Objective To investigate the effect and mechanism of matrine in improving diabetes-associated cognitive dysfunction (DACD) from activation of mouse bitter taste receptor member 4 (mTAS2R4).

Methods Male C57BL/6 mice were induced to establish the DACD model by intraperitoneal injection of streptozotocin (STZ) (50 mg/kg) for 5 consecutive days. The successfully modeled mice were divided into model group, low-dose matrine group (20 mg/kg), high-dose matrine group (40 mg/kg), and mTAS2R4 agonist quinine group (80 mg/kg), with 9 mice in each group. Additionally, another 9 mice of the same age were selected as normal control group. The Morris water maze and novel object recognition tests were used to evaluate the learning and memory functions in DACD mice. Hematoxylin-eosin (HE) staining was used to examine the pathological changes of the hippocampal neurons. Western blotting was performed to detect the protein expression of IKKβ/NF- κB signaling pathway-related proteins, NLRP3, Caspase-1, interleukin-1β (IL-1β), mTAS2R4, and phospholipase C β2 (PLCβ 2).

Results In the low-dose matrine, high-dose matrine and quinine groups, fasting blood glucose (FBG), body weight, and the learning and memory functions of mice were all improved (all P < 0.01). Compared with the normal group, the number of hippocampal neurons in CA1 and CA3 regions of mice in the model group was decreased, and the ratios of p-IKKβ/IKKβ and p-NF-κB p65/NF-κB p65, as well as the protein expression levels of NLRP3, Caspase-1, and IL-1β, were all increased, while the protein expression levels of mTAS2R4 and PLCβ2 were decreased (all P < 0.01). Compared with the model group, the number of hippocampal neurons in the lowdose matrine, high-dose matrine, and quinine groups was increased and the ratios of p-IKKβ/IKKβ and p-NF-κB p65/NF-κB p65, as well as the protein expression levels of NLRP3, Caspase-1, and IL-1β, were decreased (all P < 0.05). In the high-dose matrine group, the protein expression levels of mTAS2R4 and PLCβ2 were both increased (all P < 0.01). In the low-dose matrine group, the protein expression of PLCβ2 was upregulated (P < 0.05).

Conclusion Matrine can activate the mTAS2R4 receptor signaling in the brain and inhibit neuroinflammatory responses, thereby improving cognitive dysfunction in DACD mice.