Neuroprotective effects of traditional Chinese medicine Naofucong on diabetic cognitive impairment: Mechanisms involving insulin-degrading enzyme-mediated degradation of Amyloid-β and inhibition of ERK/JNK/p38 MAPK signaling pathway

The increasing prevalence of diabetes and its related cognitive impairments is a significant public health concern. With limited clinical treatment options and an incomplete understanding of the underlying mechanisms, traditional Chinese medicine (TCM) Naofucong is proposed as a potential neuroprotective agent against diabetic cognitive impairment (DCI). This study aims to investigate the therapeutic mechanisms of Naofucong in DCI. We hypothesize that Naofucong may improve cognitive function in diabetic rats by modulating the extracellular regulated protein kinases (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinases (MAPK) signaling pathway, enhancing insulin-degrading enzyme (IDE) expression, reducing amyloid-beta (Aβ) deposition, decreasing phosphorylated Tau (p-Tau) levels, and alleviating oxidative stress. Diabetes was induced in specific-pathogen-free male Sprague-Dawley rats using streptozotocin, and the rats were treated with oral Naofucong for 12 weeks. We assessed cognitive function and measured neuronal damage, oxidative stress injury, and the expression levels of IDE, Aβ, amyloid precursor protein (APP), p-Tau, and components of the ERK/JNK/p38 MAPK pathway. Diabetic rats showed significant declines in cognitive function, neuronal damage, oxidative stress, low IDE expression, Aβ accumulation, high APP expression, abnormal Tau phosphorylation, and overactivation of the ERK/JNK/p38 MAPK pathway. Naofucong treatment significantly reversed these symptoms. Our findings suggest that Naofucong improves cognitive impairment in diabetic rats by inhibiting the ERK/JNK/p38 MAPK pathway, upregulating IDE, reducing Aβ deposition, suppressing APP and p-Tau expression, and alleviating neuronal damage and oxidative stress. This research provides a reference for the clinical prevention and treatment of DCI using TCM Naofucong.