Glycine-gated chloride channels depress synaptic transmission in rat hippocampus

An inhibitory role for strychnine-sensitive glycine-gated chloride channels (GlyRs) in mature hippocampus is beginning to be appreciated. We have reported previously that CA1 pyramidal cells and GABAergic interneurons recorded in 3- to 4-wk-old rat hippocampal slices express functional GlyRs, dispelling previous misconceptions that GlyR expression ceases in early development. However, the effect of GlyR activation on cell excitability and synaptic circuits in hippocampus has not been fully explored. Using whole cell current-clamp recordings, we show that activation of strychnine-sensitive GlyRs through exogenous glycine application causes a significant decrease in input resistance and prevents somatically generated action potentials in both CA1 pyramidal cells and interneurons. Furthermore, GlyR activation depresses the synaptic network by reducing suprathreshold excitatory postsynaptic potentials (EPSPs) to subthreshold events in both cell types. Blockade of postsynaptic GlyRs with the chloride channel blocker 4, 4'-diisothiocyanatostilbene-2-2'-disulfonic acid (DIDS) or altering the chloride ion driving force in recorded cells attenuates the synaptic depression, strongly indicating that a postsynaptic mechanism is responsible. Increasing the local glycine concentration by blocking reuptake causes a strychnine-sensitive synaptic depression in interneuron recordings, suggesting that alterations in extracellular glycine will impact excitability in hippocampal circuits. Finally, using immunohistochemical methods, we show that glycine and the glycine transporter GlyT2 are co-localized selectively in GABAergic interneurons, indicating that interneurons contain both inhibitory neurotransmitters. Thus we report a novel mechanism whereby activation of postsynaptic GlyRs can function to depress activity in the synaptic network in hippocampus. Moreover, the co-localization of glycine and GABA in hippocampal interneurons, similar to spinal cord, brain stem, and cerebellum, suggests that this property is likely to be a general characteristic of inhibitory interneurons throughout the CNS.     

Analgesic,antipyretic, anti-inflammatory and toxic effects of andrographolide derivatives in experimental animals

Andrographolide (1) and 14-deoxy-11,12-didehydroandrographolide (2) are active constituents of Andrographis paniculata (Burm. f.), family Acanthaceae. A. paniculata extracts are reported to have antiviral, antipyretic, immunostimulant and anticancer activities. In this study, 1 and its 14-acetyl- (4) and 3,19-isopropylidenyl- (3) derivatives, as well as 2 and its 3,19-dipalmitoyl-derivative (5), were intraperitoneally tested for their analgesic, antipyretic, anti-inflammatory and acute toxicity effects in animal models. Analgesic effects were tested in mice using hot plate and writhing tests to distinguish the central and peripheral effects, respectively. The results showed that, at 4 mg/kg, all tested substances have significant analgesic effects, and the highest potency was seen with 3, 4 and 5. Increasing the dose of 3 and 5 to 8 mg/kg did not increase the analgesic effect. In the writhing test, 3 and 5, but not 1, showed significant results. In a baker’s yeast-induced fever model, 3 and 5 significantly reduced rats’ rectal temperature (p < 0.05). In a carrageenan-induced inflammation model, 1, 3 and 5 significantly reduced rats’ paw volume. Doses of 3 and 5 up to 100 mg/kg did not show any serious toxic effects. From this study, 3 and 5 are the most interesting derivatives, showing much greater potency than their parent compounds. These could be further developed as analgesic, antipyretic and anti-inflammatory agents, without any serious toxicity.     

Development of tablets containing probiotics: Effects of formulation and processing parameters on bacterial viability

The probiotic products available in the market nowadays are mostly in the form of liquid or semisolid formulations which show low cell viability after oral administration, mainly because the bacteria do not survive the harsh conditions in the stomach. The development of suitable dry dosage forms enable higher bacterial survival and consequently is the main aim of the present study. An anticipated advantage is that due to the low water-activity lyophilized bacterial cells will preserve their viability. Further, by a proper selection of a tablet forming matrix, it is foreseen that the entrapped bacteria are protected against the low pH in the stomach. In this study, the effects on bacterial survival in tablets were investigated concerning compression force, matrix forming excipients such as hydroxypropyl methylcellulose phthalate (HPMCP) or other swelling agents. The results showed that the proportion of matrix forming excipients in tablets and the compression force affected the properties of probiotic tablets in terms of tensile strength and disintegration as well as the survival of the bacteria. The tensile strength of the tablets increased with increase of HPMCP content. Tablets manufactured with high compression force showed a slow disintegration time and high bacterial cell viability (more than 80%). Incorporation of sodium alginate in the tablets resulted in higher cell survival in simulated GI fluid (>90%) and a suitable disintegration time (approximately 5 h). By a proper design of the formulation, tablets with a fast disintegration time and a high preservation of bacterial cell viability were developed.     

Effect of rosiglitazone on cardiac electrophysiology, infarct size and mitochondrial function in ischaemia and reperfusion of swine and rat heart

Rosiglitazone, a peroxisome proliferator-activated receptor γ agonist, has been used to treat type 2 diabetes. Despite debates regarding its cardioprotection, the effects of rosiglitazone on cardiac electrophysiology are still unclear. This study determined the effect of rosiglitazone on ventricular fibrillation (VF) incidence, VF threshold (VFT), defibrillation threshold (DFT) and mitochondrial function during ischaemia and reperfusion. Twenty-six pigs were used. In each pig, either rosiglitazone (1 mg kg(-1)) or normal saline solution was administered intravenously for 60 min. Then, the left anterior descending coronary artery was ligated for 60 min and released to promote reperfusion for 120 min. The cardiac electrophysiological parameters were determined at the beginning of the study and during the ischaemia and reperfusion periods. The heart was removed, and the area at risk and infarct size in each heart were determined. Cardiac mitochondria were isolated for determination of mitochondrial function. Rosiglitazone did not improve the DFT and VFT during the ischaemia-reperfusion period. In the rosiglitazone group, the VF incidence was increased (58 versus 10%) and the time to the first occurrence of VF was decreased (3 ± 2 versus 19 ± 1 min) in comparison to the vehicle group (P < 0.05). However, the infarct size related to the area at risk in the rosiglitazone group was significantly decreased (P < 0.05). In the cardiac mitochondria, rosiglitazone did not alter the level of production of reactive oxygen species and could not prevent mitochondrial membrane potential changes. Rosiglitazone increased the propensity for VF, and could neither increase defibrillation efficacy nor improve cardiac mitochondrial function.     

Prevalence and Correlates of Sexual Behaviors Among Karen Villagers in Northern Thailand

A cross-sectional survey was conducted in two mountainous villages of the Karen, a major ethnic minority in Thailand. The participants were 566 villagers aged 15–54 years (371 in Village A, 195 in Village B; response rate=81.9%). Premarital/extramarital sex was experienced by 10–20% of the sexually active respondents and sex with a female sex worker (FSW) by 12.6% of males. Premarital sex was independently associated with being a Christian and occupational experience in town; extramarital sex was associated with Village A and drug use; sex with a FSW was associated with being unmarried, a nonfarmer, and occupational experience in town. Approximately 80% of the married participants never used a condom with their spouse, and nearly one-third never did so with a boy/girlfriend or a FSW. A history of sexually transmitted infections (STIs) was associated with sex with a FSW. These findings suggest that nontraditional sexual practices are prevalent and could potentially threaten Karen communities with the spread of HIV.