Anticonvulsant dopamine type 2 receptor agonist activates inhibitory parvalbumin interneurons

Brodovskaya, Anastasia

doi:10.1111/epi.17004

Cited by 10 publications

(10 citation statements)

References 18 publications

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“…To identify some possible targets for schisandrin B that were responsible or its anticonvulsant effect in the zebrafish larvae, we conducted an analysis of the molecular docking, taking into consideration the selected receptors potentially relevant for this effect. Dopamine receptor modulation affects susceptibility to seizures [ 76 ]. In particular, dopamine D 2 receptor agonists are anticonvulsants and decrease pilocarpine and kindled seizures [ 77 , 78 ], while antagonists of this receptor are proconvulsant [ 79 ].…”

Section: Discussionmentioning

confidence: 99%

In Silico Analysis, Anticonvulsant Activity, and Toxicity Evaluation of Schisandrin B in Zebrafish Larvae and Mice

Nieoczym,

Banono,

Stępnik

et al. 2023

IJMS

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The aim of this study is to evaluate the anticonvulsant potential of schisandrin B, a main ingredient of Schisandra chinensis extracts. Schisandrin B showed anticonvulsant activity in the zebrafish larva pentylenetetrazole acute seizure assay but did not alter seizure thresholds in the intravenous pentylenetetrazole test in mice. Schisandrin B crosses the blood–brain barrier, which we confirmed in our in silico and in vivo analyses; however, the low level of its unbound fraction in the mouse brain tissue may explain the observed lack of anticonvulsant activity. Molecular docking revealed that the anticonvulsant activity of the compound in larval zebrafish might have been due to its binding to a benzodiazepine site within the GABAA receptor and/or the inhibition of the glutamate NMDA receptor. Although schisandrin B showed a beneficial anticonvulsant effect, toxicological studies revealed that it caused serious developmental impairment in zebrafish larvae, underscoring its teratogenic properties. Further detailed studies are needed to precisely identify the properties, pharmacological effects, and safety of schisandrin B.

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Section: Discussionmentioning

confidence: 99%

In Silico Analysis, Anticonvulsant Activity, and Toxicity Evaluation of Schisandrin B in Zebrafish Larvae and Mice

Nieoczym,

Banono,

Stępnik

et al. 2023

IJMS

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“…37) D2 agonists have anticonvulsant and D2 antagonists are proconvulsant. 24,38) However, the effect of the Drd2 on the Chemical and Pharmaceutical Bulletin Advance Publication seizure activity was inconsistent among different seizure models. Uridine, an endogenous neuromodulator, produced an antiepileptic effect against the status epilepticus model induced by lithium-pilocarpine (PC), and this action is related to the decreased expression of Drd2.…”

Section: Discussionmentioning

confidence: 99%

Effects of Long-Term Administration of Q808 on Hippocampal Transcriptome in Healthy Rats

Wang

Zhang

et al. 2022

Chem. Pharm. Bull.

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Epilepsy treatment with antiepileptic drugs (AEDs) is usually requires for many years. Q808 is an innovative antiepileptic chemical. It exerts effective antiepileptic effect against various epilepsy models. Exploring the gene transcriptomic profile of long-term treatment of Q808 is necessary. In the present study, hippocampus RNAsequencing was performed to reveal the transcriptome profile of rats before and after treatment of Q808 for 28 days. Results confirmed 51 differentially expressed genes (DEGs) between Q808 and healthy control groups. Gene cluster analysis showed that most upregulated DEGs linked to response to drug and nucleus, most downregulated DEGs linked to locomotory, neuronal cell body, and drug binding. Most of DEGs were enriched in the signaling transduction, substance dependence, nervous system, and neurodegenerative disease pathways. Furthermore, quantitative real-time PCR analysis confirmed that Q808 significantly increased the expression of neuroprotective genes, such as Mdk, and decreased the mRNA levels of Penk, Drd1, and Adora2a, which are highly expressed in epilepsy models. In addition, Q808 decreased the mRNA expression of Pde10A and Drd2, which are known to be closely associated with schizophrenia. Our study may provide a theoretical basis to explore the effect of Q808 on the susceptibility to epilepsy and other neurological diseases.

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“…Frontiers in Cell and Developmental Biology frontiersin.org contrary, D2R is coupled with Gi protein so that inactivation of D2R-MSN can be fulfilled through agonizing D2R. Controversial effects of dopaminergic agonists and antagonists applied in in vitro or systematic ways on seizures have been reported, but in most cases, it was reported that dopamine D1R agonists are proconvulsant and that D2R agonists are anticonvulsant (Wahnschaffe and Loscher, 1991;Starr, 1996;Sharopov et al, 2012;Brodovskaya and Kapur, 2021). In line with these previous studies showing D1R antagonists and D2R agonists are antiepileptic, our results of chemogenetic inhibition of either D1R-MSN or D2R-MSN in the NAc shell proves to be protective for the brain from more severe seizure insult.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it has been reported that seizures are modulated by the activations of dopaminergic receptors. Systematic pharmacological activation of D1R is proconvulsant ( O’Sullivan et al, 2008 ) and that of D2R displays antiepileptic effects in adult animal models ( Brodovskaya and Kapur, 2021 ). Interestingly, Wahnschaffe and Loscher reported that administration of D2R agonist LY 171555 into the NAc was enough to provide antiepileptic effects in the amygdala-kindled epilepsy model ( Wahnschaffe and Loscher, 1991 ).…”

Section: Introductionmentioning

confidence: 99%

Nucleus accumbens shell modulates seizure propagation in a mouse temporal lobe epilepsy model

Zou

Guo

Suo

et al. 2022

Front. Cell Dev. Biol.

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Temporal lobe epilepsy (TLE) is the most common form of epilepsy with focal seizures which in some conditions can develop into secondarily generalized tonic–clonic seizures by the propagation of epileptic activities in the temporal lobe to other brain areas. The nucleus accumbens (NAc) has been suggested as a treatment target for TLE as accumulating evidence indicates that the NAc, especially its shell, participates in the process of epileptic seizures of patients and animal models with TLE. The majority of neurons in the NAc are GABAergic medium spiny neurons (MSNs) expressing dopamine receptor D1 (D1R) or dopamine receptor D2 (D2R). However, the direct evidence of the NAc shell participating in the propagation of TLE seizures is missing, and its cell type-specific modulatory roles in TLE seizures are unknown. In this study, we microinjected kainic acid into basolateral amygdala (BLA) to make a mouse model of TLE with initial focal seizures and secondarily generalized seizures (SGSs). We found that TLE seizures caused robust c-fos expression in the NAc shell and increased neuronal excitability of D1R-expressing MSN (D1R-MSN) and D2R-expressing MSN (D2R-MSN). Pharmacological inhibition of the NAc shell alleviated TLE seizures by reducing the number of SGSs and seizure stages. Cell-type-specific chemogenetic inhibition of either D1R-MSN or D2R-MSN showed similar effects with pharmacological inhibition of the NAc shell. Both pharmacological and cell-type-specific chemogenetic inhibition of the NAc shell did not alter the onset time of focal seizures. Collectively, these findings indicate that the NAc shell and its D1R-MSN or D2R-MSN mainly participate in the propagation and generalization of the TLE seizures.

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Anticonvulsant dopamine type 2 receptor agonist activates inhibitory parvalbumin interneurons

Cited by 10 publications

References 18 publications

In Silico Analysis, Anticonvulsant Activity, and Toxicity Evaluation of Schisandrin B in Zebrafish Larvae and Mice

In Silico Analysis, Anticonvulsant Activity, and Toxicity Evaluation of Schisandrin B in Zebrafish Larvae and Mice

Effects of Long-Term Administration of Q808 on Hippocampal Transcriptome in Healthy Rats

Nucleus accumbens shell modulates seizure propagation in a mouse temporal lobe epilepsy model

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