Shu Hasegawa

Regional brain serotonin synthesis is increased in the olfactory bulbectomy rat model of depression: an autoradiographic study

Serotonin synthesis rates were evaluated using α‐[14C]methyl‐l‐tryptophan (α‐MTrp) autoradiographic methods in olfactory bulbectomized (OBX) rats. They were significantly (p < 0.05) increased in the frontal (50%) and parietal (40%) cortices, superior olive (over 30%), and the substantia nigra (30%) in the OBX rats as compared to the sham operated animals. There were also increases in 5‐hydroxytryptamine (5‐HT) synthesis in some limbic areas: the cingulate (32%), the medial forebrain bundle (58%), the hippocampus (13–25%) and the thalamus (22–40%). The largest increase in 5‐HT synthesis after OBX was observed in the sensory‐motor cortex (67%). 5‐HT synthesis rates were significantly decreased in the dorsal and medial raphe nuclei, but there was no significant change the ventral tegmental area and the locus coeruleus following OBX. These results indicate that olfactory bulbectomy causes an imbalance in 5‐HT synthesis in some projection areas by disproportionally increasing 5‐HT synthesis rates in specific brain regions and making more 5‐HT available for neurotransmission. This imbalance in 5‐HT synthesis and the subsequent elevation of tissue 5‐HT may be responsible for the creation of non‐physiological circuitry which may, in part, be reflected in the symptoms resembling human depression.

Chronic administration of citalopram in olfactory bulbectomy rats restores brain 5-HT synthesis rates: an autoradiographic study

RationaleThe olfactory bulbectomized (OBX) rat model is widely accepted as an animal model of depression with a proposed serotonergic imbalance in the brain.ObjectiveTo study the effects of chronic administration of citalopram on serotonin (5-HT) synthesis rates.MethodSerotonin synthesis was evaluated using the α-[14C]methyl-l-tryptophan (α-MTrp) autoradiographic method in OBX rats. Citalopram was administered continuously (10 mg kg−1 day−1) for 14 days using a subcutaneous osmotic minipump.ResultsThe OBX rats treated with citalopram (OBX-CTP) have the same 5-HT synthesis rates as the sham-operated rats treated with citalopram (Sham-CTP). The OBX-CTP rats, relative to the OBX rats treated with saline (OBX-SAL), showed a reduction in the majority of the terminal brain structures, suggesting a normalization of 5-HT synthesis in the OBX-CTP rats following treatment. The OBX-SAL rats have significantly greater synthesis than the Sham-SAL rats in a majority of the terminal structures, but lower rates in the dorsal raphe. A few structures in the OBX-CTP group have lower synthesis than in the Sham-SAL group (e.g., dorsal raphe, hippocampus, amygdala). The data suggest that receptors in some brain areas are likely still responsive to the elevated levels of the extracellular 5-HT produced by citalopram.ConclusionThere is no significant global or individual structure difference in the synthesis between the Sham-CTP and OBX-CTP groups. The similarity in the synthesis between the OBX-CTP, Sham-CTP and Sham-SAL groups is likely a result of changes in the sensitivity of the receptors through which 5-HT synthesis is controlled. Because of some of the differences in the synthesis between the Sham-CTP and Sham-SAL groups, the data suggest that receptors throughout the brain are not fully desensitized.

Therapeutic Time Window and Dose Dependence of Neuroprotective Effects of Sodium Orthovanadate following Transient Middle Cerebral Artery Occlusion in Rats

Vanadium is widely distributed in the environment and exhibits various biological and physiological effects in the human body. We previously documented the neuroprotective effect of sodium orthovanadate (SOV) against in rodents i.v. injected with 2 ml/kg 50 mM SOV just after the induction of middle cerebral artery occlusion (MCAO; 0 min post-MCAO). To evaluate its potential clinical use, we determined here therapeutic time window (0, 45, and 90 min post-MCAO) and the neuroprotective dose (2 ml/kg, 12.5, 25, 37.5, and 50 mM) of SOV in rats. A single injection of 50 mM SOV at 0 or 45 min post-MCAO produced similar neuroprotective effects, and even 50 mM delivered 90 min post-MCAO exerted significant neuroprotection. Although the maximal neuroprotective effect was obtained at 50 mM SOV, 25 mM injected once and 12.5 mM delivered at 0 and 45 min post-MCAO significantly reduced the infarct volume. We also documented that SOV treatment ameliorates ischemic neuronal cell injury via the activation of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK), inhibits serum glucose, and elicits the gradual recovery of regional cerebral blood flow (rCBF) after transient MCAO in rats. To elucidate the important factor(s) involved in the neuronal protection afforded by SOV, we measured Akt and ERK activity, physiological parameters, blood glucose levels, and rCBF following various SOV treatments. In conclusion, Akt activation was the most important factor in SOV-induced neuroprotection; ERK activation, the gradual recovery of rCBF, and decreased blood glucose were weak contributors.

Surgery and long-term outcome for ruptured anterior circulation aneurysms in patients in their ninth decade of life

BACKGROUND The present pilot study was undertaken to analyze the long-term results of surgery for ruptured anterior circulation aneurysms in patients in their 9th decade of life. METHODS Between 1992 and 1997, we treated 10 consecutive patients with ruptured anterior circulation aneurysms who were 80 years or older on admission and judged eligible for surgery based on stringent criteria. The outcomes at discharge and the latest outcomes (obtained at a median of 41.6 months) were assessed using the Glasgow Outcome Scale and the Barthel Score, respectively. RESULTS Upon discharge, six of the 10 patients showed good recovery, two patients were moderately disabled, and two patients who suffered symptomatic vasospasm were severely disabled. As for the latest outcomes, assessed using Barthel Score, four patients had the maximum score of 100, two a score of 90, one a score of 35, two a score of 10, and one patient died. Of four patients who were in poor condition, two experienced deterioration attributable to unrelated causes 18 and 32 months after the ictus. CONCLUSION Advanced age alone does not preclude successful surgery for ruptured anterior circulation aneurysms. Carefully selected patients over 80 years should also be considered for surgical treatment.

Activities of calcineurin and phosphatase 2A in the hippocampus after transient forebrain ischemia

We investigated the changes in the enzyme activity and immunoreactivity of calcineurin in the rat hippocampus after transient forebrain ischemia. Immediately after 20-min transient forebrain ischemia, calcineurin activity decreased to about 40% of the control in the CA1 region and to about 55% in other regions. Protein phosphatase 2A activity showed no remarkable changes. By 12 h after ischemia, calcineurin activity recovered, more in the CA1 region than in other regions. At 24 h it decreased again, but only in the CA1 region. Immunohistochemical- and immunoblot analyses showed no remarkable change in calcineurin in any region of the hippocampus within 12 h after ischemia. Thus, the activity of calcineurin is dissociated from its immunoreactivity and quantity. Several studies have suggested that unknown inhibitory factor(s) and/or reversible changes in calcineurin act to modify enzyme activity after ischemia. In contrast, phosphatase 2A activity underwent no obvious changes during the post-ischemia period we examined. This unique time course of calcineurin activity may contribute to the mechanism of ischemic neuronal injury.

Expression of neuron specific phosphatase, striatal enriched phosphatase (STEP) in reactive astrocytes after transient forebrain ischemia

We studied the distribution and change of striatal enriched phosphatase (STEP) in the gerbil hippocampus after transient forebrain ischemia. STEP was expressed in the perikarya and in neuronal processes; it was not detected in non‐neuronal cells of control animals. After 5‐min forebrain ischemia, STEP immunoreactivity (STEP‐IR) was preserved for 2 days; it disappeared 4 and more days after ischemia with completion of delayed neuronal death (DND) in the CA1 subfield. Furthermore, only in the CA1 after ischemia, STEP was expressed in reactive astrocytes for 4 to 28 days, showing different patterns of glial fibrillary acidic protein (GFAP)‐positive reactive astrocytes. After non‐or less‐than lethal ischemia, STEP expression in reactive astrocytes corresponded with the degree of neuronal degeneration. Immunoblot analysis of the CA1 subfield revealed the expression of three isoforms, STEP45, ‐56 and ‐61; their expression patterns changed with time after ischemia. These data suggest that neuronal STEP is preserved until cell degeneration after ischemia and that STEP is expressed in reactive astrocytes only after lethal ischemia, with different expression patterns for its isoforms. Of STEP45, ‐56 and ‐61, STEP61 was the most strongly expressed in the reactive astrocytes; both STEP45 and ‐61 were expressed in neurons and the expression of STEP56 was weak. STEP may play an important role not only in neurons but also in reactive astrocytes after ischemia, depending on neuronal degeneration. GLIA 29:316–329, 2000.

Correlation Between Magnetic Resonance Images and Draining Patterns in Dural Arteriovenous Fistulas with Leptomeningeal Venous Drainage

Summary¶ Objective. To compare abnormal intensity areas on intracranial magnetic resonance images (MRI) and the pattern of venous drainage in dural arteriovenous fistulas (DAVFs) with retrograde venous drainage. Methods. Thirteen patients with retrograde venous drainage of DAVFs were divided into two groups based on the venous drainage pattern determined by detailed angiographic and MRI study. In group 1 there was an accessory route draining into another sinus besides the main draining sinus. In group 2 no such accessory route was present. Results. In group 1 patients (n=8), MRI detected no unusual intensity areas; 5 patients in this group had episodes of bleeding. Angiographically, in this group retrograde venous drainage tended to occur via multiple varices. On the other hand, none of the 5 group 2 patients experienced a bleeding episode. Angiographically, there was a low incidence of varices. On T2-weighted images, these patients had a hyperintensity area. Following treatment, these areas of abnormality disappeared on T2-weighted MRI. Conclusion. Among 13 patients with DAVFs which drained retrogradely, those with a variceal accessory route (Group 1, n=8) had a higher incidence of haemorrhage. In patients without such an accessory route (Group 2, n=5) abnormal signal intensity on MRI was indicative of venous congestion. Continuous-mode angiography and MRI study were useful in the precise identification of DAVFs with a venous drainage route.

Multiple Cerebral Arteriovenous Malformations (AVMs) Associated with Spinal AVM

Summary The co-existence of multiple cerebral arteriovenous malformations (AVMs) and a spinal AVM is extremely rare. A 22-year-old man suddenly developed severe headache. Computed tomography (CT) scan showed intracerebral haemorrhage in the left occipital lobe. Cerebral angiography revealed eight AVMs; four were in the right frontal lobe and two each were in the right temporal and left occipital lobe, respectively. A huge high-flow spinal AVM was found incidentally. He had no other vascular lesions such as hereditary haemorrhagic telangiectasia. A left occipital craniotomy was performed and the ruptured left occipital AVMs were removed. Further therapeutic treatment was refused. To our knowledge, except for one autopsy case, this is the first reported patient with multiple cerebral AVMs with a spinal AVM. We discuss the characteristics of this case and review reported cases with cerebral and spinal AVMs.

Delayed Posttraumatic Middle Cerebral Artery Vasospasm Demonstrated by Magnetic Resonance Angiography: Case Report

OBJECTIVE AND IMPORTANCE Magnetic resonance (MR) angiographic diagnosis is a noninvasive method having high sensitivity and specificity in the detection of various cerebrovascular disorders. This is the first report of MR angiographic detection of delayed posttraumatic middle cerebral artery vasospasm, the occurrence of which has been rarely described. CLINICAL PRESENTATION A 42-year-old man sustained head trauma in a traffic accident, which caused a right subdural hematoma. Even though the hematoma was irrigated through one burr hole on Day 10, the patient subsequently developed left hemiparesis in association with dysarthria 4 days after surgery. MR angiography demonstrated decreased flow signal in the right M1 and M2 portions, suggestive of vasospasm. INTERVENTION The patient underwent intravascular volume expansion/ hemodilution therapy for 3 days. CONCLUSION After the therapy, the ischemic symptoms completely disappeared. Follow-up study confirmed resolution of the flow signal in the right middle cerebral artery. It is suggested that MR angiography is a useful noninvasive method in the evaluation of posttraumatic cerebrovascular disorders, which constitute important secondary insults in head trauma.

Rapidly enlarging chordoid meningioma with abundant mucin production.

This 77‐year‐old woman with a rapidly enlarging chordoid meningioma first noticed a growing, non‐pulsatile, non‐painful soft mass in the left temporal region after a head trauma 2 years earlier. Neuroimaging showed a homogeneously enhanced osteolytic mass lesion in the left temporal bone. Surgery revealed an extradural tumor without significant adhesions. Histopathologically it was a meningioma with features reminiscent of chordoma. Most of the tumor cells contained mucin‐rich chordoid elements. Immunohistochemically, the lesion was positive for vimentin and epithelial membranous antigen; it was negative for cytokeratin and S‐100 protein. Based on these findings a diagnosis of chordoid meningioma was made. We posit that the rapid enlargement of the tumor over a relatively short period was attributable to its high mucin‐producing activity.