Neuroprotective Effect of Cocoa and Its Main Bioactive Molecules in Association with Postbiotics in Microglial Cells (BV2) Under Glucotoxicity

Diabetes mellitus (DM) is characterized by chronic hyperglycemia and is associated with oxidative stress, inflammation, and gut dysbiosis, which may contribute to neurodegenerative processes. This study investigated the neuroprotective effects of cocoa (Theobroma cacao L.) and its bioactive compounds, caffeine and (+)-catechin, alone or combined with postbiotics, in BV2 microglial cells under glucotoxic conditions. BV2 cells were exposed to cocoa, caffeine, or (+)-catechin, with or without 5% cell-free supernatant (CFS) derived from Lactobacillus casei, in the presence of 200 mM glucose for 24 and 72 h. Cellular metabolic activity (MTT), reactive oxygen species (ROS), nitric oxide (NO), nucleoside triphosphate diphosphohydrolase (NTPDase) and myeloperoxidase (MPO) levels were assessed. High glucose exposure reduced cellular metabolic activity and increased oxidative stress. Cocoa and (+)-catechin improved cellular metabolic activity under glucotoxic conditions, while cocoa, caffeine, and (+)-catechin reduced oxidative stress at specific time points. The combination with CFS enhanced the protective effects, particularly by reducing ROS and NO levels, as well as by decreasing MPO activity, improving cellular metabolic activity, and modulating ATP hydrolysis. These findings suggest that cocoa and its bioactive compounds, especially when associated with L. casei-derived postbiotics, may attenuate glucose-induced oxidative damage in microglial cells and represent a potential strategy for modulating neuroimmune alterations associated with hyperglycemia. This study provides a basis for exploring combined nutritional and postbiotic strategies targeting microglial alterations associated with chronic hyperglycemia and the gut–brain axis. Further studies using more complex cellular and in vivo models are warranted to elucidate the underlying molecular mechanisms and determine the translational relevance of these interventions for diabetes-associated neuroinflammation and neurodegeneration.