Exploring the Effects and Mechanisms of Zuogui Jiangtang Jieyu Formula on Hippocampal Synaptic Plasticity in a Rat Model of Diabetes Mellitus Complicated with Depression Based on the Hippocampal Microglial P2X7/NLRP3 Signaling Pathway

OBJECTIVE To explore the related mechanisms of Zuogui Jiangtang Jieyu formula in ameliorating neuroinflammation and enhancing neuroprotective effects in model rats with diabetes mellitus complicated with depression(DD) based on the P2X purinoceptor 7(P2X7)/nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3) axis.

METHODS A DD rat model was established by feeding high-fat diet for 4 weeks combined with intraperitoneal injection of streptozotocin(STZ), followed by 4-week chronic unpredictable mild stress combined with single-housing. The rats were divided into normal group, model group, positive drug group(metformin 0.18 g·kg⁻¹+fluoxetine 1.8 mg·kg⁻¹), low-, medium-, and high-dose groups of Zuogui Jiangtang Jieyu formula, as well as medium-dose Zuogui Jiangtang Jieyu formula+P2X7 receptor specific antagonist(brilliant blue G, BBG) group. The open field experiment, forced swimming experiment, and Morris water maze were used to detect depression like behavior and memory cognitive function in rats; ELISA was used to detect the levels of norepinephrine(NE), 5-hydroxytryptamine(5-HT), and dopamine(DA) in serum; immunofluorescence detection of hippocampal P2X7/Iba-1, NLRP3/Iba-1, postsynaptic density protein-95(PSD95), and synapsin-1(SYN1); hematoxylin eosin(HE) staining and Nissl staining were used to detect hippocampal neuronal damage; Western blotting was used to detect the expression levels of proteins related to the P2X7/NLRP3 axis, including P2X7, NLRP3, apoptosis-associated spot-like protein(ASC), Caspase-1, interleukin-1β(IL-1β) and brain-derived neurotrophic factor(BDNF).

RESULTS Compared with the model group, Zuogui Jiangtang Jieyu formula could improve depressive behaviors and enhance neuroprotective effects in DD rats; it significantly upregulated the expression levels of PSD95, SYN1, and BDNF(P<0.05 or P<0.01), and decreased the expression levels of P2X7/Iba-1, NLRP3/Iba-1, ASC, Caspase-1, and IL-1β(P<0.05 or P<0.01).

CONCLUSION Zuogui Jiangtang Jieyu formula may alleviate neuroinflammation by inhibiting the P2X7/NLRP3 pathway, thereby upregulating the expression of PSD95/SYN1/BDNF and exerting neuroprotective effects.