Poly (ADP-ribose) polymerase pathway inhibitor (Olaparib) upregulates SERCA2a expression and attenuates doxorubicin-induced cardiomyopathy in mice.

The cardiotoxicity induced by doxorubicin is dose-dependent. The present study tested the potential cardioprotective effect of Poly ADP Ribose Polymerase (PARP) pathway inhibitor "olaparib" in a mouse model of doxorubicin-induced cardiomyopathy (DOX-CM). Seventy-two male BALB/c mice were randomized into six equal groups; control, DOX-CM, dexrazoxane-treated, and three olaparib-treated groups (5, 10, and 50 mg/kg/day). Cardiomyopathy was assessed by heart weight/Tibial length (HW/TL) ratio, cardiac fibrosis, oxidative stress, and electron microscope. Myocardial expression of SERCA2a mRNA and cleaved PARP-1 protein were also assessed. Similar to dexrazoxane, olaparib (10 mg/kg/day) significantly ameliorated oxidative stress, and preserved cardiac structure. It also suppressed myocardial PARP-1 protein expression and boosted SERCA2a mRNA expression. Olaparib (5 or 50 mg/kg/day) failed to show comparable effects. The current study detected the cardioprotective effect of olaparib at a dosage of 10 mg/kg/day. Also, the present study discovered a new cardioprotective mechanism of dexrazoxane by targeting PARP-1 in the heart.

Sacubitril/valsartan combination enhanced cardiac glycophagy and prevented the progression of murine diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM) is linked to disturbance in cardiac glucose handling and increased cardiac glycogen storage. This study tested the potential role of sacubitril/valsartan on the progression of DCM in high fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetic rats compared to valsartan alone, including their effects on the cardiac glycophagy process. MATERIALS AND METHODS: Rats were fed on HFD for 6 weeks followed by single low-dose STZ (35 mg/kg). After confirming hyperglycemia, diabetic rats were continued on HFD and divided into three subgroups: Untreated-diabetic, Valsartan-treated diabetic and Sacubitril/valsartan-treated diabetic groups; in addition to a control group. Changes in ECG, blood glucose, serum insulin, lipid profile, and Homeostasis model of assessment of insulin resistance (HOMA-IR) were assessed and the degree of cardiac fibrosis was examined. Cardiac glycogen content and glycophagy process were evaluated. RESULTS: Sacubitril/valsartan administration to diabetic rats resulted in improvement of metabolic changes more than valsartan alone. Also, sacubitril/valsartan effectively prevented diabetes-associated cardiac hypertrophy, QTc prolongation, and fibrosis. Finally, cardiac glycogen concentrations in diabetic rats were decreased by sacubitril/valsartan combination, coupled with significant induction of glycophagy process in the diabetic rats' heart. CONCLUSION: Sacubitril/valsartan therapy provides a more favorable metabolic and cardioprotective response compared to valsartan alone in a rat model of DCM. These findings may be due to a direct cardioprotective impact of sacubitril/valsartan and secondary beneficial effects of improved hyperglycemia and dyslipidemia. In addition, these beneficial cardiac effects could be attributed to the induction of the glycophagy process and alleviating cardiac glycogen overload.

Pentosan polysulfate exerts anti-inflammatory effect and halts albuminuria progression in diabetic nephropathy: Role of combined losartan.

Pentosan polysulfate sodium (PPS) is a polysulfated glycosaminoglycan approved for the treatment of interstitial cystitis. It also showed renoprotective effects in chronic kidney injury models, for example, 5/6 nephrectomy and diabetic nephropathy (DN). In the present study, we addressed to evaluate the therapeutic value of PPS in DN of rats in combination with losartan (LSR). Sixty male Sprague-Dawley rats were randomly divided into six groups: control group, untreated diabetic groups (8 and 16 weeks after diabetes induction by streptozotocin "STZ", 60 mg/kg, intraperitoneal [I.P.]), LSR-treated diabetic group (10 mg/kg/day, P.O.), PPS-treated diabetic group (25 mg/kg/day, P.O.), and combination-treated diabetic group. Drug treatment was started 8 weeks after induction of diabetes and continued for a further 8 weeks. Renal functions, albuminuria, renal IL-6, oxidative stress, and renal histopathology were evaluated. STZ-treated diabetic rats developed progressive albuminuria, renal dysfunction, and significant glomerular change 16 weeks after induction of diabetes. Administration of PPS, alone or in combination with LSR, showed some beneficial effects on DN evolution and significantly decreased renal inflammation as detected by IL-6 level. The best beneficial effect on DN evolution was obtained by PPS sole therapy based on albuminuria evaluation and renal histopathology. However, the combination of PPS and LSR did not show additive benefits. This study reported that the renoprotection of PPS in the setting of DN is evident by exerting anti-inflammatory and antioxidant effects, but this effect could be masked when combined with an angiotensin receptor blocker.

Clopidogrel combats neuroinflammation and enhances learning behavior and memory in a rat model of Alzheimer's disease.

BACKGROUND AND AIM: Alzheimer's disease (AD) is a progressive neurodegenerative disease. Multiple molecular mechanisms have been employed in its pathogenesis such as Amyloid ß (Aß) formation, tau protein hyperphosphorylation, reduced acetylcholine (ACh) level, and neuroinflammation. This study aimed to assess the possible neuroprotective effect of clopidogrel in AD model induced by aluminum chloride (AlCl3) in rats. METHODS: Sixty adult male Sprague-Dawley rats were divided into four different groups: Control, AlCl3, AlCl3 + donepezil, and AlCl3 + Clopidogrel. AlCl3 and the drugs were given orally once/day for 42 days. The spatial learning and memory and recognition memory were evaluated using Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests, respectively. After euthanasia, hippocampal acetylcholinesterase (AChE) activity, tumor necrosis factor-alpha (TNF-α), and interleukin-1ß (IL-1ß) levels were biochemically assessed. Moreover, amyloid precursor protein (APP) mRNA gene expression was analyzed in the hippocampi of all rats. Histopathology for amyloid plaques was done. RESULTS: Clopidogrel co-treatment significantly ameliorated the cognitive deficits induced by AlCl3 in rats. Besides, clopidogrel significantly reduced AChE activity, TNF-α and IL-1ß concentrations, and APP mRNA gene expression in the hippocampi of rats compared to AlCl3 rats. The decrease of hippocampal TNF-α and IL-1ß concentrations by clopidogrel was significant compared to donepezil co-treated rats. Clopidogrel co-treatment lessened amyloid plaque deposition in the hippocampal tissues of rats compared to AlCl3 rats. CONCLUSION: These findings demonstrate that clopidogrel could alleviate learning and memory deficit induced by AlCl3 in rats and significantly reduced AChE activity. The neuroprotective outcome of clopidogrel might be assigned to its anti-inflammatory effect.