Diabetes is a systemic disease that causes structural and functional alterations in various tissues and organs. Central nervous system symptoms such as memory loss and cognitive dysfunction are major complications of diabetes[15]. GLCCI1 plays many roles in asthma, glaucoma and rheumatoid arthritis and mediates neuronal alterations, autophagy and proliferation[12, 16, 17]. However, the relationship between GLCCI1 and DCD has not been determined. In the present study, we found that hippocampal GLCCI1 expression was decreased in mice with DCD. However, GLCCI1 upregulation attenuated DCD, and SAL had therapeutic effects on DCD and increased hippocampal GLCCI1 expression. Therefore, we deduced that GLCCI1 contributes to the development of DCD and is involved in the therapeutic effect of SAL on DCD.
GLCCI1 is expressed in both lung tissues and immune cells. Chapman et al. initially characterized the role of GLCCI1 in glucocorticoid signal transduction and identified a gene polymorphism in GLCCI1 in a thymus-derived cell line [18]. They also observed significant upregulation of GLCCI1 gene expression in cells stimulated with dexamethasone, a long-acting glucocorticoid. GLCCI1 is closely related to the onset and treatment of asthma, the development of the kidney, the differentiation of renal cells, susceptibility to glaucoma, and therapeutic responsiveness in patients with rheumatoid arthritis. Qiufen Xun et al. reported that during the occurrence and development of asthma, GLCCI1 inhibited autophagy and promoted airway remodelling by inhibiting WDR45 expression, thus alleviating asthma[19]. Qiufen Xun et al reported that GLCCI1 inhibits airway remodelling and ameliorates asthma by inhibiting the IL-13/periostin/TGF-β1 pathway[16]. Yukino Nishibori et al reported that GLCCI1 is highly expressed specifically in glomerular cells. Knockout of GLCCI1 in zebrafish leads to glomerular shrinkage, disappearance of podocyte foot processes, the development of proteinuria, suggesting that GLCCI1 can promote glomerular development and maintain the function of kidney podocytes[20]. These findings suggest that GLCCI1 may play an important role in diabetes. In this study, we evaluated the expression both of the neuronal markers Neun and GLCCI1. These results demonstrated the colocalization of these two proteins, suggesting that GLCCI1 may exert regulatory effects on neurons. Furthermore, the expression of GLCCI1 in the hippocampus of diabetic mice was significantly decreased. Nissl staining revealed significant changes in the number of neurons in diabetic mice, which was consistent with the results of other studies.
We found that GLCCI1 regulates diabetic cognitive dysfunction through STAT3. STAT3 is a critical regulator of neuronal processes essential for learning and memory, including neuronal survival, synaptic plasticity, and neurotransmitter release[21, 22]. Extensive studies have demonstrated that STAT3 plays a pivotal role in synapse formation and synaptic strengthening, thereby influencing the transmission of information between neurons and ultimately impacting learning and memory. Furthermore, STAT3 is involved in the regulation of neuronal alterations—a fundamental physiological process in the nervous system that can be dysregulated in certain neurological disorders. Activation of STAT3 has been shown to promote neuronal survival and inhibit neuronal alterations, highlighting its potential significance in nervous system repair and protection, particularly in the context of neurodegenerative diseases. Notably, Jang-Hyuk Yun reported that diabetes mellitus-induced activation of microglial STAT3 exacerbates alterations in hippocampal neurons[23]. Additionally, Ting-Fa Zhou’s research indicated that the JAK2/STAT3 signalling pathway is involved in the protective effect of recombinant human erythropoietin against neuronal alterations and cognitive deficits in experimental endotoxaemia[24]. Furthermore, Qian Jiang’s study implicated Stat3-induced activation of NLRP3/Caspase-1-mediated neuronal pyroptosis in epilepsy development in mice[25].
Rhodiola rosea extract is a natural herbal ingredient extracted from the Rhodiola rosea plant that has garnered interest for its potential neuroprotective and cognition-enhancing effects[26, 27]. Preliminary experiments suggest that salidroside may contribute to improvements in cognitive function, including memory, attention, and thinking skills. However, these studies are often limited by small sample sizes, and additional large-scale studies are necessary to validate these effects. Salidroside is thought to have an anti-fatigue effect and can increase the body's tolerance to stress[28]. This may lead to better performance in learning and memory tasks. Salidroside is believed to have antioxidant effects, protecting nerve cells from damage caused by oxidative stress, and is essential for maintaining a healthy nervous system and good cognitive function. Hualong Wang reported that salidroside has neuroprotective effects in a mouse model of Alzheimer's disease[29]. Similarly, Z Tian reported that salidroside can improve cognitive ability in rats with experimental vascular dementia[30]. Our results showed that SAL could improve cognitive dysfunction in diabetic mice by upregulating GLCCI1 expression.
In summary, our findings demonstrated that GLCCI1 exerts a protective effect against DCD and that SAL has therapeutic effects on DCD. The results revealed that SAL administration reduced blood glucose levels in diabetic rats by upregulating GLCCI1 and suppressing p-STAT3 expression. It ameliorated cognitive impairment, reduced hippocampal neuronal damage, downregulated proapoptotic protein expression, and upregulated antiapoptotic protein expression, thereby ameliorating DCD. Both SAL and GLCCI1 overexpression effectively reduced hippocampal neuron damage and significantly alleviated neuronal alterations in the hippocampus of diabetic mice. These results highlight the potential therapeutic value of SAL and targeting the GLCCI1 pathway in preventing or treating DCD. By understanding the mechanisms by which SAL and GLCC11 protect against neuronal damage, we can further identify strategies to improve cognitive function in individuals with diabetes.