Effects of haloperidol and its pyridinium metabolite on plasma membrane permeability and fluidity in the rat brain

The use of antipsychotic drugs is limited by their tendency to produce extrapyramidal movement disorders such as tardive dyskinesia and parkinsonism. In previous reports it was speculated that extrapyramidal side effects associated with the butyrophenone neuroleptic agent haloperidol (HP) could be caused in part by the neurotoxic effect of its pyridinium metabolite (HPP(+)). Although both HPP(+) and HP have been shown to induce neurotoxic effects such as loss of cell membrane integrity, no information exists about the difference in the neurotoxic potency, especially in the potency to induce plasma membrane damage, between these two agents. In the present study, we compared the potency of the interaction of HPP(+) and HP with the plasma membrane integrity in the rat brain. Membrane permeabilization (assessed as [(18)F]2-fluoro-2-deoxy-d-glucose-6-phosphate release from brain slices) and fluidization (assessed as the reduction in the plasma membrane anisotropy of 1,6-diphenyl 1,3,5-hexatriene) were induced by HPP(+) loading (at >or=100 microM and >or=10 microM, respectively), while comparable changes were induced only at a higher concentration of HP (=1 mM). These results suggest that HPP(+) has a higher potency to induce plasma membrane damage than HP, and these actions of HPP(+) may partly underlie the pathogenesis of HP-induced extrapyramidal side effects.     

Relation between the level of care needed and frailty for labial functions

AIM: The purpose of this study was to examine whether the improvement of oral functions could prevent increase in the level of care needed in the elderly by analyzing the relationship between the level of care needed and labial functions. METHODS: The subjects were 114 elderly people who were healthy or needing care (44 men, 70 women; average age 81.3 +/- 6.3 years), all of whom maintained posterior occlusal support with their natural dentition and had no defect in front teeth. They were divided into four groups; Group 1: healthy elderly, Group 2: elderly requiring assistance or Care Category 1, Group 3: elderly requiring Care Categories 2 and 3, Group 4: elderly requiring Care Categories 4 and 5, according to the classification of certification of eligibility for long-term care by the Japanese Ministry of Health, Labor and Welfare. Water-repellent pressure sensors (PS-2KA, Kyowa Electric Co, Japan) were embedded in an acrylic plate. The device was used to measure the labial-closing pressure during 1-gram yogurt ingestion, the maximum labial pressure with effort and the reserve capacity of pressure. Drooling of food as feeding/swallowing dysfunction of the subjects was surveyed. RESULTS: 1) The mean value of labial pressure with effort was 296.4 +/- 153.9 Pa, and that of the reserve capacity of labial pressure was 209.6 +/- 152.3 Pa. They showed significant declines in accordance with the aggravation level of needing care (p < 0.01). 2) The labial pressure with effort and the reserve capacity of pressure in subjects who showed drooling of food symptom were significantly lower compared to those who showed no drooling of food symptom (p < 0.05). CONCLUSION: Labial functions declined in accordance with the increased level of care needed, and a relationship between drooling of food and labial-closing pressure was recognized. It was suggested that the improvement of labial functions might prevent increased need of care.     

Electrochemical Behaviors of Quercetin and Kaempferol in Neutral Buffer Solution

Ｑｕｅｒｃｅｔｉｎａｎｄｋａｅｍｐｆｅｒｏｌ,ｆｌａｖｏｎｏｌｓ,ａｒｅｐｒｅｄｏｍｉｎａｎｔｉｎｖｅｇｅｔａｂｌｅｓａｎｄｆｒｕｉｔｓ ,ａｎｄａｒｅｃｏｍ ｐｏｎｅｎｔｓｉｎｔｈｅｈｕｍａｎｄｉｅｔ .[1] Ｔｈｅｙａｒｅｒｅｐｏｒｔｅｄｔｏｂｅｐｏｔｅｎｔａｎｔｉｏｘｉｄａｎｔｓ .[2 ,3] Ｏｎｅｍｅｃｈａｎｉｓｍｏｆｔｈｅｉｒａｎｔｉｏｘｉｄａｎｔａｃｔｉｖｉｔｙｉｓｒｅｇａｒｄｅｄａｓｓｃａｖｅｎｇｉｎｇｆｒｅｅｒａｄｉｃａｌｓｂｙｄｏｎａｔｉｏｎｏｆｅｌｅｃｔｒｏｎｓ.[4]Ｓｏｋｎｏｗｌｅｄｇｅａｂｏｕｔｔｈｅｅｌｅｃｔｒｏｃｈｅｍｉｃａｌｐｒｏｐｅｒｔｉｅｓｏｆｔｈｅｓｅｔｗｏｆｌａｖｏｎｏｌｓｃａｎｈｅｌｐｕｓｔｏｕｎｄｅｒｓｔａｎｄｔｈｅｉｒａｎｔｉｏｘｉｄａｎｔａｃｔｉｖｉｔｙ .Ｗｈｅｎｓｔｕｄｙｉｎｇｅｌｅｃｔｒｏｃｈｅｍｉｃａｌｂｅｈａｖｉｏｒｏｆｆｌａｖｏｎｏｉｄｓｉｎｔｈｅｎｅｕｔｒａｌｂｕｆｆｅｒｓｏｌｕｔｉｏｎ ,[5 ] ｗｅｆｏｕｎｄｔｈａｔｑｕｅｒｃｅｔｉｎａｎｄｋａｅｍｐｆｅｒｏｌｇａｖｅａｒｅｖｅｒｓｉｂｌｅａｎｄａｎｉｒｒｅ ｖｅｒｓｉｂｌｅｃｙｃｌｉｃ...     

Determination of hesperidin in Pericarpium Citri Reticulatae by semi-micro HPLC with electrochemical detection

Determination of hesperidin contents in Pericarpium Citri Reticulatae was performed by a simple extraction with methanol and semi-micro high-performance liquid chromatography with electrochemical detection (muHPLC-ECD). Chromatography was performed using a microbore octadecylsilica (ODS) column, methanol-water-phosphoric acid (40:60:0.5, v/v/v), as a mobile phase and applied potential at +0.9 V versus Ag/AgCl. Peak heights were found linearly related to the concentrations of hesperidin injected 9.16 ng/ml to 3.06 microg/ml (r>0.999). The detection limit (S/N=3) was 3.06 ng/ml (15.3 pg). Hesperidin of 305 ng/ml was detected with a relative standard deviation (R.S.D.) of 0.79% (n=5). Hesperidin in Pericarpium Citri Reticulatae was extracted with methanol, diluted with the mobile phase, and injected into the muHPLC-ECD for determination. The hesperidin content of Pericarpium Citri Reticulatae from four different districts in China were determined with R.S.D. of 3.59%, 2.29%, 2.36%, and 2.32% (n=5), respectively. Recoveries of hesperidin from the four Pericarpium Citri Reticulatae sources were 100.3%, 99.83%, 100.7%, and 100.6%, respectively. This method is useful for the determination of hesperidin in Pericarpium Citri Reticulatae, and especially so for instances when samples are sparse.     

Graft-versus-Tax response in adult T-cell leukemia patients after hematopoietic stem cell transplantation

Adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type I (HTLV-I) is characterized by poor prognosis after chemotherapy. Recent clinical trials have indicated, however, that allogeneic but not autologous hematopoietic stem cell transplantation (HSCT) for ATL can yield better clinical outcomes. In the present study, we investigated cellular immune responses of ATL patients who obtained complete remission after nonmyeloablative allogeneic peripheral blood HSCT from HLA-identical sibling donors. In the culture of peripheral blood mononuclear cells (PBMCs) from a post-HSCT but not pre-HSCT ATL patient, CD8(+) CTLs proliferated vigorously in response to stimulation with autologous HTLV-I-infected T cells that had been established before HSCT in vitro. These CTLs contained a large number of monospecific CTL population directed to a HLA-A2-restricted HTLV-I Tax 11-19 epitope. The frequency of Tax 11-19-specific CD8+ CTLs in this patient markedly increased also in vivo after HSCT, as determined by staining with HLA-A2/Tax 11-19 tetramers. Similar clonal expansion of HTLV-I Tax-specific CTLs exclusively directed to a HLA-A24-restricted Tax 301-309 epitope was observed in the PBMCs from another ATL patient after HSCT from a HTLV-I-negative donor. Among four post-HSCT ATL patients tested, HTLV-I-specific CTLs were induced in the PBMC culture from three patients but not from the remaining one who had later recurrence of ATL. These observations suggested that reconstituted immunity against antigen presentation in ATL patients after HSCT resulted in strong and selective graft-versus-HTLV-I response, which might contribute to graft-versus-leukemia effects.     

Sequential changes of brain CT and MRI after febrile status epilepticus in a 6-year-old girl

Brain CT or MRI occasionally shows transient or permanent changes in the brain after status epilepticus (SE). The mechanism for these changes has not been well elucidated. We performed repeated imaging studies on a patient with febrile SE characterized by right hemiconvulsion. CT showed transient mild edema on both hemispheres immediately after the cessation of SE. The edema improved the next day. But aphasia and right hemiparesis were observed. On day 17, CT revealed edema on left hemisphere and MRI showed a high signal intensity in cortex and subcortical white matter of the left hemisphere on T2-weighted images. Although right hemiparesis and aphasia were improved, severe atrophy of the left hemisphere was noted on CT and MRI. The results suggest that brain edema observed in several days after SE but not edema observed immediately after the cessation of SE is more pathological for the permanent brain damage. Possible mechanisms of the initial brain edema and the second edema preceded severe atrophy in left hemisphere were discussed.     

Protective effect of fluvastatin,an HMG-CoA reductase inhibitor,on the formation of 8-oxo-2'-deoxyguanosine in the nuclear DNA of hamster pancreas after a single administration of N-nitrosobis(2-oxopropyl)amine

We examined whether fluvastatin (FV), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has antioxidant activity against oxidative DNA damage to hamster pancreas induced by a chemical carcinogen, N-nitrosobis(2-oxopropyl)amine (BOP). Female Syrian golden hamsters were treated with FV by gastric intubation 30 min before BOP administration. Control animals were intubated with saline. Animals were injected subcutaneously with BOP (20 mg/kg body weight) or saline, and sacrificed 1 and 4 h later. The contents of 8-oxo-2'-deoxyguanosine (8-oxodG) in the nuclear DNA and thiobarbituric acid-reacting substances (TBARS) were measured in the pancreas and liver of hamsters. Treatment with more than 0.22 mg/kg body weight FV significantly inhibited the increase in 8-oxodG content induced by BOP treatment. The TBARS contents in pancreas changed similarly by intubation of FV. In the liver, the contents of 8-oxodG and TBARS were not affected by a single administration of BOP. The protective effect of FV was stronger than those of pravastatin and other antioxidants such as Trolox, ascorbic acid and green tea catechin. These results suggest that FV inhibits oxidative damage to DNA and lipids caused by reactive oxygen species formed through the metabolism of chemical carcinogens.     

Changes in autonomic activity and baroreflex sensitivity with the hypertension process and age in rats

1. Autonomic activity and baroreflex sensitivity (BRS) were compared in age-matched conscious groups of Wistar Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP). 2. Male WKY rats, SHR and SHRSP aged 4-30 weeks were used. Autonomic activity and BRS were estimated by power spectral and cross-spectral analysis of systolic blood pressure (SBP) and SBP-SBP (SS) interval fluctuations, respectively. 3. The time-course of heart rate (HR), SBP, the amplitude of the low-frequency component of SBP fluctuation (SBP-LF; prazosin-sensitive index) and the amplitude of the high-frequency component of the SS interval fluctuation (SS-HF; atropine-sensitive index) consisted of two periods. In the first period (up to 10 or 15 weeks of age), BP, SBP-LF and SS-HF increased with age. The order of SBP-LF was SHRSP > SHR > WKY rats throughout this period. During the second period, BP was sustained at certain levels in all strains, but changes in SBP-LF and SS-HF with age were different among strains. In particular, in SHRSP, SBP-LF markedly decreased with age after 10 weeks. Baroreflex sensitivity in WKY rats increased gradually with age, whereas the BRS in SHR and SHRSP decreased before 6 weeks of age and remained lower than that in WKY rats. 4. In conclusion, the present study shows that both prazosin-sensitive and atropine-sensitive indices are associated with the elevation of BP in all strains studied. However, hypertension after 15 weeks of age in SHRSP is sustained despite a paradoxical reduction in sympathetic activity with an abnormal control of BRS. Therefore, the contribution of autonomic activity to hypertension may be discussed separately as a developmental period and a sustained period.     

Paradigm shift from classic anatomic theories to contemporary cell biological views of CAKUT

Ectopic budding of the ureter from the Wolffian duct is the first ontogenic misstep that leads to many-if not all-congenital anomalies of the kidney and urinary tract (CAKUT). The ectopia results in hypoplastic kidney, ectopia of ureterovesical orifice, urinary outflow obstruction and/or reflux. Studies in several mutant mouse models have verified that ectopic ureteric budding indeed precedes formation of CAKUT. Often, the genes involved in navigating ureteric budding to the correct site also regulate later ontogenic events of the kidney and urinary tract. The wide spectrum of CAKUT, for example, multicystic dysplastic kidney, megaureter and atretic ureter, portray the additional important functions of these same genes that are activated at multiple sites and stages during the normal morphogenesis of the kidney and urinary tract