Promising strategies for the treatment of neuroinflammation-associated pathologies

Neurodegenerative diseases (NDDs) are characterized by impaired synthesis of neurosteroids, molecules with known anti-inflammatory properties and neuroprotective effects. However, clinical trials with steroid administration have failed to yield effective therapeutic outcomes. The rate-limiting step of neurosteroidogenesis is represented by the mitochondrial import of cholesterol, which is mediated by the mitochondrial 18 kDa Translocator protein (TSPO). The TSPO targeting to restore endogenous synthesis of neurosteroids has been recently proposed as a promising therapeutic strategy to mitigate NDDs. Here, TSPO-mediated neurosteroidogenesis has been found to be involved in the autocrine regulation of cholesterol homeostasis, which is essential for maintaining proper human microglial function and preventing the acquisition of a pathological hypersensitive phenotype, notoriously NDDs-associated and characterized by toxic accumulation of intracellular cholesterol. Additionally, TSPO ligands have demonstrated neuroprotective effects in murine cortical neurons exposed to fibrillated amyloid-β peptide, preventing synaptotoxicity and neurite breakdown, further supporting their potential in Alzheimer's disease therapy. Beyond TSPO-related function, mitochondrial dysfunction is a key factor in NNDs, particularly disruptions in mitochondrial translation. Herein, the role of mitochondrial translation termination factors was investigated, aiming to elucidate their role in maintaining cellular well-being and paving the way for novel therapeutic approaches to counteract these pathological conditions.