Unlocking the Body’s Natural Defenses Against Epileptic Drug Resistance
Scientists have made a breakthrough discovery that could significantly improve the efficacy of anti-epileptic drugs (AEDs) for individuals experiencing drug-resistant epilepsy. A study, conducted by a team from the Department of Neurology at Fudan University’s Jinshan Hospital and published in Biological & Pharmaceutical Bulletin, has identified a small regulatory RNA molecule, known as microRNA-146a-5p, which has the capacity to reduce the expression of P-glycoprotein (P-gp)—a protein that often facilitates drug resistance in epilepsy patients.
The study, which holds the DOI: 10.1248/bpb.b18-00937 provides hope for the countless individuals whose seizures remain uncontrolled despite medication. The researchers behind this study, including Xiaolin Deng and colleagues, believe that targeting microRNA-146a-5p could be part of a strategic approach to combat drug-resistant epilepsy.
The Research on P-Glycoprotein
P-glycoprotein has been identified as a major hurdle in the treatment of epilepsy. It functions as an efflux transporter in the brain, actively expelling AEDs from the cells in the epileptogenic zone and consequently lowering their concentration at the critical sites. Thus, it has been associated with inadequate seizure control in people with epilepsy.
Deng and colleagues, in their publication, describe how seizures, particularly those associated with status epilepticus (SE)—a serious form of epilepsy characterized by continuous seizure activity—can enhance the expression of P-gp, thus promoting drug resistance. The study focused on the intricate influence of microRNAs (miRNAs), particularly miR-146a-5p, on the expression of P-gp in an established rat model of lithium-pilocarpine-induced SE.
The Role of MicroRNA-146a-5p
MicroRNAs are known to be major players in the regulation of gene expression, with their primary function being the suppression of specific gene activity. The researchers meticulously measured the expression of miR-146a-5p in the cortex and hippocampus of rats two weeks after SE induction. Their observations revealed an upsurge in miR-146a-5p levels.
The study further investigated the consequent effects of this increase on P-gp expression within the brain. Using techniques such as quantitative RT-PCR, Western blotting, and immunohistochemistry, the connection between the activation of miR-146a-5p and the reduced expression of P-gp was established, presenting a genetic mechanism through which drug resistance could be modulated.
The Insight into NF-κB Signaling
In an effort to unearth the underlying molecular pathways, the team studied the expression of specific proteins associated with the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway. This pathway is known to play a pivotal role in the inflammatory response and has been implicated in various cellular processes including immunity, inflammation, and apoptosis.
Deng and his team found that the upregulated expression of miR-146a-5p could downregulate the expression of critical components in the NF-κB pathway such as interleukin-1 receptor-associated protein kinases-1 (IRAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), and NF-κB p-p65/p65 itself. It was also interesting to note that P-gp expression was subject to control by this very pathway, specifically influenced by miR-146a-5p.
Implications for Future Treatments
The study’s findings have far-reaching implications for the future management of drug-resistant epilepsy. MicroRNA-146a-5p and the NF-κB signaling pathway could potentially be targeted therapeutically to overcome P-gp mediated drug resistance. This could manifest in the development of new drugs or treatment protocols that boost the expression of miR-146a-5p within the brain, or alternatively, the direct modulation of the NF-κB signaling components.
References
1. Deng, X., Shao, Y., Xie, Y., Feng, Y., Wu, M., Wang, M., & Chen, Y. (2019). MicroRNA-146a-5p Downregulates the Expression of P-Glycoprotein in Rats with Lithium-Pilocarpine-Induced Status Epilepticus. Biological & Pharmaceutical Bulletin, 42(5), 744-750. DOI: 10.1248/bpb.b18-00937
2. Loscher, W., & Potschka, H. (2005). Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Progress in Neurobiology, 76(1), 22-76. DOI: 10.1016/j.pneurobio.2005.04.004
3. O’Brien, F. E., Clarke, G., Fitzgerald, P., Dinan, T. G., Griffin, B. T., & Cryan, J. F. (2012). P-glycoprotein inhibition increases the brain distribution and antidepressant-like activity of escitalopram in rodents. Neuropsychopharmacology, 37(9), 2207-2217. DOI: 10.1038/npp.2012.70
4. Sisodiya, S. M. (2003). Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy. Brain, 126(Pt 2), 376-385. DOI: 10.1093/brain/awg028
5. Zibell, G., Unkruer, B., Pekcec, A., Hartz, A. M., Bauer, B., Miller, D. S., & Potschka, H. (2009). Prevention of seizure-induced up-regulation of endothelial P-glycoprotein by COX-2 inhibition. Neuropharmacology, 56(5), 849-855. DOI: 10.1016/j.neuropharm.2009.01.008
Keywords
1. MicroRNA-146a-5p epilepsy
2. P-glycoprotein drug resistance
3. Epilepsy treatment advancements
4. Status epilepticus research
5. NF-κB signaling pathway epilepsy
This groundbreaking exploration of the inner genetic workings of drug-resistant epilepsy offers renewed hope for more effective treatments in the future. As research like that of Xiaolin Deng and his team progresses, it may one day result in a world where no individual with epilepsy will have to endure uncontrolled seizures due to drug resistance.