Search Results (4)

DNA methylation is implicated in epileptogenesis. Sarcosine, a glycine transporter 1 (GlyT1) inhibitor and methyl donor, attenuates behavioral progression during rapid hippocampal kindling and alters hippocampal DNA methylation, but its locus-specific epigenetic effects remain poorly understood. Here, reduced representation bisulfite sequencing (RRBS) was combined with targeted gene expression analysis in the hippocampi of sarcosine-treated kindled rats. RRBS identified 563, 533, and 390 differentially methylated regions (DMRs), corresponding to 521, 499, and 374 DMR-associated genes, in vehicle-kindled versus sham (vKD vs. vSH), sarcosine-kindled versus sham (sKD vs. vSH), and sarcosine-kindled versus vehicle-kindled (sKD vs. vKD) comparisons, respectively. Pathway enrichment analysis identified 217 significantly affected pathways, including glutamatergic signaling, extracellular matrix (ECM) organization, chromatin regulation, axon guidance, and apoptotic processes. Eleven candidate genes involved in epigenetic regulation, excitatory neurotransmission, and ECM remodeling were selected for transcriptional validation. All 11 genes were significantly upregulated in kindled hippocampi, whereas sarcosine was associated with reduced expression relative to vehicle-kindled rats for eight genes (Hdac9, Fos, Smad7, Unc5a, Grik2, Gpr37l1, Cacna2d2, and Yy1). Collectively, these findings indicate that sarcosine remodels DNA methylation-associated transcriptional networks during rapid hippocampal kindling and support GlyT1 inhibition as a potential disease-modifying approach in experimental epileptogenesis. Full article

Opioid analgesic tolerance (OAT), among other central side effects, limits opioids’ indispensable clinical use for managing chronic pain. Therefore, there is an existing unmet medical need to prevent OAT. Extrasynaptic N-methyl D-aspartate receptors (NMDARs) containing GluN2B subunit blockers delay OAT, indicating the involvement of glutamate in OAT. Glycine acts as a co-agonist on NMDARs, and glycine transporters (GlyTs), particularly GlyT-1 inhibitors, could affect the NMDAR pathways related to OAT. Chronic subcutaneous treatments with morphine and NFPS, a GlyT-1 inhibitor, reduced morphine antinociceptive tolerance (MAT) in the rat tail-flick assay, a thermal pain model. In spinal tissues of rats treated with a morphine–NFPS combination, NFPS alone, or vehicle-comparable changes in µ-opioid receptor activation, protein and mRNA expressions were seen. Yet, no changes were observed in GluN2B mRNA levels. An increase was observed in glycine and glutamate contents of cerebrospinal fluids from animals treated with a morphine–NFPS combination and morphine, respectively. Finally, GlyT-1 inhibitors are likely to delay MAT by mechanisms relying on NMDARs functioning rather than an increase in opioid efficacy. This study, to the best of our knowledge, shows for the first time the impact of GlyT-1 inhibitors on MAT. Nevertheless, future studies are required to decipher the exact mechanisms. Full article

Resveratrol has anti-inflammatory, anti-cancer, and anti-aging pharmacological activities. There is currently a gap in academic research regarding the uptake, transport, and reduction of H₂O₂-induced oxidative damage of resveratrol in the Caco-2 cell model. This study investigated the role of resveratrol in the uptake, transport, and alleviation of H₂O₂-induced oxidative damage in Caco-2 cells. In the Caco-2 cell transport model, it was observed that the uptake and transport of resveratrol (10, 20, 40, and 80 μM) were time dependent and concentration dependent. Different temperatures (37 °C vs. 4 °C) could significantly affect the uptake and transportation of resveratrol. The apical to basolateral transport of resveratrol was markedly reduced by STF-31, a GLUT1 inhibitor, and siRNA intervention. Furthermore, resveratrol pretreatment (80 μM) improves the viability of Caco-2 cells induced by H₂O₂. In a cellular metabolite analysis combined with ultra-high performance liquid chromatography-tandem mass spectrometry, 21 metabolites were identified as differentials. These differential metabolites belong to the urea cycle, arginine and proline metabolism, glycine and serine metabolism, ammonia recycling, aspartate metabolism, glutathione metabolism, and other metabolic pathways. The transport, uptake, and metabolism of resveratrol suggest that oral resveratrol could prevent intestinal diseases caused by oxidative stress. Full article

The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30–60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP. Full article