Biology subjects

Gil, B.

Publications and source records attributed to Gil, B..

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↗

bioRxiv2022

Elucidation of Amyloid-Beta's Gambit in Oligomerisation:Truncated Aβ fragments of residues Aβ1-23, Aβ1-24 and Aβ1-25 rapidly seed to form SDS-stable, low molecular weight Aβ oligomers that impair synaptic plasticity.

In Alzheimers disease (AD), Amyloid-beta (A{beta}) oligomers are considered an appealing therapeutic- and diagnostic target. However, to date, the molecular mechanisms associated with the pathological accumulation or structure of A{beta} oligomers remains an enigma to the scientific community. Here we demonstrate the strong seeding properties of unique A{beta} fragment signatures and show that the truncated A{beta} peptides of residues A{beta}1-23, A{beta}1-24 and A{beta}1-25, rapidly seed to form small, SDS-PAGE stable assemblies of [~]5kDa to [~]14kDa molecular mass range. Mass spectrometry analysis of SDS-PAGE fractionated and gel extracted oligomers revealed that the truncated A{beta} isoforms of residues 1-23 to 1-25 form stable entities with low molecular weight (LMW) oligomers, which strongly resemble the regularly reported A{beta} entities of putative dimeric or trimeric assemblies found in human post-mortem AD and Tg mouse brain extracts. Furthermore, electrophysiological recordings in the mouse hippocampus indicate that LMW A{beta} assemblies formed by fragments A{beta}1-23 to A{beta}1-25 significantly impair long-term-potentiation (LTP) in the absence of full-length A{beta}1-42. Extensive antibody screening highlights the important observation, that the LMW A{beta} assemblies formed by these truncated A{beta} peptides escape immuno-detection using conventional, conformation specific antibodies but, more importantly, the clinical antibody aducanumab. Our novel findings suggest that there are new A{beta} target "loopholes" which can be exploited for the development of therapeutic antibodies with binding properties against stable target hotspots present in A{beta} oligomers. We provide here a first example of a new class of monoclonal antibody with unique binding properties against LMW A{beta} oligomers, in the absence of binding to large fibrillar A{beta} assemblies, or dense amyloid plaques. Our research supports a novel, unparalleled approach for targeting early, pathological A{beta} species during the insidious phase of AD and prior to the appearance of large oligomeric or protofibrilar assemblies.

neuroscience↗