Neuroprotective effect of ranolazine improves behavioral discrepancies in a rat model of scopolamine-induced dementia.

Background: Ranolazine (Rn), an antianginal agent, acts in the central nervous system and has been used as a potential treatment agent for pain and epileptic disorders. Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases and the leading factor in dementia in the elderly. Aim: We examined the impact of Rn on scopolamine (Sco)-induced dementia in rats. Methods: Thirty-two albino male rats were divided into four groups: control, Rn, Sco, and Rn + Sco. Results: A significant decrease in the escape latency in the Morris water maze test after pre-treatment with Rn explained better learning and memory in rats. Additionally, Rn significantly upregulated the activities of the antioxidant enzymes in the treated group compared to the Sco group but substantially reduced acetylcholinesterase activity levels in the hippocampus. Moreover, Rn dramatically reduced interleukin-1 ß (IL-1ß) and IL-6 and upregulated the gene expression of brain-derived neurotrophic factor (BDNF). Furthermore, in the Sco group, the hippocampal tissue's immunohistochemical reaction of Tau and glial factor activating protein (GFAP) was significantly increased in addition to the upregulation of the Caspase-3 gene expression, which was markedly improved by pre-treatment with Rn. The majority of pyramidal neurons had large vesicular nuclei with prominent nucleoli and appeared to be more or less normal, reflecting the all-beneficial effects of Rn when the hippocampal tissue was examined under a microscope. Conclusion: Our findings indicated that Rn, through its antioxidative, anti-inflammatory, and anti-apoptotic effects, as well as the control of the expression of GFAP, BDNF, and Tau proteins, has a novel neuroprotective impact against scopolamine-induced dementia in rats.

Effect of vanillic acid and exercise training on fatty liver and insulin resistance in rats: Possible role of fibroblast growth factor 21 and autophagy.

BACKGROUND AND AIMS: The prevalence of non-alcoholic fatty liver disease has been alarmingly increased with no lines of effective treatment. Vanillic acid is a naturally occurring polyphenol with promising therapeutic effects. Exercise is well known to be an effective tool against obesity and its consequences. Thus, we aim to study the effect of vanillic acid alone and along with exercise on fatty liver induced by a high-fat diet in a rat model and to investigate possible novel mechanisms involved in their action. METHODS: In this study, 40 male rats were divided equally into five groups: control (standard chow diet), HFD (high-fat diet), HFD+VA (HFD+ vanillic acid (50 mg/kg/day orally), HFD+EX (HFD+ swimming exercise 5 days/week), HFD+VA+EX (HFD+ vanillic acid+ swimming exercise) for eight weeks. RESULTS: Body mass, liver weight, liver enzymes, cholesterol, and triglycerides were significantly decreased in the combined VA+EX group, with marked improvement in hyperglycemia, hyperinsulinemia, and consequently HOMA-IR index compared to the HFD group. These improvements were also reflected in the pathological view. VA and swimming, either solely or in combination, markedly increased hepatic and circulating fibroblast growth factor 21. Additionally, VA and swimming increased the immunohistochemical expression of the autophagosomal marker LC3 and decreased the expression of P62, which is selectively degraded during autophagy. CONCLUSIONS: These results suggest the hepatoprotective effect of VA and swimming exercise against fatty liver and the involvement of FGF21 and autophagy in their effect.

Cardamonin exerts a protective effect against autophagy and apoptosis in the testicles of diabetic male rats through the expression of Nrf2 via p62-mediated Keap-1 degradation.

Cardamonin (CARD) is a chalconoid with anti-inflammatory and antioxidant properties, and it is present in several plants. We sought to explore whether CARD exerts any positive effects against hyperglycemia-induced testicular dysfunction caused by type 2 diabetes and aimed to identify its possible intracellular pathways. Adult male rats were subdivided into six groups: control, CARD, diabetic (DM), DM + glibenclamide (GLIB), DM + CARD and DM + GLIB + CARD. Type 2 DM induced a significant increase in blood glucose and insulin resistance, along with diminished serum insulin, testosterone and gonadotropins levels, which were associated with the impairment of key testicular androgenic enzymes and cellular redox balance. Administration of CARD at a dose of 80 mg/kg for 4 weeks effectively normalized all of these alterations, and the improvement was confirmed by epididymal sperm analysis. After treatment with CARD, the pathological changes in spermatogenic tubules were markedly improved. Significantly, CARD upregulated testicular glucose transporter-8 (GLUT-8) expression and had inhibitory effects on elevated autophagy markers and caspase-3 immunoreactive cells. Furthermore, our results revealed that CARD was able to attenuate damage via activation of Nrf2 through the p62-dependent degradation of testicular anti-Kelch-like ECH-associated protein-1 (Keap-1). In conclusion, this study suggests that CARD provides protection against diabetic stress-mediated testicular damage. The use of CARD with conventional anti-diabetic therapy was associated with improved efficacy compared with conventional therapy alone.

A novel gastroprotective effect of zeaxanthin against stress-induced gastritis in male rats targeting the expression of HIF-1α, TFF-1 and MMP-9 through PI3K/Akt/JNK signaling pathway.

Stress-induced gastritis is a common problem in the intensive care unit. Zeaxanthin (ZE), a non-provitamin A carotenoid has been known to exert antioxidant and anti-inflammatory effects. In this study, we examined the effect of ZE on water avoidance stress (WAS)-induced gastritis in rats. 24 Sprague' Dawley male rats were divided into four groups; control, ZE, WAS and WAS+ZE. In the stressed rats, treatment with ZE effectively downregulated the gastric levels of total oxidant status (TOS), myeloperoxidase (MPO) and malondialdehyde (MDA), with significant upregulation of the antioxidant enzymes' activities and gastric levels of prostagladin-E2 (PGE2) as compared to the untreated stressed one. As noticed in the present study, ZE significantly decrease the gastric levels of interleukin-1 ß (IL-1ß) and IL-6 as well as suppression of nuclear transcription factor kappa-B (NF-κB) immunohistochemical expression together with upregulation of trefoil factor-1 (TFF-1) gene expression. Moreover, in the untreated WAS-induced gastritis group, gastrin and corticosterone levels were significantly increased together with upregulation of the gene expression of hypoxia inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), PI3K, Akt and JNK in the gastric tissues, which significantly improved by ZE administration. These all positive effects of ZE reflected on reduction of microscopic gastric mucosal damage and inflammatory cell infiltration with improvement of ulcer score. Our results discover that ZE has a new gastroprotective effect against stress-induced gastritis in rats, primarily through its antioxidative and anti-inflammatory effects, which are expressed in the regulation of the MMP-9 and HIF-1α signaling pathways.

Abscisic acid: a novel uterine stimulator in normal and diabetic rats.

Diabetes is usually associated with alterations in myometrial contractility with altered oxytocin responsiveness that increase the incidence of fetal and maternal morbidity and mortality. Pancreatic ß-cells release abscisic acid (ABA) in response to glucose, which in turn potentiates insulin secretion. The aim of the study was to find out the effect of ABA on the uterine contractility in normal and diabetic induced rats and tried to detect its possible underlying signaling pathway. Adult non-pregnant female rats were divided into normal nondiabetic group (n = 27) and diabetic group (n = 12). The effect of ABA on the normal and diabetic isolated myometrium was determined alone or after different blockers. Spontaneous diabetic myometrial contraction showed significant decrease and less responsiveness to oxytocin, KCL, and acetylcholine than nondiabetic samples. ABA showed 60% of oxytocin stimulatory effects on myometrial contraction in a dose-response manner in both groups. Meanwhile, this effect was decreased after blocking L-type calcium channels and completely abolished after blocking prostaglandin F (FP) and inositol trisphosphate (IP3) receptors. ABA is found to have an uterotonic effect that is mediated mainly via FP receptor through increasing the level of IP3. So, ABA by its novel effect could be beneficial as pre-labor prescription, especially in diabetic females.

Omega-3 polyunsaturated fatty acid docosahexaenoic acid and its role in exhaustive-exercise-induced changes in female rat ovulatory cycle.

Exhaustive exercises can cause delayed menarche or menstrual cycle irregularities in females. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are incorporated into a wide range of benefits in many physiological systems. Our work aimed to assess the role of ω-3 PUFA docosahexaenoic acid (DHA) on the deleterious effects of exhaustive exercise on the female reproductive system in rats. Virgin female rats were randomly divided into 4 groups (12 rats in each): control group, omega-3 group treated with DHA, exhaustive exercise group, and exhaustive exercised rats treated with DHA. Omega-3 was given orally to the rats once daily for 4 estrous cycles. Exhaustive exercises revealed lower levels in progesterone and gonadotropins together with histopathological decrease in number of growing follicles and corpora lutea. Moreover, the exercised rats showed low levels of ovarian antioxidants with high level of caspase-3 and plasma cortisol level that lead to disruption of hypothalamic-pituitary-gonadal axis. ω-3 PUFA DHA has beneficial effects on the number of newly growing follicles in both sedentary and exercised rats with decreasing the level of caspase-3 and increasing the antioxidant activity in ovaries. Exhaustive exercises can cause ovulatory problems in female rats that can be improved by ω-3 supplementation.

Effect of L-carnitine on diabetes-induced changes of skeletal muscles in rats.

BACKGROUND: Patients with diabetes mellitus (DM) are at risk of experiencing chronic complications such as retinopathy, nephropathy and myopathy. We aimed to evaluate the effects of L-carnitine on type II DM (T2DM)-induced biochemical, contractile and pathological changes in skeletal muscles of rats. METHODS: Thirty-two male Sprague Dawley rats were divided into the control, control+L-carnitine, T2DM and T2DM+L-carnitine groups. Plasma levels of glucose, insulin, malondialdehyde and antioxidants such as reduced glutathione, catalase and superoxide dismutase, haemoglobin A1c (HbA1c), insulin sensitivity index (ISI) as well as the contractile properties of the gastrocnemius muscle were measured. Also, histopathological studies and immunohistochemical examination of the gastrocnemius muscle using the MuRF1 (muscle RING-finger protein-1) marker were performed. RESULTS: In diabetic rats, malondialdehyde, glucose, insulin, HbA1c and MuRF1 were increased, whereas ISI and antioxidants were decreased and the contractile properties deteriorated. L-carnitine decreased malondialdehyde, glucose, insulin, HbA1c and MuRF1 and increased ISI and antioxidants. Also, L-carnitine improves the contractile properties in diabetic rats. Histopathological studies confirm our data. CONCLUSIONS: We conclude that L-carnitine exhibits protective effects on skeletal muscles of T2DM rats through its hypoglycemic and antioxidant actions as well as its inhibitory effect on protein degradation.

What is the effect of ghrelin on rat uterine contractility in vitro?

BACKGROUND: Ghrelin, a recently isolated gastric hormone, is an endogenous ligand for growth hormone secretagogue receptors. There is novel evidence that ghrelin might be expressed in rat ovaries, placental tissues, and the uterus. It has been reported to have modulatory effects on smooth muscle contractility. In this study, we investigated the effects of ghrelin on spontaneous and oxytocin-induced contractions in the rat uterus in vitro and tried to detect its signaling pathway. METHODS: Myometrium strips were removed from virgin female albino Wister rats and placed in a jacketed tissue bath. After initiation of spontaneous contractions, ghrelin was added to the tissue bath alone or after administration of indomethacin or NG-nitro-L-arginine methyl ester (L-NAME) or propranolol HCl. Student's t-test was used for statistical analysis. RESULTS: Our results revealed an inhibitory effect of ghrelin on both spontaneous and oxytocin-induced myometrial contractions. This effect was not affected by the application of indomethacin or L-NAME but was blocked after propranolol HCl administration. CONCLUSIONS: Ghrelin has an inhibitory effect on basal and oxytocin-induced rat myometrial contractions in vitro, and this myometrial response to ghrelin might be mediated by ß-receptor signaling pathway.