Novel Trajectories of Bromocriptine Antidiabetic Action: Leptin-IL-6/ JAK2/p-STAT3/SOCS3, p-IR/p-AKT/GLUT4, PPAR-γ/Adiponectin, Nrf2/PARP-1, and GLP-1

Bromocriptine (BC), a sympatholytic dopaminergic D2 receptor agonist, has been comprehensively used in clinic to treat Parkinson’s disease (PD) and prolactinomas. Besides, BC represents a novel therapeutic option in type 2 diabetes (T2DM); however, the precise mechanisms are not completely unveiled. Hence, the objective of the current work is to clarify the potential molecular pathways of the insulin sensitizing effect of BC in the skeletal muscle of diabetic rats and to evaluate its possible interaction with sitagliptin (SG) as an add-on therapy. Here experimental model impersonates unhealthy dietary habit and T2DM was adopted, in which rats were fed high caloric diet of fat and fructose for 6 weeks followed by a single sub-diabetogenic dose of streptozotocin (STZ) (35 mg/kg; HF/Fr/STZ). Diabetic rats were treated with BC, SG at two dose levels (SG10 and SG20) and combination of BC + SG10 for 2 weeks. BC successfully corrected glucose/lipid profile, as well as leptin and GLP-1. On the muscular molecular level, BC curtailed the inflammatory signal IL-6/JAK2/p-STAT3/SOCS3, while enhanced the PPAR-γ/adiponectin signaling, resulting in activation of the insulin signaling pathway (p-IR/p-AKT/GLUT4). Moreover, BC confirmed its antioxidant capabilities by altering Nrf2 and PARP-1; the study also highlighted novel mechanisms for SG as well. On almost all tested parameters/pathways, the combination regimen surpassed each drug alone to reach a comparable level to the high dose of SG. In conclusion, our finding shed some light on novel anti-diabetic mechanisms of BC. The study also points to the potential use of BC as an adds-on to standard anti-diabetic therapies

Effect of topiramate on the indicators of glucose homeostasis of obese/insulin resistant rats.

<p>Effect of topiramate (40, 100 mg/kg; TPM₄₀, TPM₁₀₀) on serum levels of glucose, insulin, and fructosamine, HOMA-index and area under the curve of the GTT of obese/insulin resistant rats fed high fat and high fructose diet [HFFD] for 10 weeks. Values are means (± S.D.) of 10 animals. Treatments were administered once daily for 2 weeks. As compared with normal control (^*), HFFD (<b>^†</b>) and HFFD+TPM₄₀<b>(^‡)</b> groups (one-way ANOVA followed by Tukey–Kramer Test), <i>P</i><0.05.</p

Correlation coefficient (<i>r</i>) between HOMA-I and serum adiponectin with hepatic GLUT2, adiponectin receptors (Adipo- R1, R2), insulin receptor isoforms (LAIR, HAIR), and tyrosine kinase.

<p>Correlation was carried out in untreated and treated hyperglycemic animals.</p

The glucose tolerance test (GTT).

<p>The curve depicts the changes in serum glucose response in normal control, non-treated obese/insulin-resistant rats (HFFD), and treated ones by either dose of topiramate (40 & 100 mg/kg;HFFD+TPM40, HFFD+TPM₁₀₀), after 0, 30, 60, 90, and 120 min following administration of glucose (2 g/kg, ip). Values are means (± S.D) of 10 animals; as compared with normal control (^*), and HFFD (<b>^†</b>) groups (one-way ANOVA followed by Tukey–Kramer Test), <i>P</i><0.05.</p

Effect of topiramate on serum and tissue biomarkers of normal control rat.

<p>Effect of 14 days administration of topiramate (40, 100 mg/kg) to normal control rats fed normal diet. The following markers were assessed: serum levels of glucose, insulin, and fructosamine, HOMA-index and area under the curve (AUC); serum triglycerides (TGs), total cholesterol (TC), free fatty acids (FFAs), ALT (IU/L), tumor necrosis alpha (TNF-α) and adiponectin; body weight (BW) and liver weight (LW)/−, visceral fat weight (VFW)/− and epididymal fat weight (EFW)/−BW ratio. Values are means (± S.D.) of 10 animals. Treatments were administered once daily for 2 weeks. Statistical analysis between groups was carried out using one-way ANOVA followed by Tukey-Kramer Test, <i>P</i><0.05.</p

Effect of topiramate on body-, liver- and fat weights of obese/insulin resistant rats.

<p>Effect of topiramate (40, 100 mg/kg; TPM₄₀, TPM₁₀₀) on body weight (BW) and liver weight (LW)/−, visceral fat weight (VFW)/− and epididymal fat weight (EFW)/−BW ratio of obese/insulin resistant rats fed high fat and high fructose diet [HFFD] for 10 weeks. Values are means (± S.D.) of 10 animals. Treatments were administered once daily for 2 weeks. As compared with normal control (<b>^*</b>), and HFFD (<b>^†</b>) groups (one-way ANOVA followed by Tukey-Kramer Test), <i>P</i><0.05.</p

CoQ10 Augments Rosuvastatin Neuroprotective Effect in a Model of Global Ischemia via Inhibition of NF-κB/JNK3/Bax and Activation of Akt/FOXO3A/Bim Cues

Statins were reported to lower the Coenzyme Q10 (CoQ10) content upon their inhibition of HMG-CoA reductase enzyme and both are known to possess neuroprotective potentials; therefore, the aim is to assess the possible use of CoQ10 as an adds-on therapy to rosuvastatin to improve its effect using global I/R model. Rats were allocated into sham, I/R, rosuvastatin (10 mg/kg), CoQ10 (10 mg/kg) and their combination. Drugs were administered orally for 7 days before I/R. Pretreatment with rosuvastatin and/or CoQ10 inhibited the hippocampal content of malondialdehyde, nitric oxide, and boosted glutathione and superoxide dismutase. They also opposed the upregulation of gp91phox, and p47phox subunits of NADPH oxidase. Meanwhile, both agents reduced content/expression of TNF-α, iNOS, NF-κBp65, ICAM-1, and MPO. Besides, all regimens abated cytochrome c, caspase-3 and Bax, but increased Bcl-2 in favor of cell survival. On the molecular level, they increased p-Akt and its downstream target p-FOXO3A, with the inhibition of the nuclear content of FOXO3A to downregulate the expression of Bim, a pro-apoptotic gene. Additionally, both treatments downregulate the JNK3/c-Jun signaling pathway. The effect of the combination regimen overrides that of either treatment alone. These effects were reflected on the alleviation of the hippocampal damage in CA1 region inflicted by I/R. Together, these findings accentuate the neuroprotective potentials of both treatments against global I/R by virtue of their rigorous multi-pronged actions, including suppression of hippocampal oxidative stress, inflammation, and apoptosis with the involvement of the Akt/FOXO3A/Bim and JNK3/c-Jun/Bax signaling pathways. The study also nominates CoQ10 as an adds-on therapy with statins