Summary
Ghrelin has anticonvulsant and neuroprotective effects in models of chemoconvulsant‐induced seizures and status epilepticus. In this study we investigated whether deletion of the ghrelin ...receptor could alter the kindling process in the 6 Hz corneal kindling model and whether ghrelin receptor ligands possess anticonvulsant effects in fully kindled mice. Ghrelin receptor wild‐type and knockout mice were electrically stimulated at a subconvulsive current twice daily via corneal electrodes until they reached the fully kindled state. Mice lacking the ghrelin receptor showed similar seizure severity during kindling acquisition as well as in the maintenance phase when compared to their wild‐type littermates. Subsequently we proceeded by investigating possible anticonvulsant effects of the ghrelin receptor ligands in the acute 6 Hz seizure model and the fully 6 Hz kindled mice. The ghrelin receptor agonist JMV‐1843 decreased the seizure severity score both in acutely 6 Hz stimulated mice and in fully kindled ghrelin receptor wild‐type mice, but not in fully kindled ghrelin receptor knockout mice. No effect on seizure severity was observed following the ghrelin receptor antagonist JMV‐2959 in both models. This finding indicates that JMV‐1843 exerts an anticonvulsant effect in kindled mice via the ghrelin receptor.
•Exposure of mice to 2- and 8-Hz amplitude modulated 10-GHz microwaves for 6days.•Altered active behavior immediately after exposure to 8-Hz amplitude modulation normalized within 4weeks post ...exposure.•No significant changes were found in striatal dopamine and DOPAC levels.•No significant changes were found in cortical glutamate concentrations.
Despite the numerous benefits of microwave applications in our daily life, microwaves were associated with diverse neurological complaints such as headaches and impaired sleep patterns, and changes in the electroencephalogram (EEG). To which extent microwaves influence the brain function remains unclear. This exploratory study assessed the behavior and neurochemistry in mice immediately or 4weeks after a 6-day exposure to low-intensity 10-GHz microwaves with an amplitude modulation (AM) of 2 or 8Hz. These modulation frequencies of 2 and 8Hz are situated within the delta and theta-alpha frequency bands in the EEG spectrum and are associated with sleep and active behavior, respectively. During these experiments, the specific absorbance rate was 0.3W/kg increasing the brain temperature with 0.23°C. For the first time, exposing mice to 8-Hz AM significantly reduced locomotor activity in an open field immediately after exposure which normalized after 4weeks. This in contrast to 2-Hz AM which didn’t induce significant changes in locomotor activity immediately and 4weeks after exposure. Despite this difference in motor behavior, no significant changes in striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels and DOPAC/DA turnover nor in cortical glutamate (GLU) concentrations were detected. In all cases, no effects on motor coordination on a rotarod, spatial working memory, anxiety nor depressive-like behavior were observed. The outcome of this study indicates that exposing mice to low-intensity 8-Hz AM microwaves can alter the locomotor activity in contrast to 2-Hz AM which did not affect the tested behaviors.
Abstract
Accumulating evidence shows a key function for astrocytic connexin43 (Cx43) signaling in epilepsy. However, the lack of experimental distinction between Cx43 gap junction channels (GJCs) and ...hemichannels (HCs) has impeded the identification of the exact contribution of either channel configurations to epilepsy. We therefore investigated whether TAT‐Gap19, a Cx mimetic peptide that inhibits Cx43 HCs but not the corresponding Cx43 GJCs, influences experimentally induced seizures in rodents. Dye uptake experiments in acute hippocampal slices of mice demonstrated that astroglial Cx43 HCs open in response to the chemoconvulsant pilocarpine and this was inhibited by TAT‐Gap19.
In vivo
, pilocarpine‐induced seizures as well as the accompanying increase in D‐serine microdialysate levels were suppressed by Cx43 HC inhibition. Moreover, the anticonvulsant action of TAT‐Gap19 was reversed by exogenous D‐serine administration, suggesting that Cx43 HC inhibition protects against seizures by lowering extracellular D‐serine levels. The anticonvulsive properties of Cx43 HC inhibition were further confirmed in electrical seizure mouse models,
i.e
. an acute 6 Hertz (Hz) model of refractory seizures and a chronic 6 Hz corneal kindling model. Collectively, these results indicate that Cx43 HCs play a role in seizures and underscore their potential as a novel and druggable target in epilepsy treatment.
Within the hippocampus, the major somatostatin (SRIF) receptor subtype, the sst2A receptor, is localized at postsynaptic sites of the principal neurons where it modulates neuronal activity. Following ...agonist exposure, this receptor rapidly internalizes and recycles slowly through the trans-Golgi network. In epilepsy, a high and chronic release of somatostatin occurs, which provokes, in both rat and human tissue, a decrease in the density of this inhibitory receptor at the cell surface. The insulin-regulated aminopeptidase (IRAP) is involved in vesicular trafficking and shares common regional distribution with the sst2A receptor. In addition, IRAP ligands display anticonvulsive properties. We therefore sought to assess by in vitro and in vivo experiments in hippocampal rat tissue whether IRAP ligands could regulate the trafficking of the sst2A receptor and, consequently, modulate limbic seizures. Using pharmacological and cell biological approaches, we demonstrate that IRAP ligands accelerate the recycling of the sst2A receptor that has internalized in neurons in vitro or in vivo. Most importantly, because IRAP ligands increase the density of this inhibitory receptor at the plasma membrane, they also potentiate the neuropeptide SRIF inhibitory effects on seizure activity. Our results further demonstrate that IRAP is a therapeutic target for the treatment of limbic seizures and possibly for other neurological conditions in which downregulation of G-protein-coupled receptors occurs.
The somatostatin type 2A receptor (sst2A) is localized on principal hippocampal neurons and displays anticonvulsant properties. Following agonist exposure, however, this receptor rapidly internalizes and recycles slowly. The insulin-regulated aminopeptidase (IRAP) is involved in vesicular trafficking and shares common regional distribution with the sst2A receptor. We therefore assessed by in vitro and in vivo experiments whether IRAP could regulate the trafficking of this receptor. We demonstrate that IRAP ligands accelerate sst2A recycling in hippocampal neurons. Because IRAP ligands increase the density of sst2A receptors at the plasma membrane, they also potentiate the effects of this inhibitory receptor on seizure activity. Our results further demonstrate that IRAP is a therapeutic target for the treatment of limbic seizures.
Objectives: The cystine/glutamate antiporter (system xc-) is believed to contribute to nonvesicular glutamate release from glial cells in various brain areas. Although recent investigations implicate ...system xc- in mood disorders, unambiguous evidence has not yet been established. Therefore, we evaluated the possible role of system xc- in the depressive state.
Methods: We conducted a protein expression analysis of the specific subunit of system xc- (xCT) in brain regions of the corticosterone mouse model, Flinders Sensitive Line rat model and post-mortem tissue of depressed patients. We next subjected system xc- deficient mice to the corticosterone model and analysed their behaviour in several tests. Lastly, we subjected additional cohorts of xCT-deficient and wild-type mice to N-acetylcysteine treatment to unveil whether the previously reported antidepressant-like effects are dependent upon system xc-.
Results: We did not detect any changes in xCT expression levels in the animal models or patients compared to proper controls. Furthermore, loss of system xc- had no effect on depression- and anxiety-like behaviour. Finally, the antidepressant-like effects of N-acetylcysteine are not mediated via system xc-.
Conclusions: xCT protein expression is not altered in the depressed brain and system xc- deficiency does not affect depression-associated behaviour in the corticosterone mouse model.
Abstract
The communication between the immune and central nervous system (CNS) is affected in many neurological disorders. Peripheral injections of the endotoxin lipopolysaccharide (LPS) are widely ...used to study this communication: an LPS challenge leads to a biphasic syndrome that starts with acute sickness and is followed by persistent brain inflammation and chronic behavioral alterations such as depressive‐like symptoms.
In vitro
, the response to LPS treatment has been shown to involve enhanced expression of system
. This cystine‐glutamate antiporter, with xCT as specific subunit, represents the main glial provider of extracellular glutamate in mouse hippocampus. Here we injected male xCT knockout and wildtype mice with a single intraperitoneal dose of 5 mg/kg LPS. LPS‐injection increased hippocampal xCT expression but did not alter the mainly astroglial localization of the xCT protein. Peripheral and central inflammation (as defined by cytokine levels and morphological activation of microglia) as well as LPS‐induced sickness and depressive‐like behavior were significantly attenuated in xCT‐deficient mice compared with wildtype mice. Our study is the first to demonstrate the involvement of system
in peripheral and central inflammation
in vivo
and the potential therapeutic relevance of its inhibition in brain disorders characterized by peripheral and central inflammation, such as depression.
PDF
