Overexpression of Homer1b/c Induces Valproic Acid Resistance in Epilepsy

Overview

Journal CNS Neurosci Ther

Specialties Neurology
Pharmacology

Date 2022 Nov 10

PMID 36353757

Authors

Yan Wang

Youbin Li

Guangfei Wang

Jinmiao Lu

Zhiping Li

Affiliations

Soon will be listed here.

Abstract

Aims: Resistance to valproic acid (VPA) is a major challenge for epilepsy treatment. We aimed to explore the mechanism underlying this resistance.

Methods: Pentylenetetrazol-induced chronic epileptic rats were administered VPA (250 mg/Kg) for 14 days; rats with controlled seizure stages (seizure score ≤0) and latent time (latent time ≥0) were considered VPA-responsive, while the others were considered nonresponsive. Differentially expressed genes (DEGs) between the VPA-responsive and nonresponsive rat hippocampus transcriptomes were identified, and their functions were evaluated. The roles of postsynaptic density (PSD) and Homer1 were also determined. Furthermore, a subtype of Homer1 (Homer1b/c) was overexpressed or silenced in HT22 cells to determine its effect on VPA efficacy. Moreover, the membrane levels of mGluR1/5 directly bound to Homer1b/c were assessed.

Results: Overall, 264 DEGs commonly enriched in the PSD between VPA-responsive and nonresponsive rats. Among them, Homer1 was more highly expressed in the hippocampus of nonresponses compared to that of responses. Overexpression of Homer1b/c interrupted VPA efficacy by increasing reactive oxygen species production, lactate dehydrogenase release, and calcium content. Furthermore, it induced the overexpression of mGluR1 and mGluR5.

Conclusion: Overexpression of Homer1b/c influenced VPA efficacy, revealing it could be a target to improve the efficacy of this treatment.

Citing Articles

Anti‑epileptic mechanism of isopimaric acid from based on network pharmacology, molecular docking and biological validation.

Wang Y, Wang Y, Li C, Liu D, Cai Y, Li Q Exp Ther Med. 2024; 28(3):348.

PMID: 39006452 PMC: 11240864. DOI: 10.3892/etm.2024.12637.

The microRNA-211-5p/P2RX7/ERK/GPX4 axis regulates epilepsy-associated neuronal ferroptosis and oxidative stress.

Li X, Quan P, Si Y, Liu F, Fan Y, Ding F J Neuroinflammation. 2024; 21(1):13.

PMID: 38191407 PMC: 10773122. DOI: 10.1186/s12974-023-03009-z.

A Potential Anti-Glioblastoma Compound LH20 Induces Apoptosis and Arrest of Human Glioblastoma Cells via CDK4/6 Inhibition.

Wang Y, Li Y, Liu D, Zheng D, Li X, Li C Molecules. 2023; 28(13).

PMID: 37446710 PMC: 10343613. DOI: 10.3390/molecules28135047.

Overexpression of Homer1b/c induces valproic acid resistance in epilepsy.

Wang Y, Li Y, Wang G, Lu J, Li Z CNS Neurosci Ther. 2022; 29(1):331-343.

PMID: 36353757 PMC: 9804053. DOI: 10.1111/cns.14008.

References

Dhir A . Pentylenetetrazol (PTZ) kindling model of epilepsy. Curr Protoc Neurosci. 2012; Chapter 9:Unit9.37. DOI: 10.1002/0471142301.ns0937s58. View

Kato A, Ozawa F, Saitoh Y, Hirai K, Inokuchi K . vesl, a gene encoding VASP/Ena family related protein, is upregulated during seizure, long-term potentiation and synaptogenesis. FEBS Lett. 1997; 412(1):183-9. DOI: 10.1016/s0014-5793(97)00775-8. View

Rakitin A, Koks S, Haldre S . Valproate modulates glucose metabolism in patients with epilepsy after first exposure. Epilepsia. 2015; 56(11):e172-5. DOI: 10.1111/epi.13114. View

Huizenga M, Wicker E, Beck V, Forcelli P . Anticonvulsant effect of cannabinoid receptor agonists in models of seizures in developing rats. Epilepsia. 2017; 58(9):1593-1602. DOI: 10.1111/epi.13842. View

Jensen K, Covault J . Human miR-1271 is a miR-96 paralog with distinct non-conserved brain expression pattern. Nucleic Acids Res. 2010; 39(2):701-11. PMC: 3025550. DOI: 10.1093/nar/gkq798. View

Notenboom R, Hampson D, Jansen G, van Rijen P, van Veelen C, van Nieuwenhuizen O . Up-regulation of hippocampal metabotropic glutamate receptor 5 in temporal lobe epilepsy patients. Brain. 2005; 129(Pt 1):96-107. DOI: 10.1093/brain/awh673. View

Celli R, Fornai F . Targeting Ionotropic Glutamate Receptors in the Treatment of Epilepsy. Curr Neuropharmacol. 2020; 19(6):747-765. PMC: 8686308. DOI: 10.2174/1570159X18666200831154658. View

El-Tallawy H, Abuhamdah S, Nassar A, Farghaly W, Saleem T, Atta S . Gephyrin and Genetic Polymorphisms in Patients with Pharmacoresistant Epilepsy. Pharmgenomics Pers Med. 2021; 14:1133-1140. PMC: 8437390. DOI: 10.2147/PGPM.S327808. View

Kammermeier P . Surface clustering of metabotropic glutamate receptor 1 induced by long Homer proteins. BMC Neurosci. 2006; 7:1. PMC: 1361788. DOI: 10.1186/1471-2202-7-1. View

10.

Buscemi L, Ginet V, Lopatar J, Montana V, Pucci L, Spagnuolo P . Homer1 Scaffold Proteins Govern Ca2+ Dynamics in Normal and Reactive Astrocytes. Cereb Cortex. 2016; 27(3):2365-2384. PMC: 5963825. DOI: 10.1093/cercor/bhw078. View

11.

Singh E, Pillai K, Mehndiratta M . Characterization of a lamotrigine-resistant kindled model of epilepsy in mice: evaluation of drug resistance mechanisms. Basic Clin Pharmacol Toxicol. 2014; 115(5):373-8. DOI: 10.1111/bcpt.12238. View

12.

De Benedittis S, Fortunato F, Cava C, Gallivanone F, Iaccino E, Caligiuri M . Circulating microRNA: The Potential Novel Diagnostic Biomarkers to Predict Drug Resistance in Temporal Lobe Epilepsy, a Pilot Study. Int J Mol Sci. 2021; 22(2). PMC: 7828221. DOI: 10.3390/ijms22020702. View

13.

Trinka E, Hofler J, Zerbs A, Brigo F . Efficacy and safety of intravenous valproate for status epilepticus: a systematic review. CNS Drugs. 2014; 28(7):623-39. PMC: 4078236. DOI: 10.1007/s40263-014-0167-1. View

14.

Xiao W, Liu C, Zhong K, Ning S, Hou R, Deng N . CpG methylation signature defines human temporal lobe epilepsy and predicts drug-resistant. CNS Neurosci Ther. 2020; 26(10):1021-1030. PMC: 7539843. DOI: 10.1111/cns.13394. View

15.

Blumcke I, Becker A, Klein C, Scheiwe C, Lie A, Beck H . Temporal lobe epilepsy associated up-regulation of metabotropic glutamate receptors: correlated changes in mGluR1 mRNA and protein expression in experimental animals and human patients. J Neuropathol Exp Neurol. 2000; 59(1):1-10. DOI: 10.1093/jnen/59.1.1. View

16.

Cikic S, Chandra P, Harman J, Rutkai I, Katakam P, Guidry J . Sexual differences in mitochondrial and related proteins in rat cerebral microvessels: A proteomic approach. J Cereb Blood Flow Metab. 2020; 41(2):397-412. PMC: 8370005. DOI: 10.1177/0271678X20915127. View

17.

Hiroi T, Wei H, Hough C, Leeds P, Chuang D . Protracted lithium treatment protects against the ER stress elicited by thapsigargin in rat PC12 cells: roles of intracellular calcium, GRP78 and Bcl-2. Pharmacogenomics J. 2005; 5(2):102-11. DOI: 10.1038/sj.tpj.6500296. View

18.

Acher F, Selvam C, Pin J, Goudet C, Bertrand H . A critical pocket close to the glutamate binding site of mGlu receptors opens new possibilities for agonist design. Neuropharmacology. 2010; 60(1):102-7. DOI: 10.1016/j.neuropharm.2010.07.002. View

19.

Wang Y, Li Z . RNA-seq analysis of blood of valproic acid-responsive and non-responsive pediatric patients with epilepsy. Exp Ther Med. 2019; 18(1):373-383. PMC: 6566089. DOI: 10.3892/etm.2019.7538. View

20.

Zeng Q, Michael I, Zhang P, Saghafinia S, Knott G, Jiao W . Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature. 2019; 573(7775):526-531. PMC: 6837873. DOI: 10.1038/s41586-019-1576-6. View