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

Abstract

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.

Pharmacokinetic study of Q808 in rhesus monkey using liquid chromatography–tandem mass spectrometry

“…Although AEDs are widely used in treating SE to prevent further brain damage, they may cause adverse effects such as drowsiness, ataxia, gastrointestinal disturbances, hepatotoxicity, megaloblastic anemia ( Leppik, 1994 ; Perucca, 1996 ; Lin and Kadaba, 1997 ; Sun et al, 2010 ) and potentially life-threatening conditions ( Al-Soud et al, 2003 ; Sun et al, 2010 ). Additionally, a study has reported that AEDs were thought to trigger psychosis in up to 40% of cases ( Thompson, 1999 ; Li et al, 2022b ).…”

“…The underlying mechanism of Q808 involves modulation of the GABAergic system in specific brain regions, particularly increasing GABA levels in the hippocampus. Q808 has demonstrated effectiveness against various epilepsy models such as seizures induced by pentylenetetrazole (PTZ), isoniazid, thiosemicarbazide, and 3-mercaptopropionic acid ( Li et al, 2022b ). Previous studies have shown that a single dose of Q808 significantly increases GABA ( Olsen, 1981 ; Okada et al, 1989 ; Li et al, 2017 ) in the rat hippocampal region while enhancing the frequency of spontaneous inhibitory postsynaptic currents in the hippocampus ( Li et al, 2017 ; Li et al, 2022b ).…”

“…Q808 has demonstrated effectiveness against various epilepsy models such as seizures induced by pentylenetetrazole (PTZ), isoniazid, thiosemicarbazide, and 3-mercaptopropionic acid ( Li et al, 2022b ). Previous studies have shown that a single dose of Q808 significantly increases GABA ( Olsen, 1981 ; Okada et al, 1989 ; Li et al, 2017 ) in the rat hippocampal region while enhancing the frequency of spontaneous inhibitory postsynaptic currents in the hippocampus ( Li et al, 2017 ; Li et al, 2022b ). Treatment with Q808 also elevates angiotensin I-converting enzyme (ACE) levels—a protein related to GABA—potentially through upregulation of ACE gene and protein expressions in PTZ-kindled rats’ hippocampus ( Li et al, 2022c ).…”