Aims
To evaluate the effects of Jiawei Kongsheng Zhenzhong Pill (JKZP) on rats with ischemic mild cognitive impairment (MCI) and investigate the underlying mechanisms.
Conclusions
These results manifested that JKZP promoted neurological recovery after chronic cerebral ischemia by alleviating synaptic damage and activating the S100A10/tPA/BDNF pathway, thereby providing a novel perspective and a solid foundation against MCI.
Methods
The components of JKZP were analyzed using Q-Orbitrap high-resolution mass spectrometry (HRMS). The MCI rat model was prepared through gradual bilateral common carotid artery occlusion (BCCAO). The cognitive function, hippocampal pathological lesions, dendritic spine damage, synapse-related, and S100 calcium-binding protein A10 (S100A10)/tissue-type plasminogen activator (tPA)/brain-derived neurotrophic factor (BDNF) pathway-associated molecules alterations were measured. Primary hippocampus neurons were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) injury, and JKZP-containing serum was utilized for treatment. Lentiviral-infected neurons were constructed with S100A10 knockdown using RNAi technology to investigate whether JKZP exerted its anti-MCI effects via S100A10/tPA/BDNF pathway.
Results
A total of 64 major components, including β-asarone, ferulic acid, loganin, senkyunolide H, and cryptotanshinone, were identified by Q-Orbitrap HRMS technology. JKZP had a notable impact on enhancing the cognitive abilities of rats with MCI. JKZP reduced the damage to the hippocampal CA1 region neuron and synaptic structure, reversed the decrease in dendritic spines, and increased the expressions of synapse-associated proteins such as synaptophysin (SYN), growth-associated protein 43 (GAP43), and postsynaptic density protein 95 (PSD95). Furthermore, JKZP treatment dramatically reduced the ratio of protein of BDNF (proBDNF)/mature BDNF (mBDNF) by activating S100A10/tPA, which was confirmed in primary hippocampus neurons in vitro. Moreover, sh-S100A10 tremendously mitigated the inhibitory action of JKZP on OGD/R-mediated synapse injury, decreased the activity of tPA, and thus improved the downstream pathway targets' ratio, proBDNF/mBDNF. Conclusions: These results manifested that JKZP promoted neurological recovery after chronic cerebral ischemia by alleviating synaptic damage and activating the S100A10/tPA/BDNF pathway, thereby providing a novel perspective and a solid foundation against MCI.