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Objective Naratriptan has been reported to reduce the frequency of cluster headache. The purpose of this study was to determine whether naratriptan is effective as a prophylactic treatment for cluster headache in Japan. Methods We retrospectively reviewed all 43 patients with cluster headache who received preventive treatment with naratriptan from April 2009 to April 2015. The International Classification of Headache Disorders, 3rd Edition (beta version) (ICHD-3 beta) was used to diagnose cluster headache. This study was conducted at 3 centers (Department of Neurology, Saitama Medical University; Saitama Neuropsychiatric Institute; Saitama Medical University International Medical Center). Patients were recruited from these specialized headache outpatient centers. Naratriptan was taken before the patient went to bed. Results The study population included 30 men (69.8%) and 13 women (30.2%). Twenty-two cases received other preventive treatments (51.2%), while 21 cases only received naratriptan (48.8%). Among the 43 cases, 37 patients (86.0%) achieved an improvement of cluster headache on naratriptan. Conclusion Naratriptan has been suggested as a preventive medicine for cluster headache because of the longer the biological half-life in comparison to other triptans. The internal use of naratriptan 2 hours before attacks appears to achieve a good response in patients with cluster headache.

In this study, we examined alterations in the enzymatic antioxidant defenses associated with learning deficits induced by type 2 diabetes, and studied the effects of the peroxisome proliferator-activated receptor γ agonist pioglitazone on these learning deficits. Learning ability was assessed by visual discrimination tasks in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, as a model of spontaneous type 2 diabetes. Levels of the antioxidant enzymes glutathione peroxidase (GPx), Cu 2+ –Zn 2+ superoxide dismutase (CuZn-SOD) and manganese SOD were measured in the cortex, hippocampus and striatum. Half the rats received oral pioglitazone (20 mg/kg/day) from the early stage of diabetes (22 weeks old) to 27 weeks old. OLETF rats showed learning deficits compared with control, Long-Evans Tokushima Otsuka (LETO) rats. GPx levels in the cortex and hippocampus were increased in OLETF rats compared with LETO rats, with an inverse correlation between GPx in the hippocampus and learning score. CuZn-SOD levels were also increased in the hippocampus in OLETF rats. Pioglitazone reduced blood glucose and increased serum adiponectin levels, but had no effect on learning tasks or antioxidant enzymes, except for CuZn-SOD. These results suggest that an oxidative imbalance reflected by increased brain antioxidant enzymes plays an important role in the development of learning deficits in type 2 diabetes. Early pioglitazone administration partly ameliorated diabetic symptoms, but was unable to completely recover cerebral oxidative imbalance and functions. These results suggest that diabetes-induced brain impairment, which results in learning deficits, may have occurred before the appearance of the symptoms of overt diabetes.

The purpose of this study was to clarify the kinetics of nitric oxide (NO) induced by either endothelial NO synthase (eNOS) or neuronal NO synthase (nNOS) after transient global forebrain ischemia. We investigated NO production and ischemic changes to hippocampal CA1 neurons in eNOS knockout (-/-) mice and nNOS (-/-) mice during cerebral ischemia and reperfusion. NO production was continuously monitored by in vivo microdialysis. Global forebrain ischemia was produced by occlusion of both common carotid arteries for 10 minutes. Levels of nitrite (NO2-) and nitrate (NO3-), as NO metabolites, in dialysate were determined using the Griess reaction. Two hours after the start of reperfusion, animals were perfused with 4% paraformaldehyde. Hippocampal CA1 neurons were divided into three phases (severely ischemic, moderately ischemic, surviving), and the ratio of surviving neurons to degenerated neurons was calculated as the survival rate. The relative cerebral blood flow (rCBF) was significantly higher in nNOS (-/-) mice than in control mice after reperfusion. Levels of NO3- were significantly lower in eNOS (-/-) mice and nNOS (-/-) mice than in control mice during ischemia and reperfusion. NO3- levels were significantly lower in nNOS (-/-) mice than in eNOS (-/-) mice after the start of reperfusion. Survival rate tended to be higher in nNOS (-/-) mice than in control mice, but not significantly. These in vivo data suggest that NO production in the striatum after reperfusion is closely related to activities of both nNOS and eNOS, and is mainly related to nNOS following reperfusion. Theme: Disorders of the nervous system. Topic: Ischemia.

慢性透析患者の急性期脳梗塞について臨床的特徴を検討した. 対象は2003年5月から2006年8月までに, 当科で入院加療した慢性維持透析中 (血液透析29例, CAPD4例) の急性期脳梗塞患者33例 (男25例, 女8例) である. 発症時年齢は44～88歳, 平均68歳で, 発症までの透析期間は平均5.6年. 透析導入疾患は慢性糸球体腎炎が16例, 糖尿病性腎症が10例, その他7例. 臨床病型はアテローム血栓性脳梗塞13例, ラクナ梗塞9例および心原性脳塞栓11例で, 動脈硬化性病変と心臓内血栓の存在が示唆された. 入院時のNIHSSは平均9で, 高血圧は79%に, 心房細動は21%に認めた. 透析中ないし透析直後の発症が12%にみられ, 動脈硬化に加え透析に伴う血行力学的機序が関係していると考えられた. 平均在院日数は25日で, 退院時mRS4以上の重症患者が42%, 死亡例も15%含まれ予後不良例が多かった.

発症からエダラボン投与開始までの時間が心原性脳塞栓症の機能予後におよぼす影響を検討した.対象は2001年8月からの4年間に当院に入院し,エダラボン60mg/日を7～14日間投与された中大脳動脈起始部閉塞の連続51症例.発症から投与開始までの時間が3時間以内の症例をA群(16例),3～6時間をB群(16例),6～24時間をC群(19例)とした. Japan Stroke Scale (JSS), NIH Stroke Scale (NIHSS) および modified Rankin Scale (mRS) を用い,入院時と28日後に評価しA～C群で比較した. JSS スコアの改善度は投与時期と負の相関(r=－0.7602,p

It has been suggested that antihypertensive drug therapy is attributable to the lower blood pressure variability, we investigated the effects of 4 classes of antihypertensives on the blood pressure variability; in addition, we also compared the effects among 4 calcium channel blockers.We measured the 24-hour blood pressure variability in 309 patients with a history of cerebrovascular disease treated with angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, β blocker, or calcium channel blocker.The daytime blood pressure variability treated with β blockers (14.3 ± 3.1) was higher than that treated with an angiotensin receptor blockers (11.5 ± 3.1) or calcium channel blockers (12.6 ± 3.4) in patients with cerebrovascular disease (P.05). In the analysis of the patient distribution of blood pressure variability, patients receiving β blockers occurred more frequently in the higher blood pressure variability (P = .0023). Treatment with angiotensin receptor blockers and cilnidipine, which blocks N-type calcium channels, was shown to be more frequently associated with the lower blood pressure variability (P = .0202 and .0467). The mean blood pressure of patients grouped by distribution of blood pressure variability was found to be independent to blood pressure variability, for any of the antihypertensive drugs or calcium channel blockers examined.From the results, it is suggested that angiotensin receptor blocker and calcium channel blockers rather than β blockers may be more favorable for blood pressure management in patients with cerebrovascular disease. Among the calcium channel blockers, cilnidipine may be more favorable than other calcium channel blockers.

Background/Aims: Pioglitazone (PGZ), one of the thiazolidinediones, has been known to show renoprotective effects. In this study, we focused on the effect of PGZ on glomerular hyperfiltration (GHF), resultant glomerular injury and altered macula densa signaling as a cause of sustained GHF through modified tubuloglomerular feedback in rats with diabetic nephropathy. Methods: Kidneys from 24-week-old male OLETF rats and LET rats, nondiabetic controls, were used for the experiment. PGZ was administered (10 mg/kg/day, p.o.) for 2 weeks from 22 to 24 weeks of age in some of the OLETF rats (OLETF+PGZ). Results: Parameters relating GHF, kidney weight, creatinine clearance, urine albumin/creatinine ratio and glomerular surface were all increased in OLETF rats and partially restored in OLETF+PGZ rats. Expressions of desmin and TGF-β were also increased in OLETF rats and restored in OLETF+PGZ rats. The changes in TGF-β expression were confirmed to be independent of podocyte number. Finally, the immunoreactivity of neuronal nitric oxide synthase (nNOS) and cyclooxygenase 2 (COX-2) in the macula densa was assessed for the evaluation of macula densa signaling. Altered intensities of nNOS and COX-2 in OLETF rats were restored in OLETF+PGZ rats, which agreed with the gene expression analysis (nNOS: 100.2 ± 2.9% in LET, 64.2 ± 2.7% in OLETF, 87.4 ± 12.1% in OLETF+PGZ; COX-2: 100.8 ± 7.4% in LET, 249.2 ± 19.4% in OLETF, 179.9 ± 13.5% in OLETF+PGZ; n = 5) and the semiquantitative analysis of nNOS/COX-2-positive cells. Conclusion: PGZ effectively attenuated the GHF and hyperfiltration-associated glomerular injury in diabetic nephropathy. The restoration of altered macula densa signaling might be involved in the renoprotective effect of PGZ.

The possible effect of antihypertensive therapy on Alzheimer's disease (AD) has been studied, and angiotensin II receptor blockers (ARBs) have been suggested to exert an effect on cognitive decline. The purpose of this study is to clarify the functional effects of telmisartan, a long-acting ARB, on AD brain using prospective longitudinal (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) studies. For this purpose, brain glucose metabolism of four hypertensive patients with AD was examined with FDG-PET before and after administration of telmisartan. Studied subjects underwent three FDG-PET studies at intervals of 12 weeks. Antihypertensive treatment except for telmisartan was started after the first FDG-PET and continued for 24 weeks. Then 40-80 mg of telmisartan was added after the second FDG-PET and continued for 12 weeks.Glucose metabolism was significantly decreased during the first 12 weeks without telmisartan use at an area (-10, 21, -22, x, y, z; Z = 3.56) caudal to the left rectal gyrus and the olfactory sulcus corresponding to the left olfactory tract. In contrast, the introduction of telmisartan during the following 12 weeks preserved glucose metabolism at areas (5, 19, -20, x, y, z; Z = 3.09; 6, 19, -22, x, y, z; Z = 2.88) caudal to the bilateral rectal gyri and olfactory sulci corresponding to the bilateral olfactory tracts. No areas showed decreased glucose metabolism after the introduction of telmisartan. In AD, amyloid-β deposition is observed in the anterior olfactory nucleus (AON) of the olfactory tract. Glucose metabolism in AON may be progressively decreased and preserved by telmisartan.

A 77-year-old right-handed woman was admitted to our hospital with memory disturbance. Neurological examination was normal except for amnesia. Neuropsychological tests showed severe impairments in verbal and visual memories. Brain MRI revealed a fresh lacunar infarction in the genu of the right internal capsule. Decreased perfusion in the right thalamus and frontal lobe on (99m)Tc-ECD SPECT was attributable to disconnection of the thalamo-cortical tract by infarction. We consider that the patient's amnesia in this case was induced by infarction of the capsular genu, which includes some fibers from the anterior and inferior thalamic peduncles. Our findings demonstrated that lacunar infarction in the genu of the right internal capsule caused severe and persistent amnesia.

Background and Purpose— Activators of peroxisome proliferator-activated receptor-γ (PPARγ), a member of the PPAR family, increase levels of CuZn-superoxide dismutase (SOD) in cultured endothelium, suggesting a mechanism by which it may exert its protective effect within the brain. These properties raise the question of whether a PPARγ agonist may be neuroprotective in models of ischemia without reperfusion, in which oxidative injury is less prevalent. Methods— In 2 groups of rats, 90 minutes of middle cerebral artery (MCA) occlusion was followed by 1 day of reperfusion, with 1 group receiving pioglitazone (a PPARγ agonist) starting 72 hours before MCA occlusion (MCAO) and continuing through the day of occlusion, whereas the other group received vehicle only. In 2 comparable groups, the MCA was occluded permanently. One day after occlusion, the animals were tested neurologically and infarct volumes were calculated. In a separate group, rats were treated with pioglitazone or vehicle for 4 days. Tissue was obtained from the cortex and the striatum 2 hours into reperfusion after 90 minutes of MCAO, and the tissue was examined for CuZn-SOD by Western blot. Results— Results show a significant reduction in infarct size in the treated rats, with transient MCAO but not permanent MCAO. There was also an improvement in neurological score in the treated animals after transient MCAO. The level of CuZn-SOD was increased in the cortex in treated animals. Conclusions— These data, which show that a PPARγ agonist reduces infarct size in transient but not permanent MCAO, suggest that the role of PPARγ is specific to events occurring during reperfusion. Our data point to CuZn-SOD as the mediator of this neuroprotection.

The synthesis and evaluation of a new serotonin transporter (SERT) imaging agent, N,N-dimethyl-2-(2-amino-5-[18F]fluorophenylthio)benzylamine (5-[18F]-ADAM) is reported. Nucleophilic substitution of N,N-dimethyl-2-(2-nitro-5-bromophenylthio)benzylamine with K[18F]/Kryptofix 2.2.2 in DMSO at 125 degrees C followed by reduction with NaBH4-Cu(OAc)2 in EtOH at 78 degrees C and purification with HPLC produces the desired compound with an unoptimized yield of approximately 5-10% in a synthesis time of 150 min from EOB. The biodistribution of 5-[18F]-ADAM in rats showed a high initial uptake and relatively rapid clearance in the brain (3.221+/-0.762, 0.440+/-0.059, 0.160+/-0.035 and 0.028+/-0.003% injected dose/organ at 2, 30, 60 and 120 min after I.V. injection, respectively) with the specific binding peaking at 1 h postinjection (hypothalamus/cerebellum and hippocampus/cerebellum were 2.97 and 3.59, respectively). The initial uptake in blood, lung, kidney and heart were also high, but it cleared rapidly. The radioactivity in the femur increased with time for 5-[18F]-ADAM indicating that in vivo defluorination may occur. Metabolism studies in rats showed that 5-[18F]-ADAM was not metabolized in rat brain, but was metabolized rapidly in the blood. Blocking experiments showed that there were significant decreases in the uptake of 5-[18F]-ADAM in the brain regions (hypothalamus, hippocampus and striatum) where SERT concentrations are high when rats were pretreated with (+)McN 5652 (2 mg/kg, 5 min prior to IV injection of 5-[18F]-ADAM). These results suggest that 5-[18F]-ADAM may be a potential new serotonin transporter PET imaging agent. However, due to its rapid wash-out from the brain, defluorination in vivo and lower uptake in the brain than 4-[18F]-ADAM, 5-[18F]-ADAM may not be as useful as 4-[18F]-ADAM as a SERT imaging agent.

Adrenomedullin(AM)is a vasodilatory hormone secreted mainly by the vascular wall, and its expression is remarkably enhanced after stroke. Several studies have shown that AM inhibits ischemic injury in the brain. The present study investigates the effects of AM on nitric oxide(NO)production during forebrain ischemia and reperfusion. Halothane anesthesia was administered to AM-knockout(AM )and control(C57 BL 6J)mice and then NO production was continuously monitored in the left striatum by in vivo microdialysis. A laser Doppler probe was fixed on the right scalp to measure relative cerebral blood flow(rCBF)continuously. Blood pressure(BP), blood gases and body temperature were monitored and physiologically maintained. After equilibrium for 2 hours, fractions were collected every 10 minutes. Forebrain cerebral ischemia was produced by occluding both common carotid arteries. After 10 minutes, the loops around both common carotid arteries were released. Levels of nitrite and nitrate in dialysates were determined using the Griess reaction. At 6 hours after forebrain cerebral ischemia, the degrees of the ischemic damage in hippocampal CA1 neurons were investigated. Knockout of the AM gene did not affect BP and rCBF. Levels of total NO(nitrite+nitrate) were lower in AM-knockout mice at baseline, during ischemia and after reperfusion. The survival cell rate of hippocampal CA1 neurons in AM-knockout mice was lower than that of control mice. These data suggest that AM exert protective effects by activating NO synthase in the brain during ischemia and reperfusion. (Cerebral Blood Flow and Metabolism 21:1―6,2010)