Tomokazu Shimazu

A Peroxisome Proliferator-Activated Receptor-γ Agonist Reduces Infarct Size in Transient but not in Permanent Ischemia

Background and Purpose— Activators of peroxisome proliferator-activated receptor-&ggr; (PPAR&ggr;), 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 PPAR&ggr; 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 PPAR&ggr; 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 PPAR&ggr; agonist reduces infarct size in transient but not permanent MCAO, suggest that the role of PPAR&ggr; is specific to events occurring during reperfusion. Our data point to CuZn-SOD as the mediator of this neuroprotection.

Hyperphosphorylated tau deposition parallels prion protein burden in a case of Gerstmann-Sträussler-Scheinker syndrome P102L mutation complicated with dementia

Abstract. Hyperphosphorylated tau (p-tau) deposition has been documented in a limited population of patients with Gerstmann-Sträussler-Scheinker syndrome (GSS) with particular point mutations of the prion protein (PrP) gene. Although its pathogenesis is only poorly understood, p-tau in GSS is known to be identical to that in Alzheimers disease (AD). We conducted immunohistochemical and quantitative image studies on the brain from a 44-year-old man with a 7-year history of dementia, diagnosed as having GSS with a point mutation of the PrP gene at codon 102 (GSS102), the commonest mutation in GSS. Severe spongiform degeneration and numerous PrP plaques were disclosed in the cerebral cortices and hippocampus, consistent with the diagnosis. However, rarely described in GSS102, prominent p-tau deposits as pretangles, neurofibrillary tangles and degenerating neurites were demonstrated adjacent to or around PrP plaques. β-Amyloid protein (Aβ) plaques were generally sparse and appeared invariably to be of a diffuse type. Double-labeling immunohistochemistry yielded co-localization of p-tau with PrP but not with Aβ. Most PrP plaques did not contain Aβ. These results excluded a diagnosis of concomitant AD. Quantitative analysis on a fractional area density of immunoreactive pixels demonstrated that burdens of PrP and p-tau but not Aβ were significantly correlated. These results suggest that p-tau deposition in this GSS102 is secondarily induced by PrP but not by Aβ (secondary tauopathy). Our study also suggests that p-tau deposition might be a more common phenomenon in long-standing GSS.

Nitric Oxide Production during Cerebral Ischemia and Reperfusion in eNOS- and nNOS-Knockout Mice

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 (NO(2)(-)) and nitrate (NO(3)(-)), 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 NO(3)(-) were significantly lower in eNOS (-/-) mice and nNOS (-/-) mice than in control mice during ischemia and reperfusion. NO(3)(-) 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.

Cerebral antioxidant enzyme increase associated with learning deficit in type 2 diabetes rats

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 (20mg/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.

Renoprotective Effect of Pioglitazone by the Prevention of Glomerular Hyperfiltration through the Possible Restoration of Altered Macula Densa Signaling in Rats with Type 2 Diabetic Nephropathy

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.

Pilot data on telmisartan short-term effects on glucose metabolism in the olfactory tract in Alzheimer's disease

The possible effect of antihypertensive therapy on Alzheimers 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 18F‐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.

Naratriptan in the Prophylactic Treatment of Cluster Headache

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.

Evaluation of the Differences in the Effects of Antihypertensive Drugs on Blood Pressure Variability by 24-Hour Ambulatory Blood Pressure Monitoring in Chronic Cerebrovascular Disease

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Contents Vol. 122, 2012

Chronic Kidney Disease and Hypertension Vlado Perkovic , Sydney Adeera Levin, Vancouver, B.C. Ron Gansevoort, Groningen Acute Kidney Injury Ravi Mehta, San Diego, Calif. Nitin Kolhe, Derby Dialysis John Daugirdas, Chicago, Ill. Colin Hutchison, Hawkes Bay Casper Fraansen, Groningen Patient Subjective Experience, Healthcare Delivery and Innovation in Practice Richard Fluck, Derby Edwina Brown, London Crossover States with Non-Renal Organ Systems Chris Chan, Toronto, Ont. Tobias Breidthardt, Basel Nick Selby, Derby Transplantation Anil Chandraker, Boston, Mass. Alan Salama, London Editor-in-Chief

Learning deficit of OLETF in visual discrimination task

The visual acuity of rats is poorer than their auditory acuity. This study examined whether visual or auditory memory is superior in rats. Either a light stimulus (L) or a tone stimulus (T) was presented for 3 s as a discriminative stimulus (SD) in an operant chamber. Then, there was a delay of 0.25, 3, 6, or 9 s. After the delay, the rat had to press one of two levers depending on the SD: when L was presented, pressing the right lever gave a food pellet reward; when T was presented, pressing the left lever gave a similar reward. In order to perform this task correctly, the rats had to remember the SD during the delay interval. Therefore, performance of this task reflects their short-term memory (STM). When L was presented as the SD, the percent of correct responses declined as the delay interval lengthened. When T was presented as the SD, the decline in the percent of correct responses was slower than in the trials in which L was presented. These results imply that in rats STM is better for auditory information than for visual information.