Schisandrin A ameliorates the diabetes-associated memory impairment by alleviating inflammation and ferroptosis

Abstract

Schisandrin A (SchA), a bioactive lignan that was isolated from the dried fruit of Schisandra chinensis, has attracted much attention because of its diverse spectrum of pharmacological effects. The aim of this study is to clarify the function of SchA in diabetes-related fear memory impairment and its molecular mechanisms. Rats are randomly assigned to 4 groups: the control group (Con group), the DM group, the DM + SchA group, and the Con + SchA group. The results demonstrate that SchA treatment improves insulin sensitivity, reduces blood glucose, and significantly reduces memory impairment. SchA treatment also prevents histological damage, enhances synaptic protein production, and significantly decreases Aβ42 formation in the diabetic prefrontal cortex. Further research reveals that SchA therapy decreases microglial activation and the expression levels of variables linked to inflammation while increasing the phosphorylation of proteins implicated in the insulin resistance signaling pathway. Furthermore, in the prefrontal cortex of diabetic rats, SchA decreases ferroptosis by increasing the protein expressions of GPX4, SLC7A11, Nrf2, HO-1, and SIRT1. Overall, our findings suggest that SchA may lessen diabetes-associated fear memory impairment symptoms by, most likely, lowering ferroptosis and inflammatory responses in the prefrontal brain of diabetic rats. SchA may be a useful therapy for diabetes, including memory impairment.

1. Introduction

Insulin resistance and cell malfunction are the major pathogenic abnormalities in diabetes mellitus (DM), a disease characterized by metabolic and endocrine dysfunction [1]. Because this condition is becoming more common, 783 million individuals worldwide are expected to have diabetes by 2045 [2]. Epidemiological research indicates that individuals with diabetes, particularly those with type 2 diabetes (T2DM), are 20% to 60% more likely to experience cognitive dysfunctions [3]. Furthermore, diabetes mellitus and dementia rank among the top 10 causes of mortality worldwide, according to the World Health Organization [4]. The absence of a clear pathophysiology and etiology for diabetes-associated cognitive impairment results in several limitations in the therapeutic management of the disorder. Thus, the development of preventive interventions that can prevent the progression of diabetes-associated cognitive impairment is urgently needed.

An essential part of the brain that coordinates the activities of other cortical areas and functions as a continuous supervisory information system needed for everyday tasks is the medial prefrontal cortex (mPFC) [5,6]. A recent study revealed that memory-related neural circuits in the mPFC were disrupted in individuals with T2DM and prefrontal atrophy [7]. A compelling long-term neuropsychological study indicated that those with prefrontal injuries have greater cognitive impairment [8]. In several studies, acute hyperglycemia has been shown to impact memory in individuals with T2DM [9]. The streptozotocin (STZ)-induced diabetic rat model exhibits cognitive impairment and changes in the plasticity, neurotransmission, and structure of medial prefrontal cortical interneurons [10,11]. Abnormal changes in the insulin signaling system in individuals with T2DM may lead to a reduction in the structure or function of neurons, which can further impact information output, transmitter release, and nerve impulse conduction [12]. Therefore, the mechanism behind diabetes-related mPFC neuronopathy is currently being studied.

Ferroptosis, a recently described type of regulated cell death resulted from iron-dependent lipid peroxidation and cellular metabolism [13], has been connected to several degenerative diseases, such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) [14]. Ferroptosis is regulated by iron metabolism [15], the nuclear factor E2 related factor 2 (Nrf2) pathway [16], lipid synthesis [17], glutathione peroxidase 4 (GPX4) (system Xc-) [18], and other factors [19,20], according to previous studies. Similarly, research has indicated a clear link between ferroptosis and symptoms of diabetes mellitus. Although iron accumulation in the brain is known to be linked to the cognitive impairment caused by diabetes [21], the precise mechanism is yet unknown. The pancreata of diabetic rats exhibit ferroptosis, with increased iron concentrations and decreased expressions of Nrf2, GPX4, and SLC7A11 [22]. Additionally, research has demonstrated a negative correlation between insulin sensitivity and blood ferritin concentration [