Isorhamnetin exerts neuroprotective effects in STZ-induced diabetic rats via attenuation of oxidative stress, inflammation and apoptosis

https://doi.org/10.1016/j.jchemneu.2019.101709Get rights and content

Highlights

Abstract

Objective

Isorhamnetin, a derivative of quercetin, exerts antioxidant and anti-inflammatory effects in different diseases, and we examined its protective effects against diabetes-related changes in the brain.

Methods

A single dose of a freshly prepared solution of streptozotocin (STZ) (60 mg/kg body weight) was intraperitoneally injected to establish STZ-induced diabetic model in male Wistar rats. The animals were randomly divided into four groups: control, control + isorhamnetin, diabetic, diabetic + isorhamnetin. Isorhamnetin at a dose of 10 mg/kg body weight was intraperitoneally administrated once a day for 12 weeks. Formalin and tail immersion tests were performed to evaluate the severity of pain. Astrogliosis markers such as GFAP and APO-E4, DNA fragments, MDA level, and TNFα expressions were evaluated using ELISA assay. Neuronal density in the hippocampus region was evaluated using Nissl staining. The method of Ellman and fluorescent probe 2, 7-dichlorofluorescein diacetate (DCFH-DA) was used to measure brain acetyl-cholinesterase activity and detect reactive nitrogen and oxygen species (RNS and ROS), respectively.

Results

Isorhamnetin reduced pain, blood glucose levels, and increased body weight significantly compared to control. Moreover, isorhamnetin inhibited astroglial activation, acetyl-cholinesterase activity, oxidative stress, apoptosis, and inflammation.

Conclusion

These findings suggested that isorhamnetin has potential effects as neuroprotective agents against diabetes-related changes in the brain.

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.

References (60)

  • Zahra Kiasalari et al.

    Diosgenin ameliorates development of neuropathic pain in diabetic rats: involvement of oxidative stress and inflammation

    Biomed. Pharmacother.

    (2017)
  • Yurii V. Lebed et al.

    Early reaction of astroglial cells in rat hippocampus to streptozotocin-induced diabetes

    J. Neurosci. Lett.

    (2008)
  • Si-Yang Liu et al.

    Lycium barbarum polysaccharide protects diabetic peripheral neuropathy by enhancing autophagy via mTOR/p70S6K inhibition in Streptozotocin-induced diabetic rats

    J. Chem. Neuroanat.

    (2018)
  • Mei Lu et al.

    Phyto-phospholipid complexes (phytosomes): a novel strategy to improve the bioavailability of active constituents

    Asian J. Pharm. Sci.

    (2019)
  • Elena I. Mancera-Andrade et al.

    Isorhamnetin encapsulation into biogenic silica from Cyclotella sp. Using a microfluidic device for drug delivery applications

    Biocatal. Agric. Biotechnol.

    (2019)
  • Feng Qi et al.

    Anti-inflammatory effects of isorhamnetin on LPS-stimulated human gingival fibroblasts by activating Nrf2 signaling pathway

    Microb. Pathog.

    (2018)
  • Feng Qi et al.

    Anti-inflammatory effects of isorhamnetin on LPS-stimulated human gingival fibroblasts by activating Nrf2 signaling pathway

    J. Microb. Pathogenesis

    (2018)
  • Akram Sadeghi et al.

    The effects of maternal diabetes and insulin treatment on neurogenesis in the developing hippocampus of male rats

    J. Chem. Neuroanat.

    (2018)
  • Mitsuru Shinohara et al.

    ’Bidirectional interactions between diabetes and Alzheimer’s disease’

    Neurochem. Int.

    (2017)
  • M. Silva et al.

    Endovanilloid control of pain modulation by the rostroventromedial medulla in an animal model of diabetic neuropathy

    J. Neuropharmacol.

    (2016)
  • Yi Xiao et al.

    Quercetin and kaempferol increase the intestinal absorption of isorhamnetin coexisting in Elaeagnus rhamnoides (L.) A. Nelson (Elaeagnaceae) extracts via regulating multidrug resistance-associated protein 2

    Phytomedicine

    (2019)
  • Ji Hye Yang et al.

    O-methylated flavonol isorhamnetin prevents acute inflammation through blocking of NF-κB activation

    J. Food Chem. Toxicol.

    (2013)
  • Ji Hye Yang et al.

    Isorhamnetin protects against oxidative stress by activating Nrf2 and inducing the expression of its target genes

    J. Toxicol. Appl. Pharmacol.

    (2014)
  • Goksin Nilufer Yonguc et al.

    Grape seed extract has superior beneficial effects than vitamin E on oxidative stress and apoptosis in the hippocampus of streptozotocin induced diabetic rats

    J. Gene

    (2015)
  • Hamed Amani et al.

    Controlling cell behavior through the design of biomaterial surfaces: a focus on surface modification techniques

    Adv. Mater. Interfaces

    (2019)
  • Hamed Amani et al.

    Selenium nanoparticles for targeted stroke therapy through modulation of inflammatory and metabolic signaling

    Sci. Rep.

    (2019)
  • Hamed Amani et al.

    Tailoring synthetic polymeric biomaterials towards nerve tissue engineering: a review

    Artif. Cells Nanomed. Biotechnol.

    (2019)
  • Hamed Amani et al.

    Would colloidal gold nanocarriers present an effective diagnosis or treatment for ischemic stroke?

    Int. J. Nanomed.

    (2019)
  • Hamed Amani et al.

    Three-dimensional graphene foams: synthesis, properties, biocompatibility, biodegradability, and applications in tissue engineering

    ACS Biomater. Sci. Eng.

    (2018)
  • Muragundla Anjaneyulu et al.

    Quercetin Attenuates Thermal Hyperalgesia and Cold Allodynia in STZ-Induced Diabetic Rats

    (2004)
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