Ipsilateral Hippocampal Proteomics Reveals Mitochondrial Antioxidative Stress Impairment in Cortical-Lesioned Chronic Mild Stressed Rats

In this study, a two-dimensional gel-based proteomic approach was applied to profile the protein alterations underlying the significant adverse effects from post-stroke depression (PSD). In view of the close association between left prefrontal cortical dysfunction and PSD, a PSD rat model was constructed through a left anterior cortical lesion followed by chronic mild stress (CMS) for three weeks. Through sucrose preference testing, PSD rats displayed depression-like behavior during the entire CMS period. In contrast, stroke rats displayed depression-like behavior in the first week post-stroke and recovered in the second week post-stroke. To investigate the PSD-induced protein expression changes, ipsilateral hippocampal protein expression in stroke, PSD, and control rats were comparatively analyzed. 46 differential proteins were identified, 22 of which were regulated in opposing directions by stroke and post-stroke stress. The majority of these 22 proteins were involved in neurogenesis, cytoskeletal remodeling, and energy metabolism. Additional proteins were functionally related to mitochondrial antioxidative stress systems. The differential proteins expressed in opposing directions by stroke and post-stroke stress may play a role in self-repair after adult brain lesions, suggesting that stroke induces self-repair mechanisms, while post-stoke stress mitigates them, in the rat hippocampus. Among these differential proteins dysregulated in opposing directions, three mitochondrial proteins involved in mitochondrial antioxidative stress – heat shock 70 kDa protein 9, peroxiredoxin-6, and prohibitin – were validated and may play an important role in stroke-injury self-repair and PSD-induced injury of hippocampal neurons. These findings offer new insight into deciphering the molecular mechanisms underpinning PSD's adverse effects on stroke recovery.