Background/Objectives: Glucagon-like peptide-1 receptor agonists such as liraglutide are known for their neuroprotective effects in neurodegenerative disorders, but their role in temporal lobe epilepsy (TLE) remains unclear. We aimed to investigate the effects of liraglutide on several biological processes, including inflammation, antioxidant defense mechanisms, mitochondrial dynamics, and function, as well as cognitive and behavioral changes in the TLE model. Methods: Low-dose, repeated intraperitoneal injections of lithium chloride–pilocarpine hydrochloride were used to induce status epilepticus (SE) in order to develop TLE in rats. Fifty-six male Sprague Dawley rats were subjected and allocated to the groups. The effects of liraglutide on inflammatory markers (NLRP3, Caspase-1, and IL-1β), antioxidant pathways (Nrf-2 and p-Nrf-2), and mitochondrial dynamics proteins (Pink1, Mfn2, and Drp1) were evaluated in hippocampal tissues via a Western blot. Mitochondrial function in peripheral blood mononuclear cells (PBMCs) was examined using flow cytometry. Cognitive-behavioral outcomes were assessed using the open-field, elevated plus maze, and Morris water maze tests. Results: Our results showed that liraglutide modulates NLRP3-mediated inflammation, reduces oxidative stress, and triggers antioxidative pathways through Nrf2 in SE-induced rats. Moreover, liraglutide treatment restored Pink1, Mfn2, and Drp1 levels in SE-induced rats. Liraglutide treatment also altered the mitochondrial function of PBMCs in both healthy and epileptic rats. This suggests that treatment can modulate mitochondrial dynamics and functions in the brain and periphery. Furthermore, in the behavioral aspect, liraglutide reversed the movement-enhancing effect of epilepsy. Conclusions: This research underscores the potential of GLP-1RAs as a possibly promising therapeutic strategy for TLE.

Background/Objectives: Temporal lobe epilepsy (TLE) often develops following an initial brain injury, where specific triggers lead to epileptogenesis—a process transforming a healthy brain into one prone to spontaneous, recurrent seizures. Although electroencephalography (EEG) remains the primary diagnostic tool for epilepsy, it cannot predict the risk of epilepsy after brain injury. This limitation highlights the need for biomarkers, particularly those measurable in peripheral samples, to assess epilepsy risk. This study investigated urinary metabolites in a rat model of TLE to identify biomarkers that track epileptogenesis progression across the acute, latent, and chronic phases and elucidate the underlying mechanisms. Methods: Status epilepticus (SE) was induced in rats using repeated intraperitoneal injections of lithium chloride–pilocarpine hydrochloride. Urine samples were collected 48 h, 1 week, and 6 weeks after SE induction. Nuclear magnetic resonance spectrometry was used for metabolomic analysis, and statistical evaluations were performed using MetaboAnalyst 6.0. Differences between epileptic and control groups were represented using the orthogonal partial least squares discriminant analysis (OPLS-DA) model. Volcano plot analysis identified key metabolic changes, applying a fold-change threshold of 1.5 and a p-value < 0.05. Results: The acute phase exhibited elevated levels of acetic acid, dihydrothymine, thymol, and trimethylamine, whereas glycolysis and tricarboxylic acid cycle metabolites, including pyruvic and citric acids, were reduced. Both the acute and latent phases showed decreased theobromine, taurine, and allantoin levels, with elevated 1-methylhistidine in the latent phase. The chronic phase exhibited reductions in pimelic acid, tiglylglycine, D-lactose, and xanthurenic acid levels. Conclusions: These findings highlight stage-specific urinary metabolic changes in TLE, suggesting distinct metabolites as biomarkers for epileptogenesis and offering insights into the mechanisms underlying SE progression.

REM sleep deprivation (REMSD) contributes to neurodegenerative diseases like Alzheimer’s Disease (AD). This study examined REMSD’s effects on cognition, ER stress, and AD-like pathology in rats, alongside melatonin’s therapeutic potential. REMSD was induced for six days using the modified multiple platform method (MMPM). Cognitive function was tested via the Morris Water Maze (MWM). Rats received melatonin (20 mg/kg), 4-PBA (as a positive control, 100 mg/kg), or vehicle during deprivation/recovery periods. Western blotting and ELISA assessed ER stress markers (BiP, pIRE1, pPERK, peIF2-α, CHOP and GRP94, GADD34), Alzheimer related molecules (Aβ40/42, Tau, APP, GSK3β) and apoptosis-related proteins (Caspase 2, Caspase 12, BAX/Bcl-2). In addition, the mRNA expression levels of ATF4 and ATF6 were determined by PCR. Recovery sleep restored cognition, but melatonin/4-PBA enhanced it further. REMSD was associated with increased ER stress and AD-like pathology, whereas melatonin and 4-PBA appeared to attenuate these alterations, possibly by influencing the unfolded protein response (UPR) and reducing protein misfolding. Melatonin shows promise in countering SD-associated neurodegeneration, highlighting sleep’s role in proteostasis and its potential clinical use in AD and protein-misfolding disorders.

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive synaptic dysfunction, axonal pathology, and cognitive decline, with the hippocampal circuits showing particular vulnerability during disease progression. However, early-life nutritional interventions may influence long-term synaptic resilience. In this study, we investigated the long-term effects of prenatal and lactational supplementation with choline, UMP, and fish oil in the 5XFAD mouse model. To this end, hippocampal synaptic and axonal pathology was assessed at 3, 6, and 9 months using Western blotting and immunofluorescence to measure synaptophysin, PSD-95, and neurofilament medium chain (NF-M), alongside a multidimensional behavioral battery that evaluated cognitive, affective, motor, and sensory outcomes. Results showed that early-life supplementation did not significantly improve the learning performance decline, increase nociception, or reverse changes in anxiety behavior in transgenic mice. However, it attenuated synaptic decline in transgenic animals by partially preserving synaptophysin and PSD-95 levels and reducing NF-M elevations. These molecular effects were accompanied by selective behavioral modulation, including preserved learning dynamics, altered anxiety-like behavior, and delayed nociceptive hypersensitivity, while late-stage motor impairments remained largely unaffected. Overall, prenatal and lactational supplementation produced modest, age-dependent effects on synaptic markers and partially prevented neurodegenerative progression in the 5XFAD model.