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

Topiramate-Induced Modulation of Hepatic Molecular Mechanisms: An Aspect for Its Anti-Insulin Resistant Effect

Topiramate is an antiepileptic drug known to ameliorate insulin resistance besides reducing body weight. Albeit liver plays a fundamental role in regulation of overall insulin resistance, yet the effect of topiramate on this organ is controversial and is not fully investigated. The current work aimed to study the potential hepatic molecular mechanistic cassette of the anti-insulin resistance effect of topiramate. To this end, male Wistar rats were fed high fat/high fructose diet (HFFD) for 10 weeks to induce obese, insulin resistant, hyperglycemic animals, but with no overt diabetes. Two HFFD-groups received oral topiramate, 40 or 100 mg/kg, for two weeks. Topiramate, on the hepatic molecular level, has opposed the high fat/high fructose diet effect, where it significantly increased adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreased insulin receptor isoforms. Besides, it improved the altered glucose homeostasis and lipid profile, lowered the ALT level, caused subtle, yet significant decrease in TNF-α, and boosted adiponectin in a dose dependent manner. Moreover, topiramate decreased liver weight/, visceral fat weight/, and epididymal fat weight/body weight ratios. The study proved that insulin-resistance has an effect on hepatic molecular level and that the topiramate-mediated insulin sensitivity is ensued partly by modulation of hepatic insulin receptor isoforms, activation of tyrosine kinase, induction of GLUT2 and elevation of adiponectin receptors, as well as their ligand, adiponectin, besides its known improving effect on glucose tolerance and lipid homeostasis

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

Effect of topiramate on hepatic biomarkers.

<p>The panels illustrate the effect of topiramate (40 & 100 mg/kg, p.o; TPM₄₀, TPM₁₀₀) on hepatic (A, B) insulin receptor isoforms (high affinity, [HAIR, fmol/mg protein] and low affinity [LAIR, pmol/mg protein] insulin receptor), (C, D) adiponectin receptors (Adipo-R1, Adipo-R2 [ng/mg protein]), (E) protein tyrosine kinase (PTK [U/mg protein]), and (F) glucose transporter-2 (GLUT2 [mg/mg protein]) of obese/insulin resistant rats fed high fat and high fructose diet [HFFD] for 10 weeks (mean of 10 animals ± S.D.). Treatments were administered once daily for 2 weeks. As compared with normal control (^*), HFFD (<b>^†</b>) and HFFD+TPM40 ^(‡) groups (one-way ANOVA followed by Tukey–Kramer Test), <i>P</i><0.05.</p

Effect of topiramate on serum biomarkers.

<p>The panels illustrate the effect of topiramate (40 & 100 mg/kg, p.o; TPM₄₀, TPM₁₀₀) on serum (A) triglycerides (TGs, [mg/dl]), (B) total cholesterol(TC, [mg/dl]), (C) free fatty acids (FFAs, mmol/l]), (D)ALT (IU/L), (E) tumor necrosis alpha (TNF-α, [pg/ml]) and (F) adiponectin [ng/ml] of obese/insulin resistant rats fed high fat and high fructose diet [HFFD] for 10 weeks (mean of 10 animals ± S.D.). 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

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

Chenodeoxycholic Acid Ameliorates AlCl₃-Induced Alzheimer’s Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats

Insulin resistance is a major risk factor for Alzheimer&#8217;s disease (AD). Chenodeoxycholic acid (CDCA) and synthetic Farnesoid X receptor (FXR) ligands have shown promising outcomes in ameliorating insulin resistance associated with various medical conditions. This study aimed to investigate whether CDCA treatment has any potential in AD management through improving insulin signaling. Adult male Wistar rats were randomly allocated into three groups and treated for six consecutive weeks; control (vehicle), AD-model (AlCl3 50 mg/kg/day i.p) and CDCA-treated group (AlCl3 + CDCA 90 mg/kg/day p.o from day 15). CDCA improved cognition as assessed by Morris Water Maze and Y-maze tests and preserved normal histological features. Moreover, CDCA lowered hippocampal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and amyloid-beta 42 (A&#946;42). Although no significant difference was observed in hippocampal insulin level, CDCA reduced insulin receptor substrate-1 phosphorylation at serine-307 (pSer307-IRS1), while increased protein kinase B (Akt) activation, glucose transporter type 4 (GLUT4), peroxisome proliferator-activated receptor gamma (PPAR&#947;) and glucagon-like peptide-1 (GLP-1). Additionally, CDCA activated cAMP response element-binding protein (CREB) and enhanced brain-derived neurotrophic factor (BDNF). Ultimately, CDCA was able to improve insulin sensitivity in the hippocampi of AlCl3-treated rats, which highlights its potential in AD management