Ahmed Fathi Mohamed

BACKGROUND: Cyclocreatine phosphate (CCrP) is a potent bioenergetic cardioprotective compound known to preserve high levels of cellular adenosine triphosphate during ischemia. Using the standard Isoproterenol (ISO) rat model of heart failure (HF), we recently demonstrated that the administration of CCrP prevented the development of HF by markedly reducing cardiac remodeling (fibrosis and collagen deposition) and maintaining normal ejection fraction and heart weight, as well as physical activity. The novel inflammatory mediator, Nourin is a 3-KDa formyl peptide rapidly released by ischemic myocardium and is associated with post-ischemic cardiac inflammation. We reported that the Nourin-associated (marker of cell damage) and (marker of inflammation) are significantly upregulated in unstable angina patients and patients with acute myocardial infarction, but not in healthy subjects.

OBJECTIVES: To test the hypothesis that Nourin-associated and are upregulated in ISO-induced "HF rats" and that the administration of CCrP prevents myocardial injury (MI) and reduces Nourin gene expression in "non-HF rats".

METHODS: 25 male Wistar rats (180-220 g) were used: ISO/saline ( = 6), ISO/CCrP (0.8 g/kg/day) ( = 5), control/saline ( = 5), and control/CCrP (0.8 g/kg/day) ( = 4). In a limited study, CCrP at a lower dose of 0.4 g/kg/day ( = 3) and a higher dose of 1.2 g/kg/day ( = 2) were also tested. The Rats were injected SC with ISO for two consecutive days at doses of 85 and 170 mg/kg/day, respectively, then allowed to survive for an additional two weeks. CCrP and saline were injected IP (1 mL) 24 h and 1 h before first ISO administration, then daily for two weeks. Serum CK-MB (U/L) was measured 24 h after the second ISO injection to confirm myocardial injury. After 14 days, gene expression levels of and were measured in serum samples using quantitative real-time PCR (qPCR).

RESULTS: While high levels of CK-MB were detected after 24 h in the ISO/saline rats indicative of MI, the ISO/CCrP rats showed normal CK-MB levels, supporting prevention of MI by CCrP. After 14 days, gene expression profiles showed significant upregulation of and by 8.6-fold and 8.7-fold increase, respectively, in the ISO/saline rats, "HF rats," compared to the control/saline group. On the contrary, CCrP treatment at 0.8 g/kg/day markedly reduced gene expression of miR-137 by 75% and of by 44% in the ISO/CCrP rats, "non-HF rats," compared to the ISO/Saline rats, "HF rats." Additionally, healthy rats treated with CCrP for 14 days showed no toxicity in heart, liver, and renal function.

CONCLUSIONS: Results suggest a role of Nourin-associated and in the pathogenesis of HF and that CCrP treatment prevented ischemic injury in "non-HF rats" and significantly reduced Nourin gene expression levels in a dose-response manner. The Nourin gene-based mRNAs may, therefore, potentially be used as monitoring markers of drug therapy response in HF, and CCrP-as a novel preventive therapy of HF due to ischemia.

The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional antiepileptics to further deteriorate cognitive function are areas of growing concern. Glucagon-like peptide-1 (GLP-1) deficiency has been linked to reduced seizure threshold as well as cognitive dysfunction. Here, we tested whether sitagliptin (SITA), by virtue of its neuroprotective properties, could alleviate both epilepsy and associated cognitive dysfunction in a rat model of kindling epilepsy. Chemical kindling was induced by subconvulsive doses of pentylenetetrazol (PTZ) (30 mg/kg; i.p). SITA (50 mg/kg; p.o) was administered 1 h before PTZ injections. SITA conceivably attenuated PTZ hippocampal histological insult, preserved neuronal integrity and amended neurotransmitter perturbations in rat hippocampi paralleled with enhanced hippocampal GLP-1 levels as well as the downstream cAMP content and protein kinase A (PKA) activity. Moreover, SITA improved cognitive functioning of rats in the Morris water maze which was coupled with hampered hippocampal p(Ser)-tau and β-amyloid proteins. SITA replenished p(Ser)-glycogen synthase kinase-3β (GSK-3β). It also opposed the boosted matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) levels associated with PTZ administration along with mitigation of both β-secretase-1 (BACE1) immunoreactivity and receptor for advanced glycation end products (RAGE) protein level in rat hippocampi. In conclusion, SITA subdues epileptic and cognitive upshots of PTZ kindling in rats, which might correspond to the modulation of BACE1, amyloidogenic/RAGE axis as well as GSK-3β/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.

Disruption of Th17/Tregs homeostasis plays a crucial role in governing the immune response during myocardial fibrosis and its progression to heart failure. The present study aimed to assess for the first time the possible protection afforded by rupatadine against isoproterenol-induced heart failure in rats. It also explored the role of PI3k/Akt as a possible mechanistic pathway, through which rupatadine could modulate Th17/Tregs balance to display its effect. Isoproterenol (85 and 170 mg/kg/day) was injected subcutaneously for 2 successive days, respectively and rupatadine (4 mg/kg/day) was then given orally for 14 days with or without wortmannin (PI3K/Akt inhibitor). Rupatadine succeeded to completely ameliorate isoproterenol-induced cardiac dysfunction as demonstrated by improvements of electrocardiographic and echocardiographic measurements. Moreover, rupatadine prevented the marked elevation of PAF and oxidative stress in addition to Th17 promoting cytokines (IL-6, IL-23, and TGF-β). Accordingly, rupatadine prevented Th17 stimulation or expansion as indicated by increased Foxp3/RORγt ratio and decreased production of its pro-inflammatory cytokine (IL-17). Rupatadine treatment mitigated isoproterenol-induced activation of STAT-3 signaling and the imbalance in -Akt/total Akt ratio affording marked decrease in atrogin-1 and apoptotic biomarkers. Finally, this therapy was effective in averting cardiac troponin loss and reverting the histological alterations as assessed by myocardial fibrosis and hypertrophy grading. Contrariwise, co-administration of wortmannin mostly attenuated the protective effects of rupatadine affording more or less similar results to that of isoproterenol-untreated rats. In conclusion, rupatadine could be an effective therapy against the development of isoproterenol-induced heart failure where PI3K/Akt pathway seems to play a crucial role in its protective effect.

JNJ7777120, a histamine H4 receptor antagonist, was shown to be effective in different experimental settings of allergic inflammation, including contact hypersensitivity. Toll-like receptors (TLRs) are thought to function as a link between innate and adaptive immune responses to various haptens. Here, we studied the suppression of TLR signaling as a possible mechanism by which JNJ7777120 exerts its anti-inflammatory effects against the chemical hapten, fluorescein isothiocyanate (FITC). The potential anti-oxidant effect of JNJ7777120 in this model was also examined. Mice subjected to FITC sensitization and challenge showed significantly elevated plasma immunoglobulin E (IgE) level, ear interleukin-4 (IL-4), tumor necrosis factor-alpha (TNF-α), and thiobarbituric acid reactive substance (TBARS) contents as well as increased myeloid differentiation factor 88 (MyD88) gene expression, nuclear factor-kappa B p65 (NF-κB p65), and phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) protein expression. This was accompanied by enhanced ear myeloperoxidase (MPO) and eosinophil peroxidase (EPO) activities as well as diminished glutathione (GSH) content and superoxide dismutase (SOD) activity. JNJ7777120 treatment perceivably reversed these effects, denoting profound anti-inflammatory and anti-oxidant character of JNJ7777120 which was confirmed by its mitigation of FITC-induced pathological changes in mouse ear. JNJ7777120 additionally enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), providing a novel mechanism by which JNJ7777120 functions as an anti-oxidant in this model. To conclude, JNJ7777120 afforded a remarkable amendment of FITC skin insult by virtue of its anti-inflammatory and anti-oxidant effects; the mechanistic basis of these effects may include modulation of TLR and Nrf2 pathways.