Toshiharu Asai

Structural Fragility and Inflammatory Response of Ruptured Cerebral Aneurysms A Comparative Study Between Ruptured and Unruptured Cerebral Aneurysms

BACKGROUND AND PURPOSE Despite technical advances in endovascular and microsurgical treatment, patients with aneurysmal subarachnoid hemorrhage still have a high mortality and morbidity rate. To improve the treatment results in patients with aneurysms, we must better understand the pathophysiology of cerebral aneurysms and the mechanisms leading to their rupture. Therefore, we studied the pathological differences between unruptured and ruptured aneurysms. METHODS Ruptured (n=44) and unruptured (n=27) aneurysms were obtained at surgery. The aneurysmal endothelium was scored from 0 (normal) to 5 (complete disruption) by using a scanning electron microscope. The aneurysmal wall was evaluated by immunohistochemical methods. The wall structure was scored from 1 (dense collagen and rich, smooth muscle cells) to 5 (hyaline-like structure). The degree of inflammatory cell invasion into the wall was also scored from 0 (very few cells) to 3 (many cells). RESULTS Ruptured aneurysms manifested significant endothelial damage (score of 3.7 versus 0.8; Mann-Whitney U test, P<10(-3)), significant structural changes of the wall (3.7 versus 1.7, P<10(-5)), and significant inflammatory cell invasion (2.2 versus 0.8, P<10(-4)) compared with unruptured aneurysms. There was a significant correlation between the score for wall structure and the score for inflammatory cell invasion (Rs=0. 63; Spearman rank correlation test, P<10(-5)). The pathophysiology of several symptomatic unruptured aneurysms was similar to that of ruptured aneurysms. CONCLUSIONS We conclude that the pathophysiology of unruptured, asymptomatic and ruptured aneurysms is different. The wall of ruptured aneurysms was found to be fragile, possibly because macrophage infiltration into the aneurysmal wall resulted in loss of smooth muscle cells and in degradation of matrix proteins.

Difference in nature of ruptured and unruptured cerebral aneurysms

Although small aneurysms have an extremely low probability of rupture, most aneurysms that rupture are found to be less than 10 mm in diameter. Histological study of aneurysms and epidemiological analysis of subarachnoid haemorrhage revealed that ruptured and unruptured aneurysms are of a different nature.

Enhancement of vascular permeability by specific activation of protease-activated receptor-1 in rat hindpaw: a protective role of endogenous and exogenous nitric oxide.

To clarify the role of the first thrombin receptor/protease‐activated receptor (PAR)‐1 in an inflammatory process, we tested and characterized the effect of intraplantar (i.pl.) administration of the highly specific PAR‐1 agonist TFLLR‐NH2 in rat hindpaw. TFLLR‐NH2 administered i.pl. at 0.01–0.03 μmol per paw enhanced vascular permeability in the hindpaw and produced paw oedema in a dose‐dependent manner. This effect was almost completely abolished by repeated pretreatment with compound 48/80 to deplete inflammatory mediators in mast cells. The NO synthase inhibitor NG‐nitro‐L‐arginine methyl ester or N‐iminoethyl‐L‐ornithine, preadministered i.pl., stereospecifically potentiated the i.pl. TFLLR‐NH2‐induced permeability increase, while the NO donor sodium nitroprusside or NOC‐18, given i.pl., suppressed the effect of TFLLR‐NH2. These findings demonstrate that specific activation of PAR‐1 produces increased vascular permeability accompanied by oedema formation in the rat hindpaw, predominantly via mast cell degranulation, and that endogenous and exogenous NO plays a protective role in the PAR‐1‐mediated inflammatory event.

Roles of urokinase type plasminogen activator in a brain stab wound

Urokinase type plasminogen activator (uPA) may influence brain pathophysiology after injury. We studied disruption of the blood-brain barrier (BBB) and changes in the vasculature after a brain stab wound in uPA-deficient, uPA receptor-deficient, and PA inhibitor-1 (PAI-1) deficient mice. The extravasation of immunoglobulin was greater in PAI-1 deficient mice; less pronounced in uPA-deficient mice; similar to controls in uPA receptor-deficient mice. Vasculatures in the wound proliferated in PAI-1 deficient mice. Our study shows that uPA affects BBB disruption. PA enhances angiogenesis after brain injury.

Functional Changes in Thalamic Relay Neurons After Focal Cerebral Infarct: A Study of Unit Recordings from VPL Neurons After MCA Occlusion in Rats

We evaluated neuronal and histological changes of thalamic neurons 1, 4, 7, and 14 days after middle cerebral artery (MCA) occlusion in rats. After the somatosensory evoked potentials (SEPs) were measured from the cerebral cortex, the thalamic relay neuronal activities were recorded with a glass microelectrode following repetitive electrical stimulation of the contralateral forepaw at frequencies ranging from 1 to 50 Hz. In ∼95% of the occluded rats, the ipsilateral somatosensory cortex and/or the subcortical somatosensory pathway developed infarct, resulting in SEP loss. We evaluated unit data from rats with abolished SEPs. The average firing rate of the nucleus ventralis posterolateralis (VPL) neurons in response to 25 stimulations at 30 Hz was significantly reduced to 0.1 spike/stimulus 1 day after MCA occlusion. In sham-operated rats, the same stimulation produced 0.7 spike/stimulus. The firing rate recovered to 0.4 spike/stimulus at 30-Hz stimulation 4 and 7 days after occlusion. This was followed by resuppression (0.1 spike/stimulus) 14 days after occlusion. Histological study revealed some abnormal neurons in the ipsilateral thalamus 7 days after occlusion. We were unable to find normal-shaped neurons in the VPL 14 days after occlusion. The present study demonstrates that cortical infarct produces functional and morphologic changes that gradually and progressively affect the ipsilateral thalamus, although incomplete transient recovery of somatosensory transmission may occur.

Traumatic laceration of the intracranial vertebral artery causing fatal subarachnoid hemorrhage: Case report

A 36-year-old man who had been drinking alcohol had a fatal subarachnoid hemorrhage immediately after suffering a moderate craniofacial injury. Autopsy revealed a 3-mm longitudinal laceration of the left intracranial vertebral artery proximal to the posterior inferior cerebellar artery. There was no finding of arterial dissection. We discuss the mechanisms of the traumatic laceration of the vertebral artery in relation to traumatic dissection of the vertebral artery.

Energy metabolism in unrestrained fish with in vivo 31P-NMR

Abstract 1. 1. We evaluated changes in high energy phosphate metabolism in unrestrained freshwater loaches by in vivo 31 P-NMR. 2. 2. When dissolved oxygen was deficient, both an increase in Pi and a decrease in PCr were observed as the loach struggled. 3. 3. After pretreating the fish with an anesthetic agent, we observed the dependence of high energy phosphate metabolism on changes in dissolved oxygen. 4. 4. Under anesthetic [Pi]/[Pi] + [PCr] ratio, an index of metabolic state, was lower than without anesthesia. 5. 5. Decrease in high energy phosphate metabolism in fish during oxygen deficiency was not caused by poor oxygen supply but resulted from struggle movement due to lack of oxygen.

Electrophysiological changes in substantia nigra after striatal infarction.

The GABAergic efferent pathway from the striatum exerts inhibitory control on the substantia nigra pars reticulata (SNR) neurones. We studied sequential changes in spontaneous single-unit activities in the ipsilateral SNR 1 h, 1 day, 7 days and 14 days after striatal infarction induced by middle cerebral artery occlusion (MCAO) in rats. Compared with a sham-operated group, there was no change in the firing rate 1 h after MCAO, and one day after MCAO the mean firing rate decreased. The firing rate of SNR neurones at 7 and 14 days after MCAO was significantly reduced compared with the sham-operated group. Only two neurones (sham-operated group and 1 h after MCAO group) fired with high frequency. Histological examination revealed degeneration of the ipsilateral SNR 7 and 14 days after MCAO. Our results indicated that SNR neuronal degeneration accompanied by striatal ischaemia does not simply depend on hyperexcitation due to the activation of a disinhibition mechanism.

Nigral degeneration following striato-pallidal lesion in tissue type plasminogen activator deficient mice

Tissue type plasminogen activator (tPA) has been suggested as a key factor in excitotoxic neuronal death in the hippocampus. Transneuronal degeneration of the substantia nigra pars reticulata (SNR) neurons after striato-pallidal lesions is attributable to excess excitatory glutamatergic inputs into the SNR following inhibitory GABAergic deafferentation and tPA may contribute to the mechanism of transneuronal degeneration of the SNR. To examine this possibility, we studied pathological changes in the SNR following striato-pallidal lesions produced by electrocoagulation in tPA-deficient mice. There was no difference in the degree of SNR degeneration, or in microglial activation and proliferation in the degenerating SNR of tPA-deficient and control mice. Our results indicate that tPA does not contribute to transneuronal degeneration in the SNR following striato-pallidal lesions in mice.

Changes in high-energy phosphate metabolites in loaches (cobitis biwae) during 2-phenoxyethanol anesthesia

Abstract 1. We evaluated changes in high-energy phosphate metabolism in the muscle of loaches during 2-phenoxyethanol (2-PE) anesthesia by 31 P-NMR. 2. The creatine phosphate (PCr) concentration increased while the inorganic phosphate (Pi) concentration decreased in the muscle as 2-PE anesthesia was continued, but both returned to the preanesthetic values with recovery from the anesthesia. 3. The sugar phosphate (SP) concentration also increased during anesthesia, but SP did not disappear after recovery. 4. In the muscle of loaches anesthetized with 2-PE, the phosphate metabolism was aerobic, but carbohydrate metabolism was suppressed.