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- Effects of dehydroeffusol on spasmogen-induced contractile responses of rat intestinal smooth muscles. [Journal Article]
- Planta Med 2014 Aug; 80(12):978-83.
Dehydroeffusol is a naturally occurring phenanthrene isolated from Juncus effusus. In the context of screening new drugs against gastrointestinal spasms, we investigated its effects on isolated rat jejunum in vitro. Dehydroeffusol (30-90 µM) slightly and transiently enhanced contractions in a concentration-dependent manner but significantly inhibited the contractions induced by KCl (100 mM), (±)-Bay-K8644 (5 µM), pilocarpine (90 µM), and histamine (100 µM). These results show that dehydroeffusol may antagonize the spasmogenic activity of various agents, and therefore, could be a promising agent in the treatment of spasms. Its potential spasmolytic mechanism is also discussed.
- Proteomics reveals potential non-neuronal cholinergic receptor-effectors in endothelial cells. [JOURNAL ARTICLE]
- Acta Pharmacol Sin 2014 Aug 4.
Aim:The non-neuronal acetylcholine system (NNAS) in endothelial cells participates in modulating endothelial function, vascular tone, angiogenesis and inflammation, thus plays a critical role in cardiovascular diseases. In this study, we used a proteomic approach to study potential downstream receptor-effectors of NNAS that were involved in regulating cellular function in endothelial cells.Methods:Human umbilical vein endothelial cells were incubated in the presence of acetylcholine, oxotremorine, pilocarpine or nicotine at the concentration of 10 μmol/L for 12 h, and the expressed proteins in the cells were separated and identified with two-dimensional electrophoresis (2-DE) and LC-MS. The protein spots with the largest changes were identified by LC-MS. Biowork software was used for database search of the peptide mass fingerprints.Results:Over 1200 polypeptides were reproducibly detected in 2-DE with a pH range of 3-10. Acetylcholine, oxotremorine, pilocarpine and nicotine treatment caused 16, 9, 8 and 9 protein spots, respectively, expressed differentially. Four protein spots were identified as destrin, FK506 binding protein 1A (FKBP1A), macrophage migration inhibitory factor (MIF) and profilin-1. Western blotting analyses showed that treatment of the cells with cholinergic agonists significantly decreased the expression of destrin, FKBP1A and MIF, and increased the expression of profilin-1.Conclusion:A set of proteins differentially expressed in endothelial cells in response to cholinergic agonists may have important implications for the downstream biological effects of NNAS.
- Different MicroRNA Profiles in Chronic Epilepsy Versus Acute Seizure Mouse Models. [JOURNAL ARTICLE]
- J Mol Neurosci 2014 Jul 31.
Epilepsy affects around 50 million people worldwide, and in about 65 % of patients, the etiology of disease is unknown. MicroRNAs are small non-coding RNAs that have been suggested to play a role in the pathophysiology of epilepsy. Here, we compared microRNA expression patterns in the hippocampus using two chronic models of epilepsy characterised by recurrent spontaneous seizures (pilocarpine and self-sustained status epilepticus (SSSE)) and an acute 6-Hz seizure model. The vast majority of microRNAs deregulated in the acute model exhibited increased expression with 146 microRNAs up-regulated within 6 h after a single seizure. In contrast, in the chronic models, the number of up-regulated microRNAs was similar to the number of down-regulated microRNAs. Three microRNAs-miR-142-5p, miR-331-3p and miR-30a-5p-were commonly deregulated in all three models. However, there is a clear overlap of differentially expressed microRNAs within the chronic models with 36 and 15 microRNAs co-regulated at 24 h and at 28 days following status epilepticus, respectively. Pathway analysis revealed that the altered microRNAs are associated with inflammation, innate immunity and cell cycle regulation. Taken together, the identified microRNAs and the pathways they modulate might represent candidates for novel molecular approaches for the treatment of patients with epilepsy.
- [Immaturity of brain as an endophenotype of neuropsychiatric disorders]. [English Abstract, Journal Article]
- Nihon Shinkei Seishin Yakurigaku Zasshi 2014 Jun; 34(3):67-79.
Schizophrenia and bipolar disorder are severe neuropsychiatric disorders, affecting about 1% of the population. Identifying endophenotypes in the brains of neuropsychiatric patients is now considered the way to understand the underlying mechanisms and to improve therapeutic outcomes. However, the endophenotypes and brain mechanisms of the disorders remain unknown. We have previously reported that alpha-CaMKII heterozygous knockout mice show abnormal behaviors related to neuropsychiatric disorders. In these mutant mice, almost all neurons in the hippocampal dentate gyrus stay at a pseudo-immature state, which we refer to as "immature dentate gyrus (iDG)." So far, the iDG phenotype and similar behavioral abnormalities have been found in Schnurri-2 knockout, SNAP-25 mutant, and forebrain-specific calcineurin knockout mice. In addition, we found that both chronic fluoxetine treatment and pilocarpine-induced seizures can reverse the maturation state of the mature neurons, resulting in the iDG phenotype in wild-type mice. Such an iDG-like phenomenon was observed in the post-mortem brains from patients with schizophrenia/bipolar disorder. Recent studies suggest that cortex and amygdala of schizophrenia patients are also at a pseudo-immature state. Based on the findings, we proposed that immaturity of certain types of cells in the brain is a potential endophenotype of neuropsychiatric disorders.
- Changes in Hippocampal Volume are Correlated with Cell Loss but Not with Seizure Frequency in Two Chronic Models of Temporal Lobe Epilepsy. [Journal Article]
- Front Neurol 2014.:111.
Kainic acid (KA) or pilocarpine (PILO) have been used in rats to model human temporal lobe epilepsy (TLE) but the distribution and severity of structural lesions between these two models may differ. Magnetic resonance imaging (MRI) studies have used quantitative measurements of hippocampal T2 (T2HP) relaxation time and volume, but simultaneous comparative results have not been reported yet. The aim of this study was to compare the MRI T2HP and volume with histological data and frequency of seizures in both models. KA- and PILO-treated rats were imaged with a 2 T MRI scanner. T2HP and volume values were correlated with the number of cells, mossy fiber sprouting, and spontaneous recurrent seizures (SRS) frequency over the 9 months following status epilepticus (SE). Compared to controls, KA-treated rats had unaltered T2HP, pronounced reduction in hippocampal volume and concomitant cell reduction in granule cell layer, CA1 and CA3 at 3 months post SE. In contrast, hippocampal volume was unchanged in PILO-treated animals despite detectable increased T2HP and cell loss in granule cell layer, CA1 and CA3. In the following 6 months, MRI hippocampal volume remained stable with increase of T2HP signal in the KA-treated group. The number of CA1 and CA3 cells was smaller than age-matched CTL group. In contrast, PILO group had MRI volumetric reduction accompanied by reduction in the number of CA1 and CA3 cells. In this group, T2HP signal was unaltered at 6 or 9 months after status. Reductions in the number of cells were not progressive in both models. Notably, the SRS frequency was higher in PILO than in the KA model. The volumetry data correlated well with tissue damage in the epileptic brain, suggesting that MRI may be useful for tracking longitudinal hippocampal changes, allowing the assessment of individual variability and disease progression. Our results indicate that the temporal changes in hippocampal morphology are distinct for both models of TLE and that these are not significantly correlated to the frequency of SRS.
- Comparison of the discontinuation rates and side-effect profiles of pilocarpine and cevimeline for xerostomia in primary Sjögren's syndrome. [Journal Article]
- Clin Exp Rheumatol 2014 Jul-Aug; 32(4):575-7.
There are currently no head-to-head comparisons of sialagogues for Primary Sjögren's syndrome (pSS). We compared the tolerability and side effect profile of pilocarpine and cevimeline in patients with pSS and determined clinical, laboratory and pathological variables associated with therapeutic failure.We retrospectively reviewed the use of pilocarpine and cevimeline in 118 patients with pSS who fulfilled the 2002 American European Consensus Group criteria in a University-based setting. Clinical, laboratory and pathological baseline variables were collected. Failure of therapy was defined as the clinician or patient's decision to stop treatment either due to lack of efficacy or side effects.Cevimeline was associated with lower failure rates compared to pilocarpine among first-time users: 27% vs. 47% (p=0.02), and all users: 32% vs. 61% (p<0.001). Severe sweating was the most frequent side effect leading to cessation of therapy and occurred more frequently in pilocarpine (25%) than cevimeline (11%) users (p=0.02). Patients who previously failed one secretagogue were less likely to discontinue treatment with the other agent, 52% of first-time users vs. 27% of second-time users (p=0.004). Only ANA positivity was associated with failure: [59% vs. 38%] (p=0.03).pSS patients were more likely to continue cevimeline than pilocarpine long-term due to fewer reported side effects with cevimeline. Therapeutic failure of one secretagogue did not predict similar results with the other since second time users were more likely to continue long-term treatment.
- Sex differences in the neurobiology of epilepsy: A preclinical perspective. [JOURNAL ARTICLE]
- Neurobiol Dis 2014 Jul 21.
When all of the epilepsies are considered, sex differences are not always clear, despite the fact that many sex differences are known in the normal brain. Sex differences in epilepsy in laboratory animals are also unclear, although robust effects of sex on seizures have been reported, and numerous effects of gonadal steroids have been shown throughout the rodent brain. Here we discuss several reasons why sex differences in seizure susceptibility are unclear or are difficult to study. Examples of robust sex differences in laboratory rats, such as the relative resistance of adult female rats to the chemoconvulsant pilocarpine compared to males, are described. We also describe a novel method that has shed light on sex differences in neuropathology, which is a relatively new techniques that will potentially contribute to sex differences research in the future. The assay we highlight uses the neuronal nuclear antigen NeuN to probe sex differences in adult male and female rats and mice. In females, weak NeuN expression defines a sex difference that previous neuropathological studies have not described. We also show that in adult rats, social isolation stress can obscure the normal effects of 17β-estradiol to increase excitability in area CA3 of hippocampus. These data underscore the importance of controlling behavioral stress in studies of seizure susceptibility in rodents and suggest that behavioral stress may be one factor that has led to inconsistencies in outcomes of sex differences research. These and other issues have made it difficult to translate our increasing knowledge about the effects of gonadal hormones on the brain to improved treatment for men and women with epilepsy.
- Critical role of canonical transient receptor potential channel 7 in initiation of seizures. [JOURNAL ARTICLE]
- Proc Natl Acad Sci U S A 2014 Jul 21.
Status epilepticus (SE) is a life-threatening disease that has been recognized since antiquity but still causes over 50,000 deaths annually in the United States. The prevailing view on the pathophysiology of SE is that it is sustained by a loss of normal inhibitory mechanisms of neuronal activity. However, the early process leading to the initiation of SE is not well understood. Here, we show that, as seen in electroencephalograms, SE induced by the muscarinic agonist pilocarpine in mice is preceded by a specific increase in the gamma wave, and genetic ablation of canonical transient receptor potential channel (TRPC) 7 significantly reduces this pilocarpine-induced increase of gamma wave activity, preventing the occurrence of SE. At the cellular level, TRPC7 plays a critical role in the generation of spontaneous epileptiform burst firing in cornu ammonis (CA) 3 pyramidal neurons in brain slices. At the synaptic level, TRPC7 plays a significant role in the long-term potentiation at the CA3 recurrent collateral synapses and Schaffer collateral-CA1 synapses, but not at the mossy fiber-CA3 synapses. Taken together, our data suggest that epileptiform burst firing generated in the CA3 region by activity-dependent enhancement of recurrent collateral synapses may be an early event in the initiation process of SE and that TRPC7 plays a critical role in this cellular event. Our findings reveal that TRPC7 is intimately involved in the initiation of seizures both in vitro and in vivo. To our knowledge, this contribution to initiation of seizures is the first identified functional role for the TRPC7 ion channel.
- 5-HT6 Receptor Recruitment of mTOR Modulates Seizure Activity in Epilepsy. [JOURNAL ARTICLE]
- Mol Neurobiol 2014 Jul 18.
Approximately 30 % of epilepsy cases are refractory to current pharmacological treatments. Thus, novel therapeutic approaches that prevent or reverse the molecular and cellular mechanisms of epilepsy are required. 5-HT6 receptor (HTR6) blockade can modulate multiple neurotransmitter systems, and HTR6 may be a potential therapeutic treatment for neurological diseases, including epilepsy. Here, we investigated the role of HTR6 in epilepsy. We detected HTR6 expression both in human epileptic tissues and the pilocarpine rat model by western blotting. We observed behavioral changes after administration of pilocarpine in rats pretreated with a selective HTR6 antagonist, SB-399885, and recorded the electrophysiological index in the pilocarpine rat model pre- or posttreated with SB-399885 by electroencephalogram (EEG) and whole-cell clamp. We measured the activity of mammalian target of rapamycin (mTOR) in the pilocarpine rat model pretreated with the mTOR-specific inhibitor, rapamycin, and SB-399885 using western blotting. We found that HTR6 expression was upregulated in both human tissues and the pilocarpine rat model, and that SB-399885 could suppress epileptic seizures and mTOR activity in epileptic seizures. These results suggest that HTR6 plays an important role in modulating seizure activity and that the blockade of the HTR6/mTOR pathway could be a potential therapeutic target for epilepsy treatment.
- Astrocytic expression of cannabinoid type 1 receptor in rat and human sclerotic hippocampi. [Journal Article]
- Int J Clin Exp Pathol 2014; 7(6):2825-37.
Cannabinoid type 1 receptor (CB1R), which is traditionally located on axon terminals, plays an important role in the pathology of epilepsy and neurodegenerative diseases by modulating synaptic transmission. Using the pilocarpine model of chronic spontaneous recurrent seizures, which mimics the main features of mesial temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) in humans, we examined the expression of CB1R in hippocampal astrocytes of epileptic rats. Furthermore, we also examined the expression of astrocytic CB1R in the resected hippocampi from patients with medically refractory mesial TLE. Using immunofluorescent double labeling, we found increased expression of astrocytic CB1R in hippocampi of epileptic rats, whereas expression of astrocytic CB1R was not detectable in hippocampi of saline treated animals. Furthermore, CB1R was also found in some astrocytes in sclerotic hippocampi in a subset of patients with intractable mesial TLE. Detection with immune electron microscopy showed that the expression of CB1R was increased in astrocytes of epileptic rats and modest levels of CB1R were also found on the astrocytic membrane of sclerotic hippocampi. These results suggest that increased expression of astrocytic CB1R in sclerotic hippocampi might be involved in the cellular basis of the effects of cannabinoids on epilepsy.