Total paeony glycoside relieves neuroinflammation to exert antidepressant effect via the interplay between NLRP3 inflammasome, pyroptosis and autophagy.

BACKGROUND: Depression is a common mental illness characterised by abnormal and depressed emotions. Total paeony glycoside (TPG) is a naturally active saponin extracted from the traditional Chinese medicine Radix Paeoniae rubra. However, the antidepressant and neuroinflammatory effects of TPG have not been thoroughly studied. PURPOSE: To study the therapeutic potential of TGP in depression caused by neuronal injury and neuroinflammation and to explore the mechanism of TGP and the relationship between the NLRP3 inflammasome, pyroptosis, and autophagy. STUDY DESIGN: A chronic unpredictable mild stress (CUMS)-induced depression model and a cell model of corticosterone (CORT)-induced hippocampal neuron injury were established to evaluate the therapeutic effects of TPG. METHODS: The composition of TPG was analysed using high-performance liquid chromatography and mass spectrometry. The effects of TPG and fluoxetine on depression-like behaviour, neuronal injury, neuroinflammation, pyroptosis, and mitochondrial autophagy in the mice models were evaluated. RESULTS: TGP alleviated depression-like behaviours in mice and inhibited hippocampal neuronal apoptosis. The secretion of inflammatory cytokines was significantly reduced in CORT-induced hippocampal neuron cells and in the serum of a mouse model of CUMS-induced depression. In addition, TGP treatment reduced the levels of NLRP3 family pyrin structural domains, including NLRP3, pro-caspase-1, caspase-1, and IL-1ß, and the pyroptosis related proteins such as GSDMD-N. Importantly, TPG attenuated mitochondrial dysfunction, promoted the clearance of damaged mitochondria, and the activation of mitochondrial autophagy, which reduced ROS accumulation and NLRP3 inflammasome activation. An in-depth study observed that the regulatory effect of TPG on autophagy was attenuated by the autophagy inhibitor 3-methyladenine (3-MA) in vitro and in vivo. However, administration of the caspase-1 inhibitor Belnacasan (VX-765) successfully inhibited pyroptosis and showed a synergistic therapeutic effect with TPG. CONCLUSION: These results indicate that TPG can repair neuronal damage by activating autophagy, restoring mitochondrial function, and reducing inflammation-mediated pyroptosis, thereby playing an important role in the alleviation of neuroinflammation and depression. This study suggests new potential drugs and treatment strategies for neuroinflammation-related diseases and depression.

Effects of the total paeony glycoside on the focal cerebral ischemia in rats / 中成药

AIM: To investigate the protective effects of the total paeony glycoside(TPG) on the focal cerebral ischemia and regional cerebral blood flow(rCBF) in rats. METHOD: The rat model of focal cerebral ischemia was made by middle cerebral artery occlusion(MCAO) with nylon suture.TPG was injected into every group rats once a day before 48 h,and injected before MCAO 30 min and after 4 h,12 h.After 24 h the effects of the drug were studied about neurological deficit,the water content of brain tissue,the cerebral infarcted zone,under microscopic examination,as well as rCBF on each rat with laser Doppler fiowmeter(LDF). RESULTS: The sympton of brain ischemia was obvious in model rats by contrast to the sham rats,and the model rats rCBF decreased markedly after MCAO.50 mg/kg and 100 mg/kg TPG injection could obviously promote neurological deficit,decrease the water content of brain tissue and the cerebral infarcted zone.And the pathological slices also proved its protective effect on neuron.The laser Doppler flowmeter detected result indicated that 100 mg/kg TPG inject could greatly increase MCAO rats rCBF. CONCLUSIONS: TPG injection has a marked prospective activity on rat focal brain ischemia in rats,and the increase of rCBF may be one of the protection mechanism.