with no mortality in this series. It is concluded that cerebral cavernous malformations, including lesions in critical regions of the brain, can be treated microsurgically with excellent results and an acceptable morbidity.

Protection of Hippocampal Neurons from Ischemia-Induced Delayed Neuronal Death by Hepatocyte Growth Factor: A Novel Neurotrophic Factor

Hepatocyte growth factor (HGF), a natural ligand for the c-met protooncogene product, exhibits mitogenic, motogenic, and morphogenic activities for regeneration of the liver, kidney, and lung. Recently, HGF was clearly shown to enhance neurite outgrowth in vitro. To determine whether HGF has a neuroprotective action against the death of neurons in vivo, we studied the effect of HGF on delayed neuronal death in the hippocampus after 5-minute transient forebrain ischemia in Mongolian gerbils. Continuous postischemic intrastriatal administration of human recombinant HGF (10 or 30 μg) for 7 days potently prevented the delayed death of hippocampal neurons under both anesthetized and awake conditions. Even when HGF infusion started 6 hours after ischemia (i.e., in a delayed manner), HGF exhibited a neuroprotective action. We conclude that HGF, a novel neurotrophic factor, has a profound neuroprotective effect against postischemic delayed neuronal death in the hippocampus, which may have implications for the development of new therapeutic strategies for ischemic neuronal damage in humans.

Preferential conditions for and possible mechanisms of induction of ischemic tolerance by repeated hyperbaric oxygenation in gerbil hippocampus.

OBJECTIVEWe reported previously that repeated hyperbaric oxygenation (HBO) as pretreatment induced ischemic tolerance in the gerbil hippocampus. This study was conducted to determine the preferential conditions for induction of ischemic tolerance by HBO and the mechanism of this induction through immunohistochemical analysis of Bcl-2, Bax, and manganese superoxide dismutase expression. METHODSFive-minute forebrain ischemia was produced in gerbils after pretreatment with 2 atmospheres absolute (ATA) HBO once every other day for one, three, or five sessions, 2 ATA hyperbaric air once every other day for five sessions, or 3 ATA HBO once daily for 10 sessions. Histological examinations were then performed. Two days after pretreatment with 2 ATA HBO once every other day for five sessions or with 3 ATA HBO once daily for 10 sessions, sections were analyzed immunohistochemically. RESULTSPretreatment with 2 ATA HBO once every other day for three or five sessions induced ischemic tolerance; however, pretreatment with 2 ATA HBO for one session, 2 ATA hyperbaric air once every other day for five sessions, or 3 ATA HBO once daily for 10 sessions did not. Pretreatment with 2 ATA HBO once every other day for five sessions, but not with 3 ATA HBO once daily for 10 sessions, significantly increased Bcl-2 and manganese superoxide dismutase immunoreactivity in the CA1 sector. CONCLUSIONThese results suggest that protection against mitochondrial alterations after ischemia through manganese superoxide dismutase and/or Bcl-2 expression may be related to induction of ischemic tolerance by repeated HBO pretreatment.

Repeated hyperbaric oxygen induces ischemic tolerance in gerbil hippocampus

Hyperbaric oxygen (HBO; 100% oxygen at 2 atmospheres absolute) was administered for 1 h to male Mongolian gerbils either for a single session or every other day for five sessions. Two days after HBO pretreatment, the gerbils were subjected to 5 min of forebrain ischemia by occlusion of both common carotid arteries under anesthesia. Seven days after recirculation, neuronal density per 1-mm length of the CA1 sector in the hippocampus was significantly better preserved in the five-session HBO pretreatment group (n = 10: 175.7 (47.8/mm, 54.9% of normal) than in the ischemic control group (n = 10: 26.2 (11.6/mm, 8.0% of normal) and in the single-session HBO pretreatment group (n = 7: 37.3 (21.7/mm, 11.4% of normal). Immunohistochemical staining for the 72-kDa heat-shock protein (HSP-72) in the CA1 sector performed 2 days following pretreatment revealed that the five-session HBO pretreatment increased the amount of HSP-72 present compared with that in the ischemic control group and in the single HBO pretreatment group. These results suggest that tolerance against ischemic neuronal damage was induced by repeated HBO pretreatment, which is thought to occur through the induction of HSP-72 synthesis.

Differential Activation of Mitogen-Activated Protein Kinase Pathways after Traumatic Brain Injury in the Rat Hippocampus

Mitogen-activated protein kinases, which play a crucial role in signal transduction, are activated by phosphorylation in response to a variety of mitogenic signals. In the present study, the authors used Western blot analysis and immunohistochemistry to show that phosphorylated extracellular signal-regulated protein kinase (p-ERK) and c-Jun NH(2)-terminal kinase (p-JNK), but not p38 mitogen-activated protein kinase, significantly increased in both the neurons and astrocytes after traumatic brain injury in the rat hippocampus. Different immunoreactivities of p-ERK and p-JNK were observed in the pyramidal cell layers and dentate hilar cells immediately after traumatic brain injury. Immunoreactivity for p-JNK was uniformly induced but was only transiently induced throughout all pyramidal cell layers. However, strong immunoreactivity for p-ERK was observed in the dentate hilar cells and the damaged CA3 neurons, along with the appearance of pyknotic morphologic changes. In addition, immunoreactivity for p-ERK was seen in astrocytes surrounding dentate and CA3 pyramidal neurons 6 hours after traumatic brain injury. These findings suggest that ERK and JNK but not p38 cascades may be closely involved in signal transduction in the rat hippocampus after traumatic brain injury.

Mn-SOD and Bcl-2 Expression After Repeated Hyperbaric Oxygenation

To clarify the mechanism of ischemic tolerance induced by HBO, we investigated the effect of HBO on immunoreactivity to Bcl-2 and Bax, apoptosis-regulating protein, or Mn-SOD, a radical scavenging system, in the CA1 sector of the gerbil hippocampus. Pretreatment comprising, five sessions at 2 ATA (atmosphere absolute) every other day, but not that comprising, ten sessions at 3 ATA every day, caused significant increases in Bcl-2 and Mn-SOD immunoreactivity in the CA1 sector compared with in the sham pretreatment group. No significant differences in Bax immunoreactivity and neuronal density in the CA1 hippocampal neurons was observed between the groups. These results suggest that protection against mitochondrial alterations after ischemia through Mn-SOD and/or Bcl-2 expression is related to the ischemic tolerance induced by repeated HBO pre-treatment.

Nuclear accumulation of basic fibroblast growth factor in human astrocytic tumors.

The authors recently reported that nuclear accumulation of basic fibroblast growth factor (bFGF) demonstrated a significant correlation with recurrence of pituitary adenomas. The current study sought to determine whether nuclear bFGF accumulation was a predictor of survival in patients with astrocytic tumors.

Analysis of neurotrophic effects of hepatocyte growth factor in the adult hypoglossal nerve axotomy model.

Recent studies have shown that hepatocyte growth factor (HGF) promotes the survival of embryonic motor neurons. However, it remains unclear whether HGF has trophic effects on mature motor neurons. In the present study, we examined the effects of HGF on adult motoneurons using the hypoglossal nerve transection model. In adult rats, neurons in the hypoglossal nucleus show a dramatic loss of choline acetyltransferase (ChAT) protein and mRNA after the axotomy. This reduction of ChAT was markedly prevented when HGF was administered continuously at the cut end of the nerve using an osmotic pump. The HGF receptor, c‐met, protein and mRNA, which were faintly expressed in hypoglossal neurons under normal conditions, gradually increased and reached maximal levels 2 weeks after the axotomy. Administration of HGF reduced this c‐met upregulation almost to normal levels. We also quantified HGF mRNA in the tongue and hypoglossal nucleus. The tongue contained abundant HGF mRNA, whereas the nucleus contained only low levels. Interestingly, the HGF mRNA level in the nucleus did not increase after the axotomy. These findings suggest that HGF is principally produced in the tongue and contributes to maintain ChAT expression in the nucleus. HGF produced in the hypoglossal nucleus alone after disconnection from the tongue may not be sufficient for the maintenance of the motor neuron function. Thus, exogenously applied HGF was effective to prevent the downregulation of ChAT activities. These findings provide a strong rationale for the potential clinical use of HGF for the treatment of motor neuron degenerative disease.

Hepatocyte growth factor reduces the infarct volume after transient focal cerebral ischemia in rats

Abstract Hepatocyte growth factor (HGF) was originally discovered as a powerful mitogen for hepatocytes. HGF also has been reported to function as a neurotrophic factor as well as an angiogenetic factor. The present study examined the neuroprotective effect of HGF against transient focal cerebral ischemia in rats, in which an anti-apoptotic and an angiogenetic effect of HGF was assumed to contribute to the reduction of the infarct volume. The intraventricular administration of human recombinant HGF prevented neuronal death after 120 min of occlusion in the right middle cerebral artery and the bilateral common carotid arteries. HGF significantly reduced the infarct volume in a dose-dependent manner. In a separate series of experiments, we next histopathologically investigated both the anti-apoptotic effect on neurons and the angiogenetic effect of HGF. A large number of TUNEL positive neurons were observed in the inner boundary of the infarct area in both the control and the vehicle group whereas only a few TUNEL positive neurons were observed in the corresponding area in the HGF group. In the HGF group, Bcl-2 protein was obviously represented in surviving neurons subjected to ischemia. The number of the vascular lamina in HGF group were significantly higher than those in the vehicle group. These data suggest that HGF appears to have an ability to prevent apoptotic neuronal cell death while also possessing an angiogenetic effect in the central nervous system which was affected with transient focal cerebral ischemia.

Focal brain edema and natriuretic peptides in patients with subarachnoid hemorrhage

Central salt wasting syndrome may be caused by pathological increases in serum natriuretic peptides after subarachnoid hemorrhage (SAH). However, it is unclear as to why the serum concentration of atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP) increases in the subacute phase of SAH. The present study was designed to assess the correlation between focal brain edema and serum concentration of ANP or BNP in patients with SAH. Focal brain edema was found in 8 SAH-patients and peaked between days 4 and 7 of SAH. The mean serum ANP and BNP levels in patients with focal brain edema were significantly higher than those in patients without focal brain edema between days 4 and 14 of SAH. These results suggest that focal brain edema might correlate with increased levels of ANP and BNP in the subacute phase of SAH.