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AIM: Ex vivo experiments showed that the water extract of Puerariae lobatae Radix (named Gegen in Chinese) induced detrusor relaxation. The aim of this study was to prove the in vivo efficacy of Gegen on improving detrusor overactivity and its possible synergism with darifenacin (a first-line muscarinic receptor-3 inhibitor) in spontaneously hypertensive rats (SHR), a rat model exhibiting symptoms of detrusor overactivity. METHOD: After daily oral administration of Gegen 30 (Gegen, 30mg/kg); Gegen 300 (Gegen, 300mg/kg); Low_Dar (darifenacin, 3mg/kg); High_Dar (darifenacin, 30mg/kg) Low_Dar+Gegen 30 or High_Dar+Gegen 30 for 3 weeks, bladder detrusor strips of the rats were isolated and assessed with different stimulators for the measurement of tonic and phasic contractile activities (including phasic amplitude and frequency). Modes of stimulation included the use of carbachol, isoprenaline and electrical field stimulation (EFS). RESULTS: All drug treatments significantly reduced carbachol-stimulated tonic contractile activities, but did not change the phasic amplitude. Meanwhile, the treatments with Gegen 300; Low_Dar; Low_Dar+Gegen 30; and High_Dar+Gegen 30 decreased carbachol-stimulated phasic frequency. Gegen 300 and Low_Dar+Gegen 30 showed stronger potency on lowering EFS-induced responses. Under isoprenaline-induced relaxation, only Gegen 300 significantly enhanced this relaxation by decreasing tonic contraction; Gegen 300; Low_Dar; Low_Dar+Gegen 30; and High_Dar+Gegen 30 increased the reduction of phasic frequency, but all treatment did not alter their phasic amplitude. Combination Index (CI) showed that the combination with Low_Dar and Gegen 30 had very strong synergism (CI <0.1) on inhibiting EFS-induced contractile response. CONCLUSION: Gegen improved detrusor overactivity through neurogenic and anti-muscarinic mechanisms. Gegen and darifenacin together attained synergism for detrusor overactivity treatment via the neurogenic pathway.

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PURPOSE: To understand bladder contractility changes induced by chronic ketamine treatment, noting the prevalence of its abuse worldwide. METHODS: A mouse model of chronic ketamine treatment was used and detrusor strip contractility was measured. Rising and falling phases of contractile responses as well as maximal, average sustained and phasic contractions were measured. RESULTS: While maximal contractility of ketamine-treated strips was identical to the saline controls, the former displayed slower contraction rates under K(+)-Krebs, carbachol and electrical stimulation. The decay phase of electrically stimulated responses was also slower at most stimulation frequencies in the ketamine-treated strips. Greater sensitivity to varying the strengths of stimuli was observed in the ketamine-treated strips. CONCLUSIONS: Altered contractility characteristics of the bladder after chronic ketamine treatment were revealed, which could potentially be useful in the development of improved treatment regimens.

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PURPOSE: The urinary bladder expresses Ca(2+)-activated Cl(-) channels (CACC), but its physiological role in governing contractility remains to be defined. The CACC modulator niflumic acid (NFA) is widely used despite the variable results arisen from different drug concentrations used. This study was designed to examine the effects of NFA at low concentrations on detrusor strip contractility. METHODS: Rat detrusor strips with mucosa-intact (+MU) and mucosa-denuded (-MU) were prepared in transverse (Tr) and longitudinal (Lg) with respect to the bladder orientation. Isometric force measurements were made at baseline (for spontaneous phasic contractile activity) and during drug stimulation (by carbachol, CCh) with and without NFA. RESULTS: NFA (1 and 10 µmol/L) pretreatment enhanced CCh-induced contractions more in +MU than -MU strips with no selectivity on contractile direction. For spontaneous phasic contractions, NFA-treated strips in the Tr direction showed increased phasic amplitude, while phasic frequency was unchanged. CONCLUSIONS: The findings suggest low concentrations of NFA having a potentiating effect on detrusor contractions that was sensitive to the MU and contractile direction.

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NMDA receptor (NMDA-R) is an important molecular entity governing a wide range of functions in the central nervous system. For example, the NMDA-R is involved in memory and cognition, and impairment of both (as in Alzheimer's Disease) is attributed to NMDA-mediated neurotoxicity. With greater understanding of the NMDA-R structure, antagonists with varying degrees of binding-site and subtype selectivity have been developed and put into clinical use. Discovery of target-specific Chinese herbs have also been made in parallel. This article provides an overview of the known active sites on the NMDA-R, followed by a discussion of the relevant herbs and their constituents. Experimental evidence supporting the inhibitory role of the herbal compounds on the NMDA-R is highlighted. For some of the compounds, potential research directions are also proposed to further elucidate the underlying mechanisms of the herbs. It is envisaged that future investigations based on the present data will allow more clinically relevant herbs to be identified.

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Ketamine is an anesthetic and a popular abusive drug. As an anesthetic, effects of ketamine on glutamate and GABA transmission have been well documented but little is known about its long-term effects on the dopamine system. In the present study, the effects of ketamine on dopamine were studied in vitro and in vivo. In pheochromocytoma (PC 12) cells and NGF differentiated-PC 12 cells, ketamine decreased the cell viability while increasing dopamine (DA) concentrations in a dose-related manner. However, ketamine did not affect the expression of genes involved in DA synthesis. In the long-term (3 months) ketamine treated mice, significant increases of DA contents were found in the midbrain. Increased DA concentrations were further supported by up-regulation of tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis. Activation of midbrain dopaminergic neurons could be related to ketamine modulated cortical-subcortical glutamate connections. Using western blotting, significant increases in BDNF protein levels were found in the midbrain, suggesting that perhaps BDNF pathways in the cortical-subcortical connections might contribute to the long-term ketamine induced TH upregulation. These data suggest that long-term ketamine abuse caused a delayed and persistent upregulation of subcortical DA systems, which may contribute to the altered mental status in ketamine abusers.

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BACKGROUND: Stroke caused by brain ischemia is the third leading cause of adult disability. Active prevention and early treatment of stroke targeting the causes and risk factors may decrease its incidence, mortality and subsequent disability. Pien Tze Huang (PZH), a Chinese medicine formula, was found to have anti-edema, anti-inflammatory and anti-thrombotic effects that can prevent brain damage. This study aims to investigate the potential mechanisms of the preventive effects of Pien Tze Huang on brain damage caused by chronic ischemia and hypertensive stroke in rats. METHODS: The effects of Pien Tze Huang on brain protein expression in spontaneously hypertensive rat (SHR) and stroke prone SHR (SHRsp) were studied with 2-D gel electrophoresis and mass spectrometric analysis with a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF)/TOF tandem mass spectrometer and on brain cell death with enzyme link immunosorbent assay (ELISA) and immunostaining. RESULTS: Pien Tze Huang decreased cell death in hippocampus and cerebellum caused by chronic ischemia and hypertensive stroke. Immunostaining of caspase-3 results indicated that Pien Tze Huang prevents brain cells from apoptosis caused by ischemia. Brain protein expression results suggested that Pien Tze Huang downregulated QCR2 in the electron transfer chain of mitochondria preventing reactive oxygen species (ROS) damage and possibly subsequent cell death (caspase 3 assay) as caused by chronic ischemia or hypertensive stroke to hippocampus and cerebellum. CONCLUSION: Pien Tze Huang showed preventive effects on limiting the damage or injury caused by chronic ischemia and hypertensive stroke in rats. The effect of Pien Tze Huang was possibly related to prevention of cell death from apoptosis or ROS/oxidative damage in mitochondria.

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The development of the human insula was studied in the foetuses from 21 to 32 gestation weeks, using silver staining, immunohistochemistry of proliferative cell nuclear antigen (PCNA), activated caspase-3, and TdT-mediated dUTP-biotin nick end labeling (TUNEL) techniques. To test whether the insula also has a significant role in psychiatry behavior, we also mapped the major receptor of serotonin, 5HT-2A, in the developing insula as well. Opercular formation was evident by 21 weeks gestation. At this time, the cortical layers in the insula had started to organize, with silver impregnated pyramidal and stellate cells demonstrated various processes. By 25 gestation weeks, gyri in the insula were observed. PCNA positive cells decreased in density from 21 gestation weeks onwards while an increase of TUNEL positive cells was evident from 25 to 32 weeks of gestation. Activated capase-3 positive cells were detected in the insula, along with TUNEL positive cells, confirming possibly apoptosis. Serotonin 2A receptor appeared robustly in the 31/32 gestation week specimens. Our study showed early differentiation in the insula, when compared with other parts of the human cortex in the literature. In addition, proliferation as well as apoptosis were demonstration. Expression of 5HT (serotonin) 2A receptor positive cells in development was indicative of the insula as a significant psychiatric center.

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Beta-amyloid peptide (Abeta) peptides play a central role in the development of Alzheimer's disease. They are known to induce mitochondrial dysfunction and caspase activation, resulting in apoptosis of neuronal cells. In the present experiment, an Abeta-induced damage model of platelets was established to observe the effects of Abeta, estradiol benzoate (EB) and genistein on platelets and platelet mitochondria. It was found that after the addition of Abeta, platelet number, platelet mitochondrial membrane potential (DeltaPsim) and adenosine triphosphate (ATP) content were lowered while no protective effects of EB and genistein had been observed. The platelets could serve as a biomarker for detection of mitochondrial function and age related disease.

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OBJECTIVE: This experiment evaluated the perinatal hypoxic effect on the retina of offspring of the ovoviviparous fish. ANIMAL STUDIED: The ovoviviparous fish Xiphophorous maculates was used for the experiment. PROCEDURE: The mothers were kept in a hypoxic environment of 3.5% oxygen for 6 h, starting 30 h before hatching. Subsequently, the retinae of the offspring were fixed, sectioned at 6 microm and evaluated microscopically from the age of 1 to 35 days. RESULTS: Degeneration of the outer nuclear layer of the retina was noted on the 3rd day and severe retinal degeneration was observed on the 35th day. Immunocytochemistry confirmed apoptosis by TUNEL reaction. There was no difference in neovascularization, as revealed by vascular endothelial growth factor, between controls (group 1) and hypoxic fish (group 2). CONCLUSIONS: Perinatal hypoxia could have long-lasting effects on the central nervous system in some species.

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The brains of three Alzheimer patients aged 93, 94, and 104 years old were analyzed. Although cell death was apparent in different cortices, the prefrontal cortex and the Broca's appeared to be hit hardest. The different CA areas of the hippocampal formation all displayed equivalent degrees of cell death but the entorhinal areas showed the most severe degree of cell degeneration. Both apoptosis and necrosis were observed in the different cerebral regions of these very old patients, as expected.

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Hypoxia is a consistent challenge for aquatic animals. It is a pressing environmental problem; hypoxia can cause cranial edema and ovarium dysfunction in fish. Although several studies have reported the effect of hypoxic insult to the visual system, the hypoxic effect on perinatal animals and in particular their offspring has yet to be elucidated. In this study, activated caspase-3 activity was investigated using immunohistochemistry in order to examine the perinatal hypoxic damage in offspring fish. Offspring were divided into groups based on different time points of sacrifice. This allowed assessment of ocular development for different age groups. The results indicated that perinatal hypoxia induced ocular developmental defects in the offspring. The defects took the form of trabecular cell death and fibre degeneration, corneal thinning and lens fibre derangement. A concomitant change in intraocular pressure was recorded by tonometer in the experimental animals compared with the controls. Further investigation should be initiated to develop strategies to prevent developmental disability due to perinatal hypoxia and to increase survivability of the offspring.

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