Troxerutin for the Treatment of Chronic Diseases

Introduction

Troxerutin, a semi-synthetic bioflavonoid derived from rutin, has been reported to exert several pharmacological effects including antioxidant, anti-inflammatory, antihyperlipidemic, and nephroprotective. However, the related molecular details and its mechanisms remain poorly understood. In the present review, we presented evidences from the diversity in vitro and in vivo studies on the therapeutic potential of Troxerutin against neurodegenerative, diabetes, cancer and cardiovascular diseases with the purpose to find molecular pathways related to the treatment efficacy. Troxerutin has a beneficial role in many diseases through multiple mechanisms including, increasing antioxidant enzymes and reducing oxidative damage, decreasing in proapoptotic proteins (APAF-1, BAX, caspases-9 and-3) and increasing the antiapoptotic BCL-2, increasing the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and downregulating the nuclear factor κB (NFκ). Troxerutin also reduces acetylcholinesterase activity and upregulates phosphoinositide 3-kinase/Akt signaling pathway in Alzheimer’s disease models. Natural products such as Troxerutin may develop numerous and intracellular pathways at several steps in the treatment of many diseases. Molecular mechanisms of action are revealing novel, possible combinational beneficial approaches to treat multiple pathological conditions.[1]

History of Troxerutin

Troxerutin is a flavonol obtained from rutoside, a natural flavonoid, which is hydroxylated at the 3', 4' and 7th positions in the rutin structure. Troxerutin is a yellow powder and comfortably soluble in water. It was isolated from Styphnolobium japonicum Styphnolobium japonicum (L.) Schott, 1830, and also is found in significant amounts in tea, coffee, some fruits and plants. Troxerutin should be stored at 2-8°C and protected from air and light to avoid its degradation. Troxerutin belongs to the class of organic compounds identified as flavonoid-3-o-glycosides. These are phenolic compounds, including a flavonoid moiety that is O-glycosidically linked to a carbohydrate moiety at the C3-position. Troxerutin constitutes approximately 80% of tris rutin as the main compound, whereas bis rutin, tetrakis rutin, and mono rutin are occurring in a negligible extent. A study indicated that synthesizing troxerutin-acylated derivatives, significantly increases the bioavailability and antioxidant activities of TXR in cells via improving its lipophilicity. Indeed, acylation of Troxerutin by P. aeruginosa and P. stutzeri allow obtaining two products, troxerutin monoester and troxerutin diester, which showed better bioavailability, absorption and antioxidant activities than native Troxerutin.[2]

Troxerutin in the treatment of Neurodegenerative diseases

Some studies have shown that the generation of free radicals such as ROS leads to mitochondrial dysfunction and increased Aβ peptide accumulation in the brain. Several studies have been designed to determine the possible effect of Troxerutin as a neuroprotective agent. For example, in in vivo and in vitro experimental models, Troxerutin has been shown to reduce ischemic damage by reducing oxidative stress in a process mediated by increased SOD activity and decreased MDA levels in the rat cerebral tissues. In addition to the neurovascular unit (NVU) model for oxygen-glucose deprivation and reoxygenation (OGD/R) damage, Troxerutin has protective effects on neurons after cerebral ischemia/reperfusion (I/R) injury via reducing the levels of inflammatory cytokines such as IL-1β, IL-6, and TNF-α, proapoptotic markers (Bax, p53, and caspase-3), and improving blood-brain barrier maintenance. Lu and colleagues demonstrated the neuroprotective effects of Troxerutin in the D-galactose-treated mouse model induced by subcutaneous injections of D-galactose for 8 weeks. In this study, Troxerutin effectively improved learning and memory through decreasing advanced AGEs, ROS and protein carbonyl levels in the basal forebrain, hippocampus and frontal cortex. The results evidenced that Troxerutin reduced the activity of AchE, increased neuronal acetylcholine receptor subunit alpha-7(nAchRa7) expression and interaction between nAchRa7 and the memory-related proteins either postsynaptic density protein 95 (PSD95) or NMDAR1 in the basal forebrain, hippocampus and front cortex of mice. In addition, Lu and colleagues reported that oral administration of Troxerutin improved the spatial learning, memory deficits and cognitive performance and reduced oxidative stress via NGF-dependent activation of the TrkA pathway in D-galactose-treated 8-week-old male Kunming strain mice. It has been reported that Troxerutin possesses neuroprotective properties and reduces oxidative stress via decreasing the levels of neurotoxic ROS, protein carbonyl and AGEs in the hippocampus of mice fed a high cholesterol-induced diet for 20 weeks. In addition, Troxerutin significantly reduced the cognitive deficits by increasing phosphoinositide 3-kinase/Akt signaling pathway activity and inhibiting the endoplasmic reticulum stress pathway in the mouse hippocampus. Babri and colleagues demonstrated the effectiveness of Troxerutin in a mouse model of AD induced by intracerebroventricular injection of Aβ1-42. In this study, the oral administration of Troxerutin (300 mg/kg) for a period of 8 days, significantly attenuated the impairments in learning and improved memory. This ability is probably related to its anti-inflammatory and antioxidant properties, which enhance hippocampal LTP, improve the functionality of the cholinergic system, and reduce the AChE activity and/or levels of AGEs in different regions of the brain, especially, in the hippocampus. Lu and colleagues showed that DA (2 mg/kg, intraperitoneal injection) administration for 3 weeks induced a significant impairment in mitochondrial function, increased ROS generation, GFAP and Cox-2 levels and induced the release of inflammatory cytokines such as IL-1β and TNF-α, leading to memory impairment via the PKC-z–dependent K-ras/Raf/MEK/ERK1/2 signaling pathway in the hippocampus of mice. They also found that oral administration of Troxerutin significantly improved learning and memory by inhibiting Cdk1 expression. In an electrophysiological study on male Wistar rats, it was observed that intracerebroventricularly (i.c.v.) administration of Aβ1-42 in to right lateral ventricle dramatically reduced the LTP of the DG. Continuous administration of the Troxerutin for two weeks evidenced an improvement in LTP and prevented the hippocampal synaptic failure induced by Aβ peptide. Additionally, intraperitoneal injection of Troxerutin for 6 weeks, improved cognitive performance through reducing oxidative stress, decreeing MDA level and increasing the levels of GSH and the activity of SOD and in STZ-induced diabetic rats. The principal mechanism of the effects of Troxerutin, as mentioned above, probably involves glutamate-cysteine ligase expression, especially glutamate-cysteine ligase catalytic subunit in hippocampal tissues.[3]

Troxerutin in the treatment of cancer

Several studies reported that Troxerutin treatment leads to apoptosis and anticancer effects. In this sense, Thomas and colleagues found that Troxerutin administration (50 mg/kg, orally) in rats with preneoplastic liver induced by N-nitrosodiethylamine (NDEA) protected against the development of NAFLD to NASH and HCC. Troxerutin enhanced the antioxidant defenses and reduced oxidative damage and the generation of ROS. In addition, the treatment reduced the levels of CYP enzymes (CYP450 and CYP2E1), inhibited cell proliferation and inflammatory processes, reduced fibrosis and formation of nodules, modulated the imbalance in the MDM2–p53 interaction and also modulated apoptosis by reducing expression of MDM2 and Bcl-2, and increasing the expression of p53 and Bax. Another in vitro study has been shown that Troxerutin inhibited the cell viability, cell migration and induced apoptosis in HuH-7 hepatocarcinoma cells in a time-dependent manner. Subsequently, the suppression of the oxidative stress in the hepatocarcinoma cell line by Troxerutin was mediated by triggering the keap-1/Nrf-2/HO-1 signaling pathway. The results of this study showed that the Troxerutin anti-inflammatory activity was related to the inhibition of the NF-κB pathway and its downstream targets in order to induce apoptosis. Therefore, it was suggested that the anti-apoptotic effect of the Troxerutin related to NF-κB inhibition and Nrf2 activation might be related to the simultaneous regulation of both molecular pathways.

Rajamanickam and colleagues reported that supplementation with Troxerutin inhibited the activities of phase I enzymes such as cytochrome P450 and b5 and increased the activities of phase II enzymes such as GST, DT-diaphorase (DTD) and uridine diphospho glucuronyl transferase (UDPGT) in 1,2-dimethylhydrazine (DMH) induced experimental rat colon carcinogenesis. The treatment with Troxerutin also reduced the activity of bacterial enzymes such as the mucinase, β-glucosidase and β-galactosidase when compared with the DMH-treated group, and thus, increased mucin content in the colon. Troxerutin, at the dose of 25 mg/kg, dramatically reduced the formation of aberrant crypt foci (ACF) and its total number via suppressing the progression of preneoplasia to malignant neoplasia.

References

[1] Farajdokht F., Amani M., Mirzaei B.F., Alihemmati A., Mohaddes G., Babri S. Troxerutin protects hippocampal neurons against amyloid beta-induced oxidative stress and apoptosis. EXCLI J. 2017;16:1081–1089.

[2] Zamanian M., Hajizadeh M.R., Esmaeili N.A., Shamsizadeh A., Allahtavakoli M. Antifatigue effects of troxerutin on exercise endurance capacity, oxidative stress and matrix metalloproteinase-9 levels in trained male rats. Fundam. Clin. Pharmacol. 2017;31(4):447–455.

[3] Shan Q., Zhuang J., Zheng G., Zhang Z., Zhang Y., Lu J., Zheng Y. Troxerutin reduces kidney damage against BDE-47-induced apoptosis via inhibiting NOX2 activity and increasing nrf2 activity. Oxid. Med. Cell. Longev. 2017;2017:6034692.

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