Dalteparin as a Novel Therapeutic Agent to Prevent Diabetic Encephalopathy by Targeting Oxidative Stress and Inflammation

Abstract

Introduction: Hepcidin is the main modulator of systemic iron metabolism, and its role in the brain has been clarified recently. Studies have shown that hepcidin plays an important role in neuronal iron load and inflammation. This issue is of significance because neuronal iron load and inflammation are pathophysiological processes that are highly linked to neurodegeneration. Moreover, the activity of hepcidin has recently been manipulated to recover the neuronal impairment caused by brain inflammation in animal models. Methods: Streptozotocin (STZ) was used to induce type 1 diabetes. Male Wistar rats (n = 40) with a weight range of 200–250 g were divided into control, diabetic, diabetic + insulin, and diabetic + dalteparin groups. Dalteparin (100 mg/kg IP) and insulin (100 mg/kg SC) were administered for 8 weeks. At the end of the experiment, Y-maze and passive avoidance tasks were carried out. The animals were perfused randomly and their hippocampal tissue was isolated for the analysis of markers such as lipid peroxidation like Malondialdehyde (MDA), hepcidin expression, iron, and ferritin. Blood samples were taken for the measurement of serum inflammatory cytokine Interleukin (IL)-6. Results: The findings indicated that treatment with dalteparin reduced IL-6, MDA, ferritin, and hepcidin expression in diabetic rats compared to treatment with insulin (P<0.05). Moreover, treatment with dalteparin did not decrease the iron level or prevented its decline. Conclusion: Treatment with dalteparin improved the cognitive dysfunctions and symptoms of Alzheimer disease in STZ-induced diabetic rats by appropriately modulating and reducing oxidative stress and neuroinflammation. This may enhance the existing knowledge of therapeutics to reduce cognitive impairment in diabetes and is suggested to be a potential therapeutic agent in diabetes.

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

“…Interestingly, the level of ferritin was significantly increased in the hippocampus of T1DM rats, without distinguishing between FTL and TFH. 62 This seems to indicate differential regulation of ferritin in different types of DM brains, which requires further investigation of the specific mechanisms.…”

“… 72 , 73 This may be due to the characteristics of different diabetic patients and the complex regulatory factors of hepcidin, but may the same be true of hepcidin levels in the brain? 62 More experimental and clinical studies are needed to confirm or refute the specific role of hepcidin in DM.…”

“… 98 In T1DM, iron deposition in the brain is mainly caused by inflammation-induced BBB and damage, 99 and neuronal iron deposition is also strongly associated with inflammation. 62 In fact, inflammation and iron overload are like a chicken-and-egg relationship. In other words, neuroinflammation in DM does not necessarily occur earlier than brain iron overload, because it has been reported that deferoxamine can target neuroinflammation to alleviate DCI.…”

Pathophysiological Role of Microglial Activation Induced by Blood-Borne Proteins in Alzheimer’s Disease

“…In addition, enoxaparin was found to prevent the formation of ApoE4-Aβ complexes by binding to them [170]. In another study, dalteparin, a low molecular weight heparin, was found to reduce oxidative stress and inhibit the inflammatory response in the hippocampus of the streptozotocin-induced model, leading to an improvement in cognitive impairment [171]. Heparin is an anticoagulant that is primarily administered as an intravenous or subcutaneous injection to treat thrombotic disorders such as acute myocardial infarction and pulmonary embolism [163][164][165][166][167][168][169][170].…”

“…In addition, enoxaparin was found to prevent the formation of ApoE4-Aβ complexes by binding to them [170]. In another study, dalteparin, a low molecular weight heparin, was found to reduce oxidative stress and inhibit the inflammatory response in the hippocampus of the streptozotocin-induced model, leading to an improvement in cognitive impairment [171].…”