Gap junctions play an important role in brain physiology. They synchronize neuronal activity and connect glial cells participating in the regulation of brain metabolism and homeostasis. Gap junction blockers (GJBs) include various chemicals that impair gap junction communication, disrupt oscillatory neuronal activity over a wide range of frequencies, and decrease epileptic discharges. The behavioural and clinical effects of GJBs suggest that gap junctions can be involved in the regulation of locomotor activity, arousal, memory, and breathing. Severe neuropsychiatric side effects suggest the involvement of gap junctions in mechanisms of consciousness. Unfortunately, the available GJBs are not selective and can bind to targets other than gap junctions. Other problems in behavioural studies include the possible adverse effects of GJBs, for example, retinal toxicity and hearing disturbances, changes in blood-brain transport, and the metabolism of other drugs. Therefore, it is necessary to design experiments properly to avoid false, misleading or uninterpretable results. We review the pharmacological properties and electrophysiological, behavioural and cognitive effects of the available gap junction blockers, such as carbenoxolone, glycyrrhetinic acid, quinine, quinidine, mefloquine, heptanol, octanol, anandamide, fenamates, 2-APB, several anaesthetics, retinoic acid, oleamide, spermine, aminosulfonates, and sodium propionate. It is concluded that despite a number of different problems, the currently used gap junction blockers could be useful tools in pharmacology and neuroscience.

Properties of gap junction blockers and their behavioural, cognitive and electrophysiological effects: animal and human studies.

OBJECTIVE— An important mechanism in the pathogenesis of type 2 diabetes in obese individuals is elevation of plasma free fatty acids (FFAs), which induce insulin resistance and chronically decrease β-cell function and mass. Our objective was to investigate the role of oxidative stress in FFA-induced decrease in β-cell function.

RESEARCH DESIGN AND METHODS— We used an in vivo model of 48-h intravenous oleate infusion in Wistar rats followed by hyperglycemic clamps or islet secretion studies ex vivo and in vitro models of 48-h exposure to oleate in islets and MIN6 cells.

RESULTS— Forty-eight–hour infusion of oleate decreased the insulin and C-peptide responses to a hyperglycemic clamp ( P < 0.01), an effect prevented by coinfusion of the antioxidants N -acetylcysteine (NAC) and taurine. Similar to the findings in vivo, 48-h infusion of oleate decreased glucose-stimulated insulin secretion ex vivo ( P < 0.01) and induced oxidative stress ( P < 0.001) in isolated islets, effects prevented by coinfusion of the antioxidants NAC, taurine, or tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl). Forty-eight–hour infusion of olive oil induced oxidative stress ( P < 0.001) and decreased the insulin response of isolated islets similar to oleate ( P < 0.01). Islets exposed to oleate or palmitate and MIN6 cells exposed to oleate showed a decreased insulin response to high glucose and increased levels of oxidative stress (both P < 0.001), effects prevented by taurine. Real-time RT-PCR showed increased mRNA levels of antioxidant genes in MIN6 cells after oleate exposure, an effect partially prevented by taurine.

CONCLUSIONS— Our data are the first demonstration that oxidative stress plays a role in the decrease in β-cell secretory function induced by prolonged exposure to FFAs in vitro and in vivo.

https://diabetes.diabetesjournals.org/content/diabetes/56/12/2927.full.pdf

Free Fatty Acid-Induced Reduction in Glucose Stimulated Insulin Secretion–Evidence for a Role of Oxidative Stress In Vitro and In Vivo

Antifibrinolytic drugs are widely used to reduce blood loss during surgery. One serious adverse effect of these drugs is convulsive seizures; however, the mechanisms underlying such seizures remain poorly understood. The antifibrinolytic drugs tranexamic acid (TXA) and e-aminocaproic acid (EACA) are structurally similar to the inhibitory neurotransmitter glycine. Since reduced function of glycine receptors causes seizures, we hypothesized that TXA and EACA inhibit the activity of glycine receptors. Here we demonstrate that TXA and EACA are competitive antagonists of glycine receptors in mice. We also showed that the general anesthetic isoflurane, and to a lesser extent propofol, reverses TXA inhibition of glycine receptor–mediated current, suggesting that these drugs could potentially be used to treat TXA-induced seizures. Finally, we measured the concentration of TXA in the cerebrospinal fluid (CSF) of patients undergoing major cardiovascular surgery. Surprisingly, peak TXA concentration in the CSF occurred after termination of drug infusion and in one patient coincided with the onset of seizures. Collectively, these results show that concentrations of TXA equivalent to those measured in the CSF of patients inhibited glycine receptors. Furthermore, isoflurane or propofol may prevent or reverse TXA-induced seizures.

/pdf/tranexamic-acid-concentrations-associated-with-human-7kfpnbotae.pdf

Tranexamic acid concentrations associated with human seizures inhibit glycine receptors

New-onset seizures in adults: possible association with consumption of popular energy drinks.

Glycine and glycine receptor signaling in hippocampal neurons: Diversity, function and regulation

Summary: Purpose: The imbalance between neuronal inhibition and excitation contributes to epileptogenesis. Inhibition in the central nervous system (CNS) is mediated by γ-aminobutyric acid (GABA) and glycine. Recent studies indicate the expression of glycine receptor (GlyR) in hippocampus and neocortex. However, the function of GlyR in these regions is not clarified completely. The aim of this study was to investigate whether the GlyR agonists glycine and taurine promote an anticonvulsive effect.



Methods: We induced epileptiform discharges by reducing extracellular Mg2+ concentration in combined rat entorhinal cortex–hippocampal slices (400 μm). Epileptiform discharges were detected by using extracellular recording techniques.



Results: Seizure-like events were suppressed by taurine, exhibiting a half-maximal inhibitory effect (IC50) of 0.9 mM. Suppression of late recurrent discharges in the medial entorhinal cortex and recurrent short discharges in the hippocampus was obtained at an IC50 value of 1.6 and 2.1 mM, respectively. Strychnine at concentrations <1 μM abolished these effects. Likewise glycine, after an initial proconvulsant effect, suppressed epileptiform discharges.



Conclusions: These findings show that GlyR agonists, in particular taurine, could serve as potential anticonvulsants and suggest an important role of GlyR in cortical function and dysfunction.

Effects of Taurine and Glycine on Epileptiform Activity Induced by Removal of Mg2+ in Combined Rat Entorhinal Cortex–Hippocampal Slices

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Effects of Taurine and Glycine on Epileptiform Activity Induced by Removal of Mg2+ in Combined Rat Entorhinal Cortex–Hippocampal Slices