Effects of liraglutide on astrocyte polarization and neuroinflammation in db/db mice: focus on iron overload and oxidative stress

Abstract

Neuroinflammation plays a crucial role in the occurrence and development of cognitive impairment in type 2 diabetes mellitus (T2DM), but the specific injury mechanism is not fully understood. Astrocyte polarization has attracted new attention and has been shown to be directly and indirectly involved in neuroinflammation. Liraglutide has been shown to have beneficial effects on neurons and astrocytes. However, the specific protection mechanism still needs to be clarified. In this study, we assessed the levels of neuroinflammation and A1/A2-responsive astrocytes in the hippocampus of db/db mice and examined their relationships with iron overload and oxidative stress. First, in db/db mice, liraglutide alleviated the disturbance of glucose and lipid metabolism, increased the postsynaptic density, regulated the expression of NeuN and BDNF, and partially restored impaired cognitive function. Second, liraglutide upregulated the expression of S100A10 and downregulated the expression of GFAP and C3, and decreased the secretion of IL-1β, IL-18, and TNF-α, which may confirm that it regulates the proliferation of reactive astrocytes and A1/A2 phenotypes polarize and attenuate neuroinflammation. In addition, liraglutide reduced iron deposition in the hippocampus by reducing the expression of TfR1 and DMT1 and increasing the expression of FPN1; at the same time, liraglutide by up-regulating the levels of SOD, GSH, and SOD2 expression, as well as downregulation of MDA levels and NOX2 and NOX4 expression to reduce oxidative stress and lipid peroxidation. The above may attenuate A1 astrocyte activation. This study preliminarily explored the effect of liraglutide on the activation of different astrocyte phenotypes and neuroinflammation in the hippocampus of a T2DM model and further revealed its intervention effect on cognitive impairment in diabetes. Focusing on the pathological consequences of astrocytes may have important implications for the treatment of diabetic cognitive impairment.

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

“… 28 Similar to neurons, hippocampal astrocytes in T2DM models have been found to exhibit iron hyperuptake and to be associated with astrocyte polarization. 29 This is an important finding, as iron transfer from the periphery into neurons is tightly regulated by astrocytes. 30 Additional evidence suggests that iron supplementation increases the activation of microglia in the hippocampus of T2DM rats, which also leads to exacerbation of existing neuroinflammation and exacerbates the risk of neurodegenerative diseases.…”

“… 19 , 25 A recent report showed increased co-expression of DMT1 with reactive astrocytes in the hippocampus of T2DM mice. 29 Considering that upregulation of DMT1 expression leads to iron accumulation, which further promotes astrocyte activation, 50 this may partly explain the structural and metabolic abnormalities of astrocytes induced by DM. 51 , 52 This seems to be a good understanding of why iron overload occurs.…”

Liraglutide ameliorates delirium-like behaviors of aged mice undergoing cardiac surgery by mitigating microglia activation via promoting mitophagy

“…1 A. The drug dosage and treatment cycle were determined based on previous studies (An et al 2023 ; Han et al 2019 ; Hulst et al 2020a , b ) and our preliminary study. Building on prior studies, we utilized a cardiac ischemia-reperfusion (IR) animal model to emulate cardiac surgery.…”

Quantitative susceptibility mapping for iron monitoring of multiple subcortical nuclei in type 2 diabetes mellitus: a systematic review and meta-analysis

“…Poor glycemic control can contribute to the development of oxidative stress and inflammation, both of which can disrupt iron balance in neurons and glia ( 64 , 65 ). Hyperglycemia, in particular, can enhance oxidative stress and inflammation and impair the blood–brain barrier, ultimately leading to excessive accumulation of iron in the brain ( 66 , 67 ).…”

“…Increased iron levels in these nuclei may be related to a higher prevalence of cognitive decline, dementia, and movement disorders in T2DM patients. The neurotoxic effects of iron can lead to degeneration, atrophy, and dysfunction of these structures ( 17 , 31 , 40 , 62 – 64 ).…”