Biology subjects

Farrell, M. A.

Publications and source records attributed to Farrell, M. A..

3 recordsLinked to original sources

bioRxiv2026

P2X7 receptor antagonism potentiates seizure-suppressive effects of anti-seizure medications in human resected epileptic brain tissue

Resistance to anti-seizure medications (ASMs) remains a major clinical challenge in the management of epilepsy. Neuroinflammation has been implicated as a contributing mechanism and, consistent with this, antagonists of the ATP-gated P2X7 receptor (P2X7R) have been shown to enhance ASM efficacy in animal models. It remains unclear, however, if P2X7R antagonism is effective in human models of drug-resistant epilepsy. Here, we assessed the seizure-suppressive potential of the P2X7R antagonists AFC-5128 and JNJ-47965567 using electrophysiological recordings in acute resected brain slices from patients with epilepsy using artificial cerebrospinal fluid containing low Mg2+ and high K+ to evoked seizure-like events. P2X7R antagonists alone did not suppress seizure-like activity. When co-administered, however, P2X7R antagonists significantly enhanced the anti-seizure efficacy of carbamazepine and lorazepam. Notably, P2X7R antagonist treatment lowered Interleukin-1{beta} levels, and betaine, a drug targeting Interleukin-1{beta} release, mimicked the effects of P2X7R antagonists when combined with carbamazepine. Finally, mice with microglia-specific P2X7R depletion showed improved responsiveness to carbamazepine, suggesting P2X7R-mediated effects are partially mediated via their functions in microglia. These findings suggest that P2X7R-based therapies may represent an effective add-on approach for treating drug-resistant seizures associated with neuroinflammation.

neuroscience↗

bioRxiv2023

Immunoproteasome deficiency results in accelerated brain aging and epilepsy

The immunoproteasome is a central protease complex required for optimal antigen presentation. Immunoproteasome activity is also associated with facilitating degradation of misfolded and oxidized proteins, which prevents cellular stress. While extensively studied during diseases with increasing evidence suggesting a role for the immunoproteasome during pathological conditions including neurodegenerative diseases, this enzyme complex is believed to be mainly inactive in the healthy brain. Here, we show an age-dependent increase in polyubiquitination in the brain of wild-type mice, accompanied with induction of immunoproteasomes, which was most prominent in neurons and microglia. In contrast, mice completely lacking immunoproteasomes (triple-knockout (TKO) mice deficient for LMP2, LMP7 and MECL-1), displayed a strong increase in polyubiquitinated proteins already in the young brain and developed spontaneous epileptic seizures, beginning at the age of 6 months. Injections of kainic acid led to high epilepsy-related mortality of aged TKO mice, confirming increased pathological hyperexcitability states. Notably, the expression of the immunoproteasome was reduced in the brains of patients suffering from epilepsy. In addition, aged TKO mice showed increased anxiety, tau hyperphosphorylation and degeneration of Purkinje cell population with the resulting ataxic symptoms and locomotion alterations. Collectively, our study suggests a critical role for the immunoproteasome in the maintenance of a healthy brain during aging.

neuroscience↗

bioRxiv2019

Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy

The molecular mechanisms that shape the gene expression landscape during the development and maintenance of chronic states of brain hyperexcitability are incompletely understood. Here we show that cytoplasmic mRNA polyadenylation, a posttranscriptional mechanism for regulating gene expression, undergoes widespread reorganisation in temporal lobe epilepsy. Specifically, over 25% of the hippocampal transcriptome displayed changes in their poly(A) tail in mouse models of epilepsy, particular evident in the chronic phase. The expression of cytoplasmic polyadenylation binding proteins (CPEB1-4) was found to be altered in the hippocampus in mouse models of epilepsy and temporal lobe epilepsy patients and CPEB4 target transcripts were over-represented among those showing poly(A) tail changes. Supporting an adaptive function, CPEB4-deficiency leads to an increase in seizure severity and neurodegeneration in mouse models of epilepsy. Together, these findings reveal an additional layer of gene expression control during epilepsy and point to novel targets for seizure control and disease-modification in epilepsy.

neuroscience↗