Isorhamnetin exerts neuroprotective effects in STZ-induced diabetic rats via attenuation of oxidative stress, inflammation and apoptosis
Introduction
Diabetes mellitus (DM) is a group of chronic progressive metabolic disorders that are characterized by hyperglycemia and alterations in the metabolism of proteins, lipids, and carbohydrates (Kankala et al., 2018). The aforementioned disease is associated with impairments in pancreatic insulin secretion, dysfunction of pancreatic β-cells owing to hyperglycemia condition, and resistance to the action of insulin in peripheral tissues (Kasputis et al., 2018). There are two main types of this disorder including insulin-dependent (type1) and non-insulin-dependent (type2) DM (Association, 2017). Furthermore, it has been reported that hyperglycemia enhances ROS content of pancreatic islets in animal models of diabetes (Kobayashi et al., 2017). Previous studies have shown that uncontrolled blood sugar in long-standing diabetes leads to astroglial abnormalities in some regions of the brain which decline in cognitive function, anxiety, memory dysfunction, and depression (Abbondante et al., 2014; Nakano et al., 2016; Nardin et al., 2016; Liu et al., 2018; Shinohara and Sato, 2017). It has been reported that elevated intracellular ROS contributes to hyperphosphorylation of Tau protein and subsequently microtubule dissociation which in turn results in neuronal death (Farhadi et al., 2019).
STZ-induced diabetes can be used as a model to examine not only the pathobiology of diabetes but also its side effects on other organs such as diabetic neuropathy, retinopathy, and vasculopathy (Diabetes, 2017; Sickmann and Waagepetersen, 2015). In a previous report by STZ-induced diabetic animals exhibited neuronal death in the CA1, 2/3 and DG regions of the hippocampus. Likewise, this research group showed that neuronal loss in the hypothalamic and hippocampus regions in STZ-induced diabetic rats is associated with inducing oxidative stress, suppression of BDNF production, initiation of inflammation and subsequently apoptosis (Bathina et al., 2017). An imbalance between oxidant-antioxidant systems owing to an increase in the production of ROS and decreased activity of endogenous antioxidant system result in oxidative stress and subsequently glycosylation of non-enzymatic proteins, lipid peroxidation, auto-oxidation of glucose, altered metabolism of glutathione, initiation of acute inflammatory responses (Amani et al., 2019b, d). Additionally, previous reports show that reactive gliosis or astrogliosis markedly increases in the hippocampus area of STZ-induced diabetic rats owing to metabolic and oxidative insults (Moghaddam et al., 2014). It was well documented that reinforcement of endogenous antioxidant enzymes such as catalase, GPx, and SOD using exogenous antioxidant agents can decrease the side effects of DM on other body organs (Sadeghi et al., 2018). Currently, many new therapeutic agents and methods have introduced to treat DM related disorders and other degenerative diseases (Amani et al., 2019c; Liu et al., 2018; Amani et al., 2018, 2017; Amani et al., 2019a).
Isorhamnetin is an abundant O-methylated flavonol from the class of flavonoids, found in medicinal herbs and in plants of the Polygonaceae family such as water dropwort and the sea buckthorn that highly used in traditional medicine to treat various diseases (Ahn and Lee, 2017). Isorhamnetin also is an intermediate of quercetin in plants and mammals. It can act as anti-inflammatory, anti-cancer agents by targeting different cellular signaling pathways (Yang et al., 2013; Wu et al., 2018). Likewise, isorhamnetin can increase cell survival in coping with oxidative stress by targeting the Nrf2 signaling pathway (Yang et al., 2014). Some previous reports have shown that isorhamnetin might have beneficial effects on the treatment of STZ-induced diabetic rats by reducing serum glucose or inhibiting of sorbitol accumulation in the lenses, sciatic nerves, and RBCs (Lee et al., 2005; Yokozawa et al., 2002). In a previous study, we showed that isorhamnetin attenuated learning and memory disturbances in STZ-induced diabetic rats (Jamali-Raoufi et al., 2018). Here, we went on to examine the neuroprotective effects of isorhamnetin in STZ-induced diabetic rats and to explore molecular targets by which isorhamnetin may contribute to the inhibition of neurodegeneration in the hippocampus region following this disorder.
Section snippets
Animals
Male Wistar rats aged 10–14 weeks old, weighing 250–270 g were purchased from Animal Center of Iran University of Medical Sciences. Rats were housed in a room with controlled temperature (22 ± 2 °C) and humidity (62–65%) on a 12-h light and dark cycle with free access to standard chow pellet and water. All the protocols and procedures were approved by the School of Medicine Animal Care and Use Committee of Iran University of Medical Sciences (IR.IUMS.REC1393.25315).
Chemicals
Streptozotocin, Cell Death
Effect of isorhamnetin on formalin-induced pain
As shown in Fig. 1A, our results showed that significant differences were observed in the pain scores in both phases, acute and chronic, in STZ-induced diabetic rats compared to control. Significant decreases in the pain scores in both phases, acute and chronic, were found in STZ-induced diabetic rats that were treated with 120 mg/kg dose of isorhamnetin or 200 mg/kg of sodium salicylate.
Effect of isorhamnetin on Tail immersion
As depicted in Fig. 1B, tail-flick latency or flicking response markedly decreased in STZ-induced diabetic
Discussion
A valid method for assessment of CNS dysfunctions is experimental STZ-induced diabetes that leads to impairment of insulin signaling and subsequently hyperglycemia (Biessels, 2013). STZ diabetic animals are hypoinsulinemic which, in turn, result in high blood glucose levels and consequently polydipsia, polyuria, and weight loss (Song et al., 2016; Sheng et al., 2017). In this study, all these features were found in STZ-induced diabetic rats. Diabetic rats demonstrated significant weight loss
Conclusion
Collectively, our study demonstrated that isorhamnetin exerts a neuroprotective effect against diabetes-related changes in a brain through inhibition of oxidative stress, inflammation, astrocytosis, and apoptosis.
Ethics
All the protocols and procedures were approved by the School of Medicine Animal Care and Use Committee of Iran University of Medical Sciences.
Declaration of Competing Interest
The authors declare no competing interests.
Acknowledgement
The present work was supported by a research grant (25315-30-04-93) from Iran University of Medical Sciences.
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