Physical and social environmental enrichment alleviate ferroptosis and inflammation with inhibition of TLR4/MyD88/p38MAPK pathway in chronic cerebral hypoperfusion rats

A typical enriched environment (EE), which combines physical activity and social interaction, has been proven to mitigate cognitive impairment caused by chronic cerebral hypoperfusion (CCH). However, it remains unclear how the different components of EE promote cognitive recovery after CCH. This study stripped out the different components of EE into physical environmental enrichment (PE) and social environmental enrichment (SE), and compared the neuroprotective effects of PE, SE and typical EE (PSE) in CCH. The results of novel object recognition and Morris water maze tests showed that PE, SE, and PSE improved cognitive function in CCH rats. Additionally, Nissl and TUNEL staining revealed that three EEs reduced neuronal loss in the hippocampus. PSE exhibited superior neuroprotective and functional improvement effects compared to PE and SE, while there was no significant difference between PE and SE. Furthermore, three EEs reduced lipid peroxidation in the hippocampus with decreasing the levels of MDA and increasing the activities of SOD and GSH. The expression of SLC7A11 and GPX4 was increased, while the level of p53 was reduced in three EEs. This suggested that three EEs inhibited ferroptosis by maintaining the redox homeostasis in the hippocampus. Three EEs reduced the levels of IL-β, TNF-α, and IL-6, thereby inhibiting neuroinflammation. Additionally, Western blotting and immunofluorescence results indicated that three EEs also inhibited the TLR4/MyD88/p38MAPK signaling pathway. These findings collectively demonstrated that the three EEs alleviated hippocampal ferroptosis and neuroinflammation in CCH rats, thereby reducing neuronal loss, which might be associated with the inhibition of the TLR4/MyD88/p38MAPK signaling pathway. Moreover, the study results supported that it is only through the combination of physical exercise and social interaction that the optimal neuroprotective effects can be achieved. These findings provided valuable insights for the prevention and treatment of vascular cognitive impairment

Effect of Tetramethylpyrazine on Neuroplasticity after Transient Focal Cerebral Ischemia Reperfusion in Rats

Tetramethylpyrazine (TMP) has been widely used in ischemic stroke in China. The regulation of neuroplasticity may underlie the recovery of some neurological functions in ischemic stroke. Middle cerebral artery occlusion (MCAO) model was established in this study. Rats were divided into three groups: sham group, model group, and TMP group. The neurological function was evaluated using modified neurological severity score (mNSS). Following the neurological function test, expression of synaptophysin (SYP) and growth-associated protein 43 (GAP-43) were analyzed through immunohistochemistry at 3 d, 7 d, 14 d, and 28 d after MCAO. Finally, the synaptic structural plasticity was investigated using transmission electron microscopy (TEM). The TMP group showed better neurological function comparing to the model group. SYP levels increased gradually in ischemic penumbra (IP) in the model group and could be enhanced by TMP treatment at 7 d, 14 d, and 28 d, whereas GAP-43 levels increased from 3 d to 7 d and thereafter decreased gradually from 14 d to 28 d in the model group, which showed no significant improvement in the TMP group. The results of TEM showed a flatter synaptic interface, a thinner postsynaptic density (PSD), and a wider synaptic cleft in the model group, and the first two alterations could be ameliorated by TMP. Then, a Pearson’s correlation test revealed mNSS markedly correlated with SYP and synaptic ultrastructures. Taken together, TMP is capable of promoting functional outcome after ischemic stroke, and the mechanisms may be partially associated with regulation of neuroplasticity