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PharmacologyFree Access
Calorie Restriction Mimicking by Isoliquiritigenin Attenuates Experimental Diabetic Neuropathy via Induction of Mitochondrial Biogenesis and Autophagy
Veera Ganesh Yerra, Anil Kumar Kalvala, and Ashutosh Kumar
Published Online:1 Apr 2016Abstract Number:928.7
Objective
The current study assessed the pharmacological efficacy of SIRT1 activation by a natural compound, Isoliquiritigenin (ILQ) in experimental models of Streptozotocin (STZ) induced diabetic neuropathy (DN) and high glucose induced neurotoxicity in neuro2a cells.
Materials & methods
ILQ was administered at doses of 10 mg/kg and 20 mg/kg to the diabetic animals during 7th& 8thweek after diabetes induction (STZ 55mg/kg, i.p). Animals were subjected to assessment of tactile sensitivity to temperature stimuli and mechanical stimuli. Motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV) and Sciatic nerve blood flow (NBF) were determined for functional assessment of neuropathic severity. Sciatic nerves were homogenized for biochemical estimations and western blotting analysis. Nerve sections were processed for tunel assay. For in vitro studies, Neuro2a cells were used and incubated with MEM media containing 25mM glucose to simulate high glucose condition. Cells were treated with ILQ (2.5 & 5 µM) for 24 hrs and then analyzed for reactive oxygen species (ROS) generation, mitochondrial superoxide generation, neurite growth analysis and western blotting analysis.
Results
ILQ administration for 2 weeks ameliorated the diabetes induced hyperalgesia and allodynia as evident from the enhanced tail withdrawal latencies to temperature stimuli and increased paw withdrawal responses to mechanical stimuli in ILQ treated rats. ILQ administration also enhanced MNCV, SNCV and NBF in the diabetic animals. ILQ exposure to neuro2a cells reduced the high glucose induced ROS, superoxide generation and enhanced neurite length. Tunel assay and biochemical analysis showed that ILQ treatment reduced oxidative biomolecular damage by enhancing antioxidant defenses. ILQ treatment also enhanced the reductive NAD pool required for oxidative phosphorylation mediated energy production in the sciatic nerves. Western blotting analysis has shown that ILQ treatment ameliorated the diabetes induced impairment in mitochondrial biogenesis and autophagy through PGC-1a induction and mTOR inhibition respectively.
Conclusion
ILQ through SIRT1 activation improved mitochondrial biogenesis and autophagic turnover in neuronal cells and imparted mitochondrial protection. Pharmacological modulators of SIRT1 and associated mitochondrial signaling can be developed as potential therapeutic choice for the management of DN.
Support or Funding Information
Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India.
The pathological features of Parkinson’s disease (PD) include an abnormal accumulation of a-synuclein in the surviving dopaminergic neurons. Though PD is multifactorial, several epidemiological reports show an increased incidence of PD with co-exposure to pesticides such as Maneb and paraquat (MP). In pesticide-related PD, mitochondrial dysfunction and a-synuclein oligomers have been strongly implicated, but the link between the two has not yet been understood. Similarly, the biological effects of a-synuclein or its radical chemistry in PD is largely unknown. Mitochondrial dysfunction during PD pathogenesis leads to release of cytochrome c in the cytosol. Once in the cytosol, cytochrome c has one of two fates: It either binds to apaf1 and initiates apoptosis or can act as a peroxidase. We hypothesized that as a peroxidase, cytochrome c leaked out from mitochondria can form radicals on a-synuclein and initiate its oligomerization. Samples from controls, and MP co-exposed wild-type and a-synuclein knockout mice were studied using immuno-spin trapping, confocal microscopy, immunohistochemistry, and microarray experiments. Experiments with MP co-exposed mice showed cytochrome c release in cytosol and its co-localization with a-synuclein. Subsequently, we used immuno-spin trapping method to detect the formation of a-synuclein radical in samples from an in vitro reaction mixture consisting of cytochrome c, a-synuclein, and hydrogen peroxide. These experiments indicated that cytochrome c plays a role in a-synuclein radical formation and oligomerization. Experiments with MP co-exposed a-synuclein knockout mice, in which …
Abstract
Obesity is associated with strong risks of development of chronic inflammatory liver disease and metabolic syndrome following a second hit. This study tests the hypothesis that free radical metabolism of low chronic exposure to bromodichloromethane (BDCM), a disinfection byproduct of drinking water, causes nonalcoholic steatohepatitis (NASH), mediated by cytochrome P450 isoform CYP2E1 and adipokine leptin. Using diet-induced obese mice (DIO), mice deficient in CYP2E1, and mice with spontaneous knockout of the leptin gene, we show that BDCM caused increased lipid peroxidation and increased tyrosine nitration in DIO mice, events dependent on reductive metabolism by CYP2E1. DIO mice, exposed to BDCM, exhibited increased hepatic leptin levels and higher levels of proinflammatory gene expression and Kupffer cell activation. Obese mice exposed to BDCM also showed profound hepatic necrosis, Mallory body formation, collagen deposition, and higher alpha smooth muscle actin expression, events that are hallmarks of NASH. The absence of CYP2E1 gene in mice that were fed with a high-fat diet did not show NASH symptoms and were also protected from hepatic metabolic alterations in Glut-1, Glut-4, phosphofructokinase and phosphoenolpyruvate carboxykinase gene expressions (involved in carbohydrate metabolism), and UCP-1, PGC-1a, SREBP-1c, and PPAR-? genes (involved in hepatic fat metabolism). Mice lacking the leptin gene were significantly protected from both NASH and metabolic alterations following BDCM exposure, suggesting that higher levels of leptin induction by BDCM in the liver contribute to the development of NASH and metabolic alterations in obesity. These results provide novel insights into BDCM-induced NASH and hepatic metabolic reprogramming and show the regulation of obesity-linked susceptibility to NASH by environmental factors, CYP2E1, and leptin.
Key Words: bromodichloromethane, hepatocyte, lipid peroxidation, fibrosis, Glut-1, glycolysis, gluconeogenesis, PPAR-?, SREBP-1c, tumor necrosis factor, ob/ob mice.
