Cognitive protection of sinomenine in type 2 diabetes mellitus through regulating the EGF/Nrf2/HO‐1 signaling, the microbiota‐gut‐brain axis, and hippocampal neuron ferroptosis

Abstract

Recent years have witnessed a growing research interest in traditional Chinese medicine as a neuroprotective nutrient in the management of diabetic cognitive dysfunction. However, the underlying molecular mechanisms of sinomenine in mediating ferroptosis of hippocampal neurons have been poorly understood. This study sought to decipher the potential effect and molecular mechanism of sinomenine in the cognitive dysfunction following type 2 diabetes mellitus (T2DM). Multi-omics analysis was conducted to identify the microbiota-gut-brain axis in T2DM patient samples obtained from the publicly available database. In HT-22 cells, erastin was utilized to create a ferroptosis model, and streptozotocin was injected intraperitoneally to create a rat model of DM. It was noted that intestinal flora imbalance occurred in patients with T2DM-associated cognitive dysfunction. Sinomenine could reduce Erastin-induced hippocampus neuronal ferroptosis by increasing EGF expression.EGF protected hippocampal neurons against ferroptosis by activating the Nrf2/HO-1 signaling pathway. Furthermore, in vivo results confirmed that sinomenine blocked ferroptosis of hippocampal neurons and alleviated cognitive dysfunction in T2DM rats. Collectively, these results suggest that sinomenine confers neuroprotective effects by curtailing hippocampal neuron ferroptosis via the EGF/Nrf2/HO-1 signaling and microbiota-gut-brain axis. It may be a candidate for the treatment of diabetic cognitive dysfunction.

A mechanism linking ferroptosis and ferritinophagy in melatonin-related improvement of diabetic brain injury

“…Moreover, we observed that the expression of other putative biomarkers of ferroptosis, such as MDA and SOD, significantly changed both in vivo and in vitro , and these changes were similar to those observed in previous studies. 32 , 33 , 34 As expected, melatonin administration markedly reversed these ferroptosis-related changes and significantly attenuated neuronal damage in vivo and in vitro . Importantly, we observed that pretreatment with Erastin, an inducer of ferroptosis, abolished the function of melatonin on neuronal ferroptosis.…”

The Role of Iron Overload in Diabetic Cognitive Impairment: A Review

“… 25 It has also been reported that epidermal growth factor/Nrf2/heme oxygenase-1 signaling and the microbiota-gut-brain axis regulate ferroptosis in T2DM hippocampal neurons. 124 Ferroptosis of BMVECs in T2DM should also be taken seriously, as this may exacerbate BBB disruption and cognitive impairment after diabetic stroke, 47 possibly related to the p53/GPX4 axis. 125 Overall, iron overload plays an important role as well as ferroptosis, especially in the context of DM-induced cognitive decline, 89 and onset of iron overload may be the main driver of ferroptosis.…”

High‐dose sinomenine attenuates ischemia/reperfusion‐induced hepatic inflammation and oxidative stress in rats with diabetes mellitus

“… 34 SIN also exerts neuroprotective effects by curtailing hippocampal neuron ferroptosis and could be a potential candidate for preventing diabetic cognitive dysfunction. 16 Additionally, SIN suppresses microglial activation and the release of inflammatory mediators, easing the pain associated with diabetic peripheral neuropathy. 14 …”

“… 13 SIN alleviates diabetic peripheral neuropathic pain, 14 , 15 and confers cognitive protection by curtailing hippocampal neuron ferroptosis. 16 Moreover, SIN has been found to play significant protective roles against I/R‐induced multiple organ injuries, including the liver, 17 brain, 18 heart, 19 and kidney. 20 However, whether SIN also exerts protective effects in diabetic rats with hepatic I/R injury has never been explored.…”