Modulation of Fructose-Induced Insulin Resistance Syndrome in Rats by Rosiglitazone and α-Lipoic Acid

Increased fructose intake has been linked to the epidemiology of insulin resistance (IR) syndrome, type 2 diabetes mellitus, renal damage and non-alcoholic steatohepatitis. As oxidative stress plays a pivotal role in the pathology of IR, the present study was conducted to investigate the effects of rosiglitazone alone or combined with α-lipoic acid, a potent antioxidant, on fructose-induced IR syndrome in rats. Markers chosen for assessment included effects on body weight gain, glucose and insulin levels, IR, β- cell function, lipid profile, nitric oxide (NO) metabolites and antioxidant status. Moreover, liver and kidney functions were assessed both biochemically and histologically. Male rats were fed with fructose-enriched diet (FED) or standard rat chow for 16 weeks. By the end of the 10th week, FED-fed rats were divided into three groups; one was left untreated (control group) and the other 2 groups were treated p.o. with rosiglitazone (4 mg/kg) and rosiglitazone plus α-ℓipoic acid (100 mg/kg), respectively. Treatments continued daily for 6 weeks, afterwards blood samples were collected, animals were sacrificed and their livers and kidneys isolated. Feeding rats with FED resulted in increased weight gain, hyperinsulinemia, hyperglycemia, IR and β- cell dysfunction. These changes were coupled with disturbances in lipid homeostasis, antioxidant status and alterations in NO metabolites as well as liver and kidney dysfunctions. Concomitant administration of α-ℓipoic acid with rosiglitazone potentiated the effects of the latter on most of the investigated parameters. In conclusion, the combination of rosiglitazone and α-ℓipoic could ameliorate most of the symptoms associated with IR syndrome in rats

Cilostazol disrupts TLR-4, Akt/GSK-3β/CREB, and IL-6/JAK-2/STAT-3/SOCS-3 crosstalk in a rat model of Huntington's disease.

Countless neurodegenerative diseases are associated with perverse multiple targets of cyclic nucleotide signalling, hastening neuronal death. Cilostazol, a phosphodiesterase-III inhibitor, exerts neuroprotective effects against sundry models of neurotoxicity, however, its role against Huntington's disease (HD) has not yet been tackled. Hence, its modulatory effect on several signalling pathways using the 3-nitropropionic acid (3-NP) model was conducted. Animals were injected with 3-NP (10 mg/kg/day, i.p) for two successive weeks with or without the administration of cilostazol (100 mg/kg/day, p.o.). Contrary to the 3-NP effects, cilostazol largely preserved striatal dopaminergic neurons, improved motor coordination, and enhanced the immunohistochemical reaction of tyrosine hydroxylase enzyme. The anti-inflammatory effect of cilostazol was documented by the pronounced reduction of the toll like receptor-4 (TLR-4) protein expression and the inflammatory cytokine IL-6, but with a marked elevation in IL-10 striatal contents. As a consequence, cilostazol reduced IL-6 downstream signal, where it promoted the level of suppressor of cytokine signalling 3 (SOCS3), while abated the phosphorylation of Janus Kinase 2 (JAK-2) and Signal transducers and activators of transcription 3 (STAT-3). Phosphorylation of the protein kinase B/glycogen synthase kinase-3β/cAMP response element binding protein (Akt/GSK-3β/CREB) cue is another signalling pathway that was modulated by cilostazol to further signify its anti-inflammatory and antiapoptotic capacities. The latter was associated with a reduction in the caspase-3 expression assessed by immunohistochemical assay. In conclusion the present study provided a new insight into the possible mechanisms by which cilostazol possesses neuroprotective properties. These intersecting mechanisms involve the interference between TLR-4, IL-6-IL-10/JAK-2/STAT-3/SOCS-3, and Akt/GSK-3β/CREB signalling pathways