Deferoxamine has the Potential to Improve the COVID-19-Related Inflammatory Response in Diabetic Patients.

The clinical state of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been considered a pandemic disease (COVID-19) that is rapidly spreading worldwide. Despite all global efforts, the only treatment for COVID-19 is supportive care and there has been no efficient treatment to fight this plague. It is confirmed that patients with chronic diseases such as cardiovascular disorder and diabetes; are more vulnerable to COVID-19. In the severe type of COVID-19, laboratory findings showed a remarkably enhanced C-reactive protein, IL-6 serum, Iron, and ferritin, which suggest an inflammatory response. Inflammation results in iron homeostasis imbalance and causes iron overload, exacerbating the SARSCOV2 infection. More importantly, recent studies have established that SARS-CoV-2 needs iron for viral replication and also activation. As a result, managing iron overload in diabetic patients with COVID-19 could be an early therapeutic approach to limit the lethal inflammatory response of COVID-19. In this review, Deferoxamine (DFO) has been proposed as an effective iron chelator agent.

The beneficial role of Hepcidin peptide inhibitor in improved the symptoms of COVID-19 in diabetics: anti-inflammatory and potential therapeutic effects.

Coronavirus Disease 2019 (COVID-19) is a recent public health issue worldwide. Also, diabetes is a frequent condition with high mortality. There is a strong relationship between COVID-19 and diabetes. This article analyses the intricate relationship between COVID-19 and hepcidin. Hepcidin increases in aged non-insulin diabetic patients. Hepcidin is the last target treatment of several medications commonly used. Viral diseases, especially SARS-CoV19, can activate the hepcidin pathway leading to an elevation in the iron load. This increased iron is released into the bloodstream and results in cell death through ferroptosis, like free iron. Excess iron has pro-coagulative and toxic effects. Hepcidin overexpression and iron overload are associated with COVID-19 infection and can be considered potential targets for treatment. Several studies have shown dalteparin (anti-Hepcidin) could improve the symptoms of COVID-19 in diabetics by appropriately modulating and decreasing oxidative stress and inflammation. This finding can be leading to enhancing the existing knowledge about Therapeutic measures for reducing Covid-19 impairments in diabetics and is suggested as a possible therapeutic agent in diabetes.

Hepatocyte Growth Factor Attenuates the Severity of Status Epilepticus in Kainic Acid-induced Model of Temporal Lobe Epilepsy by Targeting Apoptosis and Astrogliosis.

Introduction: Although pharmacotherapy is the most common treatment for epilepsy, proper seizure control is not achieved with current medications. This study evaluated the protective effects of the Hepatocyte Growth Factor (HGF) in a rat model of Temporal Lobe Epilepsy (TLE) and explored possible molecular mechanisms. Methods: A TLE rat model was determined using an intra-hippocampal kainic acid injection (4 µg). Intra-cerebrovascular injection of HGF (6 µg) was performed 30 min before kainic acid injection. Learning and memory impairment were investigated by behavioral tests. The Enzyme-Linked Immunosorbent (ELISA) was used to determine astrogliosis and DNA fragmentation. Changes in neuronal density and mossy fiber sprouting were evaluated by Nissl and Timm staining, respectively. Results: Behavioral assessments indicated that kainate-treated rats presented spontaneous seizures. Moreover, their alternation percentage scores in the Y-Maze test were lower (P<0.001). Likewise, the passive avoidance test confirmed learning disability in Kainate-treated rats (P<0.001). HGF administration reduced the number of spontaneous seizures, alternation percentage score (P<0.001), and cognitive disturbances (P<0.001). The histopathological results also showed that a protected HGF administration contributed to the reduction of neuronal loss in the CA3 subregion of the hippocampus and inhibited the formation of aberrant Mossy Fiber Sprouting (MFS) (P<0.01). Furthermore, the ELISA data indicated a significant decrease in GFAP (P<0.01) and DNA fragmentation (P<0.05) following HGF administration. Conclusion: Our findings demonstrated the validity of HGF in protection against the progression of the kainate-induced TLE in rats. This measure improved learning, cognitive disturbances and inhibited apoptosis and astrogliosis. Highlights: Temporal lobe epilepsy results in apoptosis of neuronal cells;Hepatocyte growth factor attenuates the severity of status epilepticus in kainic acid-induced model;Hepatocyte growth factor attenuates apoptosis of neuronal cells in kainic acid-induced model of temporal lobe epilepsy. Plain Language Summary: Epilepsy is known as a disorder of the CNS which is caused by an imbalance in the electrical activity of neurons that in turn results in derangement in cognitive or causing debilitating seizures. Hepatocyte growth factor is one of neurotrophins secreted from mesenchymal and epithelial cells that regulate the growth, survival and functional changes of cells through signaling pathways such as the tyrosine kinase pathway after binding to its specific receptor. In this study, we tried to find out the effect of hepatocyte growth factor on attenuation of the severity of status epilepticus in kainic acid-induced model of temporal lobe epilepsy. Our results show that hepatocyte growth factor is able to protect against progression of the kainate-induced temporal lobe epilepsy in rats by improvement of learning, cognitive disturbances and inhibiting of apoptosis and astrogliosis.

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

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.

Ibuprofen Protection Against Restrained Chronic Stress-induced Depression in Male Rats.

INTRODUCTION: Stress predisposes organisms to depression and cognitive impairments, and seems to interact with metabolic homeostasis. The inflammatory response and the upregulation of proinflammatory cytokines are some of the consequences related to chronic stress. In this study, we investigated the preventive effect of chronic administration of ibuprofen, as an inhibitor of cyclooxygenases, on the cognitive and behavioral alterations and the weight gain reduction induced by simultaneous chronic restraint stress in rats. MATERIALS AND METHODS: Male Wistar rats were subjected to chronic restraint stress and injected daily with the variable doses of ibuprofen or vehicle, for 21 consecutive days. Then, all animals were tested with the forced swim test and passive avoidance conditioning. Also, the weight of the animals was recorded before and after the interventions. Ultimately, plasma interleukin 6 (IL-6) levels were measured. RESULTS: Chronic stress increased depressive-like behaviors, impaired learning, and disrupted the normal weight gain. However, the animals that received the highest dose of ibuprofen showed less depressive-like behaviors, a better avoidance memory, and a higher weight gain. However, the level of plasma IL-6 did not differ significantly between the study groups. CONCLUSION: The administration of ibuprofen prevents the cognitive and behavioral consequences of chronic stress. During the recovery, the plasma levels of IL-6 were not elevated by stress, and the IL-6 levels did not predict the behavioral performance of the stressed animals. The exact mechanisms of the protective effects of ibuprofen against chronic stress need to be further investigated.

Deferoxamine regulates neuroinflammation and oxidative stress in rats with diabetes-induced cognitive dysfunction.

Diabetic encephalopathy, a major complication of diabetes, is characterized by cognitive impairment and structural and neurochemical abnormalities. Neuroinflammation following impairment of iron homeostasis is a remarkable feature of several neurological disorders. In the present study, we investigated the role of deferoxamine (DFO), as a clinical iron chelator, in improvement of type 1 diabetes-induced cognitive dysfunction. Streptozotocin was utilized to induce type 1 diabetic in rat model. Animals were categorized into four groups: control, diabetic, diabetic + Iron and diabetic + DFO. Hence, DFO was administered at a dose of 100 mg/kg S.C and iron was administered at a dose of 12 mg/kg P.O for 8 weeks. Finally, Y-maze and passive avoidance were performed. Measurement of IL-6, ferritin, and the brain-derived neurotrophic factor (BDNF) expression was carried out using ELISA. Our results showed significant increased levels of ferritin (P < 0.001), IL-6 (P < 0.001), MDA (P < 0.01), as well as decreased levels of BDNF (P < 0.001) in the diabetic and iron groups compared to control. Post-treatment with DFO for 8 weeks after the induction of diabetes, markedly reduced levels of ferritin (P < 0.001), IL-6 (P < 0.01), and MDA (P < 0.001), as well as increased levels of BDNF (P < 0.01) compared to the diabetic and iron groups was observed. Collectively, these findings demonstrate the validity of DFO as a good candidate to attenuate cognitive dysfunction following diabetes by targeting oxidative stress, neuroinflammation, and modulation of iron homeostasis.

Effect of co-administration of morphine and nicotine on cardiovascular function in two-kidney one clip hypertensive (2K1C) rats.

Cardiovascular morbidity and mortality are potentiated with smoking and hypertension. The aim of this study was to investigate the effects of morphine and nicotine co-administration on cardiovascular function in two-kidney one-clip hypertensive (2K1C) rats. Thirty-two male rats were divided into four groups as follow: Vehicle, morphine, nicotine and nicotine + morphine. All drugs were administered for 8 weeks. Baroreflex sensitivity (BRS), heart rate and blood pressure were measured using a Power Lab data acquisition. Plasma rennin activity (PRA) and serum concentration of nitric oxide (NO) were measured using Elisa method. To induce hypertension, the renal artery of left kidney was clipped for 8 weeks. A significant decrease in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) was observed in nicotine + morphine group compared to vehicle and nicotine groups (p<0.05). Serum concentration of NO was lower in nicotine + morphine group compared to morphine group and significantly higher than nicotine group. The BRS was lower in the nicotine + morphine group compared to other groups. The PRA level was higher in nicotine + morphine compared to morphine group but it was higher than nicotine group. This study demonstrated that prolonged co-consumption of morphine and nicotinedecreased PRA and blood pressure and increased the serum concentration of NO in hypertensive rats. Co-administration of morphine and nicotine decreased BRS in 2k1c hypertensive rats probably via central nervous system.