Full
Outline
To investigate the mechanism of the P2X purinoceptor 7 (P2X7)-NOD like receptor family pyrin domain containing 3 (NLRP3) pathway in diabetes mellitus with depression (DD).
Sixty Sprague Dawley (SD) rats were randomly divided into six groups (n=10 per group): control (Con), diabetes mellitus (DM), depression (Dep), diabetes mellitus with depression (DD), positive drug [metformin (0.18 g·kg-1)+fluoxetine (1.8 mg·kg-1)] (Y), and P2X7 inhibitor [Brilliant Blue G (BBG), 30 mg·kg-1]. DD rat models were established using 4 weeks of high-fat diet feeding combined with intraperitoneal streptozotocin (STZ) injection, followed by 4 weeks of chronic unpredictable mild stress (CUMS) combined with single caging. Rats in the inhibitor group received daily intraperitoneal injections starting from day 15 of modeling for 14 consecutive days. After modeling and drug intervention, behavioral tests (open field test, forced swim test, Morris water maze) were used to assess depression-like behaviors and cognitive function. Serum levels of norepinephrine (NE), 5-hydroxytryptamine (5-HT), and dopamine (DA) were measured by enzyme-linked immunosorbent assay (ELISA). Immunofluorescence was performed to detect hippocampal P2X7/Iba-1, NLRP3/Iba-1, postsynaptic density protein-95 (PSD95), and synapsin-1 (SYN1). Hippocampal neuronal damage was assessed using hematoxylin-eosin (HE) and Nissl staining. Western blotting was used to measure the expression of P2X7-NLRP3 axis-related proteins (P2X7, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, interleukin-1β (IL-1β) and brain-derived neurotrophic factor (BDNF).
Both BBG and the positive drug effectively attenuated the loss of body weight and elevated fasting blood glucose in DD rats. Behavioral results showed that BBG and the positive drug reduced immobility time in the forced swim test, increased total distance traveled and total activity in the open field test, shortened escape latency, and increased the time spent in the target quadrant in the Morris water maze. Pathological results demonstrated that BBG and the positive drug ameliorated neuronal damage in the hippocampal region of DD rats. Biochemical analysis results indicated that BBG and the positive drug upregulated serum levels of 5-HT, DA, and NE. Immunofluorescence and Western blot results showed that BBG could reduce the expression of P2X7 and NLRP3 in the hippocampus, while increasing the expression of PSD-95, SYN-1, and BDNF.
BBG exerts neuroprotective effects by inhibiting the P2X7/NLRP3 axis and hippocampal microglial activation, thereby ameliorating neuroinflammation and abnormal NLRP3 inflammasome activation. This leads to increased expression of synaptic-related proteins (PSD95, SYN) and BDNF in the hippocampus.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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