Dual Stress Postischemia Deprivation Depression via Metabolic Disturbance in Rodents

Post-stroke depression (PSD) exacerbates stroke outcomes and increases the risk of suicide. The lack of tailored therapeutic drugs for PSD, to a large extent, is attributed to the lack of appropriate animal models that could characterize the complex pathophysiology of clinical patients for drug development.

Integrating clinical insights into PSD etiology and existing preclinical models, we developed a novel rat model of PSD by combining ischemic stroke with physical confinement and environmental deprivation, thereby recapitulating both pathophysiological injuries and psychosocial stressors experienced by clinical stroke patients. The model was systematically validated through multidimensional behavioral assessments, pharmacological mechanism analyses, and metabolomic profiling.

The model exhibited a typical depressive phenotype after 4 wk, with decreased levels of neurotransmitters 5-hydroxytryptamine, norepinephrine, and dopamine in the hippocampus. On the other hand, antidepressant citalopram can ameliorate these changes. Further dynamic analysis of blood metabolomics revealed the occurrence and development trajectory of PSD, which mainly involved riboflavin metabolism, glutathione metabolism, and arginine biosynthesis in the incubative period; riboflavin metabolism, glycine, serine and threonine metabolism, and arginine biosynthesis in the prodromal period; and tryptophan metabolism, biosynthesis of unsaturated fatty acid, and purine metabolism in the symptomatic period. Moreover, the important differential metabolites between the stroke and PSD animals were identical to those identified in the clinic report, including palmitic acid, tyrosine, phenylalanine, azelaic acid, betaine, proline, stearic acid, linoleic acid, and oleic acid. This confirmed that the model can excellently characterize the physiopathology of clinical PSD.

This study clones the etiology of clinic PSD to provide a reliable model for elucidating the molecular pathogenesis of PSD, exploring drug targets, and objectively evaluating the preclinical efficacy of new interventions for PSD.