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Brain-derived neurotrophic factor (BDNF) is a key molecule essential for neural plasticity and development, and is implicated in the pathophysiology of various central nervous system (CNS) disorders. It is now documented that BDNF is synthesized not only in neurons, but also in astrocytes which actively regulate neuronal activities by forming tripartite synapses. Inwardly rectifying potassium (Kir) channel subunit Kir4.1, which is specifically expressed in astrocytes, constructs Kir4.1 and Kir4.1/5.1 channels, and mediates the spatial potassium (K+) buffering action of astrocytes. Recent evidence illustrates that Kir4.1 channels play important roles in bringing about the actions of antidepressant drugs and modulating BDNF expression in astrocytes. Although the precise mechanisms remain to be clarified, it seems likely that inhibition (down-regulation or blockade) of astrocytic Kir4.1 channels attenuates K+ buffering, increases neuronal excitability by elevating extracellular K+ and glutamate, and facilitates BDNF expression. Conversely, activation (up-regulation or opening) of Kir4.1 channels reduces neuronal excitability by lowering extracellular K+ and glutamate, and attenuates BDNF expression. Particularly, the former pathophysiological alterations seem to be important in epileptogenesis and pain sensitization, and the latter in the pathogenesis of depressive disorders. In this article, we review the functions of Kir4.1 channels, with a focus on their regulation of spatial K+ buffering and BDNF expression in astrocytes, and discuss the role of the astrocytic Kir4.1-BDNF system in modulating CNS disorders. [ABSTRACT FROM AUTHOR]

Abstract: Levetiracetam (LEV) is known to inhibit convulsive seizures and is clinically used for treating both partial and generalized seizures. The study was performed to determine whether LEV possesses an inhibitory effect on absence seizures in a novel genetic animal model of absence epilepsy, Groggy (GRY) rats. Single injections of LEV at doses ranging from 20 to 160mg/kg i.p. markedly inhibited absence seizures in GRY rats. The anti-absence action of LEV was potent and the cumulative duration of spike and wave discharges (SWD) in GRY rats was almost completely suppressed even at 20mg/kg (i.p.). When the time-course of the inhibitory action of LEV (80mg/kg i.p.) was examined up to 24h after the treatment, the appearance of SWD was suppressed for over 6h after injection of LEV in contrast to the action of sodium valproate (200mg/kg i.p.) which had a very short effect (<2h). The maximum level of blood concentration of LEV was attained within 2h after administration, and the drug disappeared from the blood in 24h with T 1/2 of 2.7h. These results revealed that LEV displays potent and relatively long-lasting inhibitory effects on absence seizures in GRY rats. [Copyright &y& Elsevier]

The purpose of this study was to investigate the effect of (3S)-7-chloro-3-[2-((1R)-1-carboxyethoxy)-4-aminomethylphenyl]aminocarbonylmethyl-1,3,4,5-tetrahydrobenz[c,d]indole-2-carboxylic acid hydrochloride (SM-31900), an antagonist with high selectivity and affinity for the NMDA receptor glycine-binding site, on the cerebral infarct volume in a permanent middle cerebral artery occlusion (MCAo) model, which was constructed by electrocoagulation of a unilateral middle cerebral artery distal to the olfactory tract using spontaneously hypertensive rats (SHRs). To investigate the dose-response characteristics and the therapeutic time window of SM-31900 in this MCAo model, we conducted three experiments, in which the administration of SM-31900 was started 5 min (experiment I), 30 min (experiment II), or 60 min (experiment III) after MCAo, respectively. In all the studies, SM-31900 was administered by intravenous bolus injection followed by continuous intravenous infusion to obtain a steady-state level of this compound in blood immediately after its administration. The treatment with SM-31900 was continued until 24 h after MCAo, at which time the cerebral infarct volume was measured. In experiment I, SM-31900 significantly reduced the infarct volume by 37% at a dosage of 0.38 mg/kg bolus followed by 1.5 mg/kg/h continuous infusion (0.38 mg/kg+1.5 mg/kg/h). In experiment II, the neuroprotective effect of SM-31900 was also significant, with a 25% reduction in infarct volume at a dosage of 0.38 mg/kg+1.5 mg/kg/h, and a 40% reduction at 1.5 mg/kg+6.0 mg/kg/h. Furthermore, even in experiment III, SM-31900 exerted a significant neuroprotective effect, with a 20% reduction at 1.5 mg/kg+6.0 mg/kg/h. These studies revealed that SM-31900 can exert a neuroprotective effect when it is administered up to at least 60 min after the onset of ischemia in the MCAo model, an animal model of stroke, indicating that SM-31900 is a good candidate for treating acute brain ischemia. [Copyright &y& Elsevier]

Organophosphates (OPs) inhibit cholinesterase and hyperactivate the acetylcholinergic nervous system in the brain, causing motor disorders (e.g., tremor and seizures). Here, we performed behavioral and immunohistochemical studies in mice and rats to investigate the tremorgenic mechanism of paraoxon, an active metabolite of parathion. Treating animals with paraoxon (0.15-0.6 mg/kg, i.p.) elicited kinetic tremor in a dose-dependent manner. Expressional analysis of Fos protein, a biomarker of neural excitation, revealed that a tremorgenic dose of paraoxon (0.6 mg/kg) significantly and region-specifically elevated Fos expression in the cerebral cortex (e.g., sensory cortex), hippocampal CA1, globus pallidus, medial habenula, and inferior olive (IO) among 48 brain regions examined. A moderate increase in Fos expression was also observed in the dorsolateral striatum while the change was not statistically significant. Paraoxon-induced tremor was inhibited by the nicotinic acetylcholine (nACh) receptor antagonist mecamylamine (MEC), but not affected by the muscarinic acetylcholine receptor antagonist trihexyphenidyl (THP). In addition, paraoxon-induced Fos expression in the IO was also antagonized by MEC, but not by THP, and lesioning of the IO markedly suppressed tremorgenic action of paraoxon. The present results suggest that OPs elicit kinetic tremor at least partly by activating IO neurons via nACh receptors. [ABSTRACT FROM AUTHOR]

Highlights • HCN1-deficient rat strain was developed by TALEN mutagenesis. • The Hcn1 -deficient rats exhibited reduced hyperpolarization-activated currents. • The Hcn1 -deficient rats exhibited spontaneous SWDs accompanying behavioral arrest. • Both SWDs and behavioral arrest were suppressed by ethosuximide. • These findings demonstrate that deficiency of HCN1 caused absence epilepsy in rats. Abstract Hyperpolarized-activated cyclic nucleotide-gated (HCN) channels underlie hyperpolarization-activated current (I h) and are involved in controlling the excitability and electrical responsiveness of neurons. Absence epilepsy is clinically defined by a sudden, brief impairment of consciousness and behavioral arrest. Spike-and-wave discharges (SWDs) on electroencephalograms (EEG) are a diagnostic hallmark of absence epilepsy. In rat models of absence epilepsy, impaired function or expression of HCN1, a subtype of HCN channels, has been found. Here, to evaluate whether HCN1 deficiency causes absence epilepsy in rats, we developed Hcn1 -knockout rats by transcription activator-like effector nuclease mutagenesis. The cortical and hippocampal pyramidal neurons of these rats displayed a significant reduction of I h , a pronounced hyperpolarizing shift of the resting membrane potential, and increased input resistance, which indicated that the Hcn1 -knockout rats were deficient in HCN1 function. The Hcn1 -knockout rats were also more vulnerable to pentylenetetrazol-induced acute convulsions. More importantly, they exhibited spontaneous SWDs, which were accompanied by behavioral arrest, both of which were suppressed by ethosuximide. These results confirm the involvement of the HCN1 subunit in the regulation of input resistance and provide direct evidence that a deficiency of HCN1 caused absence epilepsy in rats. [ABSTRACT FROM AUTHOR]