Blood–Brain Barrier Permeability and Brain Uptake Mechanism of Kainic Acid and Dihydrokainic Acid

Gynther, Mikko; Petsalo, Aleksanteri; Hansen, Steen Honoré; Bunch, Lennart; Pickering, Darryl S.

doi:10.1007/s11064-014-1499-4

Cited by 17 publications

(11 citation statements)

References 26 publications

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“…LFP recordings and concomitant expression of Ca 2+ indicators in neurons confirmed a successful blockage of neurons. Since kainate to a very little degree passes the blood–brain barrier ( Gynther et al 2015 ), only a small fraction of kainate reaches the brain interstitium following intraperitoneal administration. Typical doses that are sufficient to elicit epileptiform activity in slices are as low as, or even lower than, 500 nM ( Ben-Ari and Cossart 2000 ).…”

Section: Resultsmentioning

confidence: 99%

Ca2+ Signals in Astrocytes Facilitate Spread of Epileptiform Activity

et al. 2018

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Epileptic seizures are associated with increased astrocytic Ca2+ signaling, but the fine spatiotemporal kinetics of the ictal astrocyte–neuron interplay remains elusive. By using 2-photon imaging of awake head-fixed mice with chronic hippocampal windows we demonstrate that astrocytic Ca2+ signals precede neuronal Ca2+ elevations during the initial bout of kainate-induced seizures. On average, astrocytic Ca2+ elevations preceded neuronal activity in CA1 by about 8 s. In subsequent bouts of epileptic seizures, astrocytes and neurons were activated simultaneously. The initial astrocytic Ca2+ elevation was abolished in mice lacking the type 2 inositol-1,4,5-trisphosphate-receptor (Itpr2−/−). Furthermore, we found that Itpr2−/− mice exhibited 60% less epileptiform activity compared with wild-type mice when assessed by telemetric EEG monitoring. In both genotypes we also demonstrate that spreading depression waves may play a part in seizure termination. Our findings imply a role for astrocytic Ca2+ signals in ictogenesis.

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Section: Resultsmentioning

confidence: 99%

Ca2+ Signals in Astrocytes Facilitate Spread of Epileptiform Activity

et al. 2018

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“…The ionotropic glutamate agonists selectively bind to different types of glutamate receptors and transmit their stimulation to neurons and provide neuronal activation [ 26 ]. It has been reported that glutamate agonists, including kainic acid [ 27 , 28 , 29 ], AMPA [ 30 , 31 ], and NMDA [ 31 , 32 , 33 , 34 ], can reach the central nervous system by passing the blood-brain barrier. The present study showed that these agonists can reach the nesfatin-1 neurons in the hypothalamus.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Evidence for Glutamatergic Regulation of Nesfatin-1 Neurons in the Rat Hypothalamus

2020

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Nesfatin-1, identified as an anorexigenic peptide, regulates the energy metabolism by suppressing food intake. The majority of nesfatin-1-synthesizing neurons are concentrated in various hypothalamic nuclei, especially in the supraoptic (SON), arcuate (ARC) and paraventricular nuclei (PVN). We tested the hypothesis that the glutamatergic system regulates nesfatin-1 neurons through glutamate receptors. Therefore, the first aim of the proposed studies was to examine effects of different glutamate agonists in the activation of nesfatin-1 neurons using c-Fos double immunohistochemical labeling. Experimental groups were formed containing male and female rats which received intraperitoneal injections of glutamate agonists kainic acid, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) while the control rats received vehicle. The significant increase in the number of c-Fos-expressing nesfatin-1 neurons after agonist injections were observed both in female and male subjects and some of these effects were found to be sexually dimorphic. In addition, treatment with specific glutamate antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or dizocilpine (MK-801) before each of the three agonist injections caused a statistically significant reduction in the number of activated nesfatin-1 neurons in the hypothalamic nuclei including supraoptic, paraventricular and arcuate nuclei. The second aim of the study was to determine the expression of glutamate receptor subunit proteins in the nesfatin-1 neurons by using a double immunofluorescence technique. The results showed that the glutamate receptor subunits, which may form homomeric or heteromeric functional receptor channels, were expressed in the nesfatin-1 neurons. In conclusion, the results of this study suggest that nesfatin-1 neurons respond to glutamatergic signals in the form of neuronal activation and that the glutamate receptors that are synthesized by nesfatin-1 neurons may participate in the glutamatergic regulation of these neurons.

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“…Reports in the literature have suggested that kainic acid [25][26][27][28], AMPA [29,30], and NMDA [29][30][31][32][33] can cross the blood-brain barrier and reach the central nervous system. Our immunohistochemical studies showed that systemic administration of ionotropic non-NMDA and NMDA glutamate receptor agonists directly or indirectly activate neuronostatin neurons at different rates and that the intracellular pathway of c-Fos protein plays a role in this activation.…”

Section: Investigation Of the Glutamatergic System Effects And Activamentioning

confidence: 99%

Glutamatergic Activation of Neuronostatin Neurons in the Periventricular Nucleus of the Hypothalamus

et al. 2020

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Neuronostatin, a newly identified anorexigenic peptide, is present in the central nervous system. We tested the hypothesis that neuronostatin neurons are activated by feeding as a peripheral factor and that the glutamatergic system has regulatory influences on neuronostatin neurons. The first set of experiments analyzed the activation of neuronostatin neurons by refeeding as a physiological stimulus and the effectiveness of the glutamatergic system on this physiological stimulation. The subjects were randomly divided into three groups: the fasting group, refeeding group, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)+refeeding group. We found that refeeding increased the phosphorylated signal transducers and transcription activator-5 (pSTAT5) expression in neuronostatin-positive neurons and that the CNQX injection significantly suppressed the number of pSTAT5-expressing neuronostatin neurons. The second set of experiments analyzed the activation pathways of neuronostatin neurons and the regulating effects of the glutamatergic system on neuronostatin neurons. The animals received intraperitoneal injections of glutamate receptor agonists (kainic acid, α-amino-3-hydroxy-5methyl-4-isoazepropionic acid (AMPA), and N-methyl-D-aspartate (NMDA)) or 0.9% NaCl. The number of c-Fos-expressing neuronostatin neurons significantly increased following the AMPA and NMDA injections. In conclusion, we found that the neuronostatin neurons were activated by peripheral or central signals, including food intake and/or glutamatergic innervation, and that the glutamate receptors played an important role in this activation.

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Blood–Brain Barrier Permeability and Brain Uptake Mechanism of Kainic Acid and Dihydrokainic Acid

Cited by 17 publications

References 26 publications

Ca2+ Signals in Astrocytes Facilitate Spread of Epileptiform Activity

Ca2+ Signals in Astrocytes Facilitate Spread of Epileptiform Activity

Immunohistochemical Evidence for Glutamatergic Regulation of Nesfatin-1 Neurons in the Rat Hypothalamus

Glutamatergic Activation of Neuronostatin Neurons in the Periventricular Nucleus of the Hypothalamus

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