The effect of selenium supplementation on coronary heart disease: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Selenium is a crucial mineral with antioxidant and immune functions, and selenium deficiency may increase the risk of coronary heart disease (CHD). However, the effect of selenium supplementation on CHD is still controversial according to numerous randomized controlled trials (RCTs). The aim of our meta-analysis study was to investigate the impact of selenium on CHD. METHODS: PUBMED, EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials databases were systematically searched to identify RCTs evaluating the effect of selenium supplementation on CHD mortality, blood lipid profile (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol), serum C-reactive protein (CRP), and the level of glutathione peroxidase (GSH-PX) from inception until September 20, 2016. Odds ratio of CHD mortality and the associated 95% confidence intervals (CIs) were calculated using the fixed effect model. Weighted mean difference or standardized mean difference (SMD) and 95% confidence intervals (CIs) were calculated to determine the lipid profile, serum CRP, and GSH-PX using fixed effect or random effect models depending on the observed heterogeneity. RESULTS: A total of 16 eligible RCTs with 43998 participants were included. Significant effects were observed for serum CRP (SMD=-0.48; 95% CI, -0.96 to 0; p=0.049) and GSH-PX (SMD=0.5; 95% CI, 0.36-0.64; p<0.001) after selenium supplementation. However, selenium supplementation was not statistically associated with CHD mortality and an aberrant lipid profile. CONCLUSION: Selenium supplementation decreased serum CRP and increased the GSH-PX level, suggesting a positive effect on reducing oxidative stress and inflammation in CHD. However, selenium supplementation is not sufficient to reduce mortality and to improve the lipid status.

Experience-dependent plasticity in hypocretin/orexin neurones: re-setting arousal threshold.

The neuropeptide hypocretin is synthesized exclusively in the lateral hypothalamus and participates in many brain functions critical for animal survival, particularly in the promotion and maintenance of arousal in animals - a core process in animal behaviours. Consistent with its arousal-promoting role in animals, the neurones synthesizing hypocretin receive extensive innervations encoding physiological, psychological and environmental cues and send final outputs to key arousal-promoting brain areas. The activity in hypocretin neurones fluctuates and correlates with the behavioural state of animals and intensive activity has been detected in hypocretin neurones during wakefulness, foraging for food and craving for addictive drugs. Therefore, it is likely that hypocretin neurones undergo experience-dependent changes resulting from intensive activations by stimuli encoding changes in the internal and external environments. This review summarizes the most recent evidence supporting experience-dependent plasticity in hypocretin neurones. Current data suggest that nutritional and behavioural factors lead to synaptic plasticity and re-organization of synaptic architecture in hypocretin neurones. This may be the substrate of enhanced levels of arousal resulting from behavioural changes in animals and may help to explain the mechanisms underlying the changes in arousal levels induced by physiological, psychological and environmental factors.

Membrane properties underlying patterns of GABA-dependent action potentials in developing mouse hypothalamic neurons.

Spikes may play an important role in modulating a number of aspects of brain development. In early hypothalamic development, GABA can either evoke action potentials, or it can shunt other excitatory activity. In both slices and cultures of the mouse hypothalamus, we observed a heterogeneity of spike patterns and frequency in response to GABA. To examine the mechanisms underlying patterns and frequency of GABA-evoked spikes, we used conventional whole cell and gramicidin perforation recordings of neurons (n = 282) in slices and cultures of developing mouse hypothalamus. Recorded with gramicidin pipettes, GABA application evoked action potentials in hypothalamic neurons in brain slices of postnatal day 2-9 (P2-9) mice. With conventional patch pipettes (containing 29 mM Cl-), action potentials were also elicited by GABA from neurons of 2-13 days in vitro (2-13 DIV) embryonic hypothalamic cultures. Depolarizing responses to GABA could be generally classified into three types: depolarization with no spike, a single spike, or complex patterns of multiple spikes. In parallel experiments in slices, electrical stimulation of GABAergic mediobasal hypothalamic neurons in the presence of glutamate receptor antagonists [10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 100 microM 2-amino-5-phosphonopentanoic acid (AP5)] resulted in the occurrence of spikes that were blocked by bicuculline (20 microM). Blocking ionotropic glutamate receptors with AP5 and CNQX did not block GABA-mediated multiple spikes. Similarly, when synaptic transmission was blocked with Cd(2+) (200 microM) and Ni(2+) (300 microM), GABA still induced multiple spikes, suggesting that the multiple spikes can be an intrinsic membrane property of GABA excitation and were not based on local interneurons. When the pipette [Cl-] was 29 or 45 mM, GABA evoked multiple spikes. In contrast, spikes were not detected with 2 or 10 mM intracellular [Cl-]. With gramicidin pipettes, we found that the mean reversal potential of GABA-evoked current (E(GABA)) was positive to the resting membrane potential, suggesting a high intracellular [Cl-] in developing mouse neurons. Varying the holding potential from -80 to 0 mV revealed an inverted U-shaped effect on spike probability. Blocking voltage-dependent Na+ channels with tetrodotoxin eliminated GABA-evoked spikes, but not the GABA-evoked depolarization. Removing Ca(2+) from the extracellular solution did not block spikes, indicating GABA-evoked Na+ -based spikes. Although E(GABA) was more positive within 2-5 days in culture, the probability of GABA-evoked spikes was greater in 6- to 9-day cells. Mechanistically, this appears to be due to a greater Na+ current found in the older cells during a period when the E(GABA) is still positive to the resting membrane potential. GABA evoked similar spike patterns in HEPES and bicarbonate buffers, suggesting that Cl-, not bicarbonate, was primarily responsible for generating multiple spikes. GABA evoked either single or multiple spikes; neurons with multiple spikes had a greater Na+ current, a lower conductance, a more negative spike threshold, and a greater difference between the peak of depolarization and the spike threshold. Taken together, the present results indicate that the patterns of multiple action potentials evoked by GABA are an inherent property of the developing hypothalamic neuron.

GABA, not glutamate, a primary transmitter driving action potentials in developing hypothalamic neurons.

Neuronal activity is critical for many aspects of brain development. It has often been assumed that the primary excitatory transmitter driving this activity is glutamate. In contrast, we report that during early development, synaptic release of GABA, the primary inhibitory neurotransmitter in the mature brain, is not only excitatory but in addition plays a more robust role than glutamate in generating spike activity in mouse hypothalamic neurons. Based on gramicidin perforated whole cell and extracellular recording, which leave intracellular Cl(-) unperturbed in brain slices and cultures, the GABA(A) receptor antagonist bicuculline induced a dramatic decrease in spike frequency (83% decrease) in developing neurons, three times greater than that generated by glutamate receptor antagonists 2-amino-5-phosphono-pentanoic acid and 6-cyano-7-nitroquinoxalene-2,3-dione. Thus a number of factors related to spike-dependent stabilization of neuronal connections, including Hebbian mechanisms, that are generally applied to glutamate transmission may also participate in stabilization of GABA circuits.

Kainate acts at presynaptic receptors to increase GABA release from hypothalamic neurons.

Recent reports suggest that kainate acting at presynaptic receptors reduces the release of the inhibitory transmitter GABA from hippocampal neurons. In contrast, in the hypothalamus in the presence of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor antagonists [1-(4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) and D,L-2-amino-5-phosphonopentanoic acid (AP5)], kainate increased GABA release. In the presence of tetrodotoxin, the frequency, but not the amplitude, of GABA-mediated miniature inhibitory postsynaptic currents (IPSCs) was enhanced by kainate, consistent with a presynaptic site of action. Postsynaptic activation of kainate receptors on cell bodies/dendrites was also found. In contrast to the hippocampus where kainate increases excitability by reducing GABA release, in the hypothalamus where a much higher number of GABAergic cells exist, kainate-mediated activation of transmitter release from inhibitory neurons may reduce the level of neuronal activity in the postsynaptic cell.

Neurotrophin-3 potentiates excitatory GABAergic synaptic transmission in cultured developing hypothalamic neurones of the rat.

1. Neurotrophin-3 (NT-3) supports the survival and differentiation of neurones in the central and peripheral nervous systems through a number of mechanisms that occur in a matter of hours or days. NT-3 may also have a more rapid mode of action that influences synaptic activity in mature neurones. In the present study, the effect of NT-3 on developing GABAergic synapses was investigated in 3- to 7-day-old cultures of rat hypothalamic neurones with whole-cell patch-clamp recording. 2. NT-3 induced a substantial dose-dependent potentiation of the frequency of spontaneous postsynaptic currents (sPSCs; 160 %) in developing neurones during a period when GABA evoked inward (depolarizing) current, as determined with gramicidin-perforated patch recordings. The NT-3 effect was long lasting; continued enhancement was found > 30 min after NT-3 wash-out. NT-3 evoked a substantial 202 % increase in total GABA-mediated inward current, measured as the time-current integral. Action potential frequency was also increased by NT-3 (to 220 %). 3. The frequency of GABA-mediated miniature postsynaptic currents in developing neurones in the presence of tetrodotoxin was potentiated (to 140%) by NT-3 with no change in the mean amplitude, suggesting a presynaptic locus of the effect. 4. In striking contrast to immature neurones, when more mature neurones were studied, NT-3 did not enhance the frequency of GABA-mediated spontaneous postsynaptic currents (sPSCs), but instead evoked a slight (16%) decrease. The frequency of miniature post-synaptic currents was also slightly decreased (16%) by the NT-3, with no change in amplitude. These results were recorded during a later period of neuronal maturity when GABA would evoke outward (hyperpolarizing) currents. NT-3 had no effect on the mean amplitude of GABA-evoked postsynaptic currents in either developing or mature neurones. 5. Intracellular application of K252a, a non-selective tyrosine kinase inhibitor, did not block the NT-3 effect postsynaptically. In contrast, bath application of K252a prevented the enhancement of sPSCs by NT-3, consistent with NT-3 acting through presynaptic induction of tyrosine kinase. Decreasing extracellular calcium with BAPTA or inhibiting calcium channels with Cd2+ blocked the augmentation of sPSC frequency by NT-3, suggesting that an increase of calcium entry may be required for the facilitation of NT-3. 6. Together, our results suggest NT-3 enhances GABA release during the developmental period when GABA is depolarizing and calcium elevating, but not later when GABA is inhibitory, suggesting that one mechanism through which NT-3 may influence neuronal development is via presynaptic potentiation of GABA excitation.

Glutamate inhibits GABA excitatory activity in developing neurons.

In contrast to the mature brain, in which GABA is the major inhibitory neurotransmitter, in the developing brain GABA can be excitatory, leading to depolarization, increased cytoplasmic calcium, and action potentials. We find in developing hypothalamic neurons that glutamate can inhibit the excitatory actions of GABA, as revealed with fura-2 digital imaging and whole-cell recording in cultures and brain slices. Several mechanisms for the inhibitory role of glutamate were identified. Glutamate reduced the amplitude of the cytoplasmic calcium rise evoked by GABA, in part by activation of group II metabotropic glutamate receptors (mGluRs). Presynaptically, activation of the group III mGluRs caused a striking inhibition of GABA release in early stages of synapse formation. Similar inhibitory actions of the group III mGluR agonist L-AP4 on depolarizing GABA activity were found in developing hypothalamic, cortical, and spinal cord neurons in vitro, suggesting this may be a widespread mechanism of inhibition in neurons throughout the developing brain. Antagonists of group III mGluRs increased GABA activity, suggesting an ongoing spontaneous glutamate-mediated inhibition of excitatory GABA actions in developing neurons. Northern blots revealed that many mGluRs were expressed early in brain development, including times of synaptogenesis. Together these data suggest that in developing neurons glutamate can inhibit the excitatory actions of GABA at both presynaptic and postsynaptic sites, and this may be one set of mechanisms whereby the actions of two excitatory transmitters, GABA and glutamate, do not lead to runaway excitation in the developing brain. In addition to its independent excitatory role that has been the subject of much attention, our data suggest that glutamate may also play an inhibitory role in modulating the calcium-elevating actions of GABA that may affect neuronal migration, synapse formation, neurite outgrowth, and growth cone guidance during early brain development.

GABA-dependent firing of glutamate-evoked action potentials at AMPA/kainate receptors in developing hypothalamic neurons.

Although it plays a major inhibitory role in the adult mammalian CNS, gamma-aminobutyric acid (GABA) may have an excitatory function in developing neurons. The present study focuses on the dependence of glutamate on GABA to generate action potentials in developing hypothalamic neurons. Under conditions where glutamate by itself could not evoke an action potential, GABA facilitated glutamate-mediated depolarization to fire action potentials. This facilitation had a broad time window during the decaying phase of the GABA-mediated depolarization in developing neurons in culture. The glutamate-mediated depolarization was shunted only during the peak of GABA-mediated depolarization, but was facilitated after that. Similar results were obtained in the presence of 2-amino-5-phosphonopentanoic acid (AP5), indicating that GABA can facilitate glutamate responses independent of relief of the Mg2+ block of the N-methyl-D-aspartate (NMDA) receptor. This novel interaction between GABA- and glutamate-mediated excitation could play a role in strengthening neuronal circuits during early development and would exert a maximal effect if GABA and glutamate receptors were activated after a slight temporal delay.