miR‐485's anti‐drug resistant epilepsy effects by regulating SV2A/PSD‐95 and targeting ABCC1 and neuronal signaling‐transduction proteins in hippocampus of rats

Abstract

Aim: Drug-resistant epilepsy (DRE), most subsequently developing refractory epilepsy, causes a significant burden to the society. microRNAs have been demonstrated as key regulators and therapeutic targets in epilepsy. Accordingly, the aim of the present study was to test whether miR-485 could be a potential target for DRE. Methods and results: An in vivo DRE model was developed in Sprague-Dawley rats by lithium chloride-pilocarpine and screened by antiepileptic drugs. We found that miR-485-5p in hippocampus was significant downregulated at early stage and recovered to normal level at late stage of DRE. Overexpression of miR-485-5p in dentate gyrus (DG) of hippocampus in DRE rats could significantly decrease the frequency of seizures and the numbers of epileptiform spikes of hippocampal DG neuron, and could specifically decrease SV2A expression without affecting PSD-95 expression in DG. Furthermore, miR-485-5p overexpression could significantly downregulate the expression of efflux transporter related to multidrug resistance (ABCC1) in hippocampus at late stage of DRE. Finally, a specific expression pattern of neuronal signaling-transduction proteins (LRP4, MDM4, p53, and TMBIM1) for DRE was observed, and miR-485-5p overexpression could modulate these proteins' expression levels toward normal in hippocampus both at early and late stage of DRE. Conclusion:Collectively, these results suggest that miR-485 was a potential target for anti-DRE, and this effects might be partially via miR-485-5p/homeostatic-synaptic plasticity-molecule axis and/or targeting efflux transporter (ABCC1) and other neuronal signaling-transduction proteins (LRP4, MDM4, p53, and TMBIM1).

MicroRNAs in epilepsy: a bibliometric study from 2007 to 2023

“…Silencing of miR-20a-5p has been shown to inhibit axon growth and neuronal branching in primary hippocampal neurons via the RGMa-RhoA pathway, thereby preventing epileptogenesis while also mediating synaptic plasticity (Feng, Duan et al 2020). The role of miR-485 is crucial in controlling homeostatic synaptic plasticity, with its anti-DRE effect potentially attributed to its regulation of this process (Wang, Wu et al 2021). Furthermore, miRNA levels are subject to regulation by external cues such as sensory experience, synaptic activity, and glutamatergic signaling.…”

“…Nearly 30-40% of patients suffer from drug-resistant epilepsy, which creates a significant burden for patients, their families, and society. Recent findings suggest a role for miRNAs in reversing drug resistance in the epileptic central nervous system (Wang, Wu et al 2021). First, there is growing evidence that efflux transporters, especially P-gp, play an important role in epilepsy drug resistance.…”

New Insights into the Roles of p53 in Central Nervous System Diseases

“…Epilepsy is a common neurological disease with a complex etiology. In addition, p53 is significantly upregulated in both posttraumatic epilepsy and drug-resistant epilepsy rat models, accompanied by increased apoptosis of nerve cells in the mesial temporal lobe and hippocampus ( Huang et al, 2020 ; Wang et al, 2021a ; Wang et al, 2021b ). Similarly, the occurrence of cerebral ischemia and cerebral infarction is closely related to apoptosis or cell death processes ( Qin et al, 2022 ).…”