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Zac1, a new zinc-finger protein that regulates both apoptosis and cell cycle arrest, is abundantly expressed in many proliferative/differentiation areas during brain development. In the present work, we studied Zac1 gene expression and protein in experimental seizure models following i.p. injection of pentylenetetrazole (PTZ) or kainic acid (KA). Following KA treatment, an early and intense up-regulation of Zac1 is detected in the limbic areas, such as the hippocampus, cortex and amygdaloid and hypothalamic nuclei. Pre-treatment with MK-801, an antagonist of the NMDA receptors, fully blocks the effect of KA in the hippocampus, whereas it only attenuates KA-induced Zac1 up-regulation in the other areas of the limbic system. A reduced induction is obtained with PTZ-treated animals, specifically in the entorhinal and piriform cortices as well as in amygdaloid and hypothalamic nuclei. Thus, Zac1 is highly induced in the seizure models that generate strong neuronal stimulation and/or extensive cell damage (cell death), reinforcing its putative role in the control of the cell cycle and/or apoptosis. Moreover, strong induction is observed in the granular cells of the dentate gyrus (which are resistant to neurodegeneration) and in some glial cells of the dentate gyrus and subventricular zone, suggesting that Zac1 may be implicated in the mechanisms of neural plasticity following injury. [Copyright &y& Elsevier]

For a number of years it has been known that the CNS convulsant picrotoxin inhibits the GABAA receptor, an anion-selective member of the ligand-gated ion channel (LGIC) superfamily. PTX also inhibits other anion-selective LGIC members, such as GABAC, glycine and glutamate-gated Cl- channels. In the present report, we tested the ability of picrotoxin to inhibit cation-selective 5-HT3A receptors. Murine 5-HT3A receptors were expressed in HEK293 cells, and functionally evaluated using whole-cell patch clamp recording. Picrotoxin inhibited 5-HT-gated currents in a concentration-dependent manner, with an IC50 of approximately 30 μM. Moreover, the blockade by PTX was non-competitive and use-facilitated. Pentylenetetrazole and U-93631, ligands that act at a domain similar to that of picrotoxin in GABAA receptors, also inhibited the 5-HT3A receptor. For each ligand tested, its potency was 5–10 fold lower than typically observed in GABAA receptors. Our results demonstrate that, in addition to being a relatively non-selective inhibitor of anionic LGICs, picrotoxin also inhibits the cation-selective 5-HT3A receptor. Moreover, the fact that both PTZ and U-93631 similarly inhibit the 5-HT3A receptor is consistent with the suggestion that the site of picrotoxin action in this receptor may be comparable to that in anion-selective LGICs. [Copyright &y& Elsevier]

In the mammalian hippocampus, there is a trisynaptic loop that has been often referred to in studies on learning and memory mechanisms and their physiological correlate, the long-term potentiation (LTP). The three sets of synapses are formed by the fibers of perforant pathway terminating on granule cells and by the mossy fibers and Schaeffer collaterals making connections with the pyramidal cells. Each of the three types of synapses can develop LTP. LTP is accompanied by changes in gene expression and it is the nuclear transcription, involving specific transcription factors, that is the starting point for the series of biological amplifications and consolidations both necessary for such sustained changes. The transcription factors are proteins that control gene expression, development and functional formation in every eukaryotic cell. Two categories of transcription factors have been defined to date: general factors that comprise at least 20 proteins to form multiple preinitiation complex at the TATA box (TATA rich sequence) or regulatory factors that bind to promoter or enhancer regions at specific sites on the DNA close to, or distant from, the TATA box. Transcription factors have been divided into five different major classes according to unique protein motifs. These include basic domain, zinc-finger, helix–turn–helix, β-Scaffold factors with minor groove contacts and other transcription factors not specifically classified. Much evidence has been accumulating in favor of the participation of several transcription factors in the consolidation of memory in the mammalian hippocampus following a spatial memory task. It is, therefore, of great importance that the involvement of transcription factors in de novo protein synthesis relevant to the synaptic mechanisms that mediate the formation of long-term memory should be summarized and discussed. No specific correlation between transduction of extracellular signals and expression of nuclear transcription factors, however, has been demonstrated to date. [Copyright &y& Elsevier]

Epilepsy is identified as a brain disorder and characterized by unpredictable disruption of normal brain function. Due to adverse side effect associated with antiepileptic drugs and also resistance profile, improvement of antiepileptic medications with more beneficial anticonvulsant activity is essential. Natural products have demonstrated their therapeutic properties such as anxiolytic, antidepressant and anticonvulsant activities and a source for identification of novel lead compounds. Therefore, the purpose of this study was to evaluate the effects of Onopordon acanthium secondary metabolite, onopordia, on pentylenetetrazole (PTZ)-induced seizure in male mice and investigate the possible role of nitric oxide pathway. Different doses of onopordia (0.1, 1 and 10 mg/kg) and phenobarbital (20 mg/kg) were administered intraperitoneally (i.p., 30, 60 and 120 min) prior to induction of epileptic seizure and compared to control groups. Onopordia demonstrated anticonvulsant effects when administrated at dose of 10 mg/kg, i.p. and optimum time 60 min prior to induction of seizure. Anticonvulsant effect of onopordia was blocked by applying a single dose of a non-selective nitric oxide synthase (NOS) inhibitor, Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME; 10 mg/kg, i.p.), and also a single dose of a selective neuronal NOS (nNOS) inhibitor, 7-nitroindazole (7-NI; 30 mg/kg, i.p.). Administration of ketamine as a N-Methyl-d-aspartic acid (NMDA) receptor antagonist (0.5 mg/kg; i.p.) with onopordia did not change the anticonvulsant effect of onopordia. The results of the present study demonstrated the anticonvulsant effect of onopordia as a new lead compound and also contribution of NO/nNOS pathway on PTZ-induced seizure in mice., Competing Interests: No conflict of interest exists in relation to the submitted manuscript., (© 2019 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)

Hyperhomocysteinemia due to cystathionine beta synthase deficiency confers diverse clinical manifestations. It is characterized by elevated plasma homocysteine levels, a common amino acid metabolized by remethylation to methionine or transsulfuration to cysteine. We recently found a relationship between hepatic Dyrk1A protein expression, a serine/threonine kinase involved in signal transduction in biological processes, hepatic S-adenosylhomocysteine activity, and plasma homocysteine levels. We aimed to study whether there is also a relationship between Dyrk1a and cystathionine beta synthase activity. We used different murine models carrying altered gene coy numbers for Dyrk1a, and found a decreased cystathionine beta synthase activity in the liver of mice under-expressing Dyrk1a, and an increased in liver of mice over-expressing Dyrk1a. For each model, a positive correlation was found between cystathionine beta synthase activity and Dyrk1a protein expression in the liver of mice, which was confirmed in a non-modified genetic context. The positive correlation found between liver Dyrk1a protein expression and CBS activity in modified and non-modified genetic context strengthens the role of this kinase in one carbon metabolism.

The brain has a central role in the regulation of energy stability of the organism. It is the organ with the highest energetic demands, the most susceptible to energy deficits, and is responsible for coordinating behavioral and physiological responses related to food foraging and intake. Dietary interventions have been shown to be a very effective means to extend lifespan and delay the appearance of age-related pathological conditions, notably those associated with brain functional decline. The present review focuses on the effects of these interventions on brain metabolism and cerebral redox state, and summarizes the current literature dealing with dietary interventions on brain pathology.