Effects of Stevia rebaudiana Bertoni extracts in the rat model of epilepsy induced by pentylenetetrazol: Sirt-1, at the crossroads between inflammation and apoptosis.

The current study investigated the effects of stevia extracts on a PTZ-induced epileptic rat model and its potential mechanism. Thirty male Sprague-Dawley rats were equally subdivided into 3 groups; (1) normal control (NC) group, (2) PTZ-group: received PTZ (50 mg/kg, i.p. every other day) for 2 weeks, and (3) PTZ+ Stevia group: received PTZ and stevia (200 mg/kg orally daily) for 4 weeks (2 weeks before the start of PTZ treatment and 2 weeks with PTZ administration). The first jerk latency and the seizure score were assessed in rats. Also, brain tissue samples were collected by the end of the experiment, and oxidative stress markers (catalase, MDA, and total antioxidant capacity (TAC)) were measured by biochemical analysis in hippocampal brain homogenates. Also, in the hippocampus, the expression of IL6 and Bcl-2 at the mRNA level and expression of Sirt-1, P53, caspase-3, GFAP, and NF-kB in CA3 hippocampal region by immunohistochemistry was investigated. PTZ substantially increased the seizure score and decreased the seizure latency. Also, PTZ significantly increased MDA, GFAP, IL-6, NF-kB, caspase-3, and p53 and significantly reduced Sirt-1, TAC, and Bcl-2 in hippocampal tissues compared to the control group (p < 0.01). However, Stevia Rebaudiana Bertoni (Stevia R.) significantly attenuated the PTZ-induced seizures, improved oxidative stress markers, downregulated GFAP, IL-6, NF-kB, caspase-3, and p53, and upregulated Sirt-1 and Bcl-2 in the CA3 hippocampal region (p < 0.01). In conclusion, Stevia R. exhibits neuroprotective and antiepileptic actions in PTZ-induced epilepsy due to its antioxidant, anti-apoptotic, and anti-inflammatory effects. Additionally, the Sirt-1 pathway might be involved in the antiepileptic and neuroprotective effects of stevia in PTZ-kindled epileptic rat model.

Possible mechanisms for the renoprotective effects of date palm fruits and seeds extracts against renal ischemia/reperfusion injury in rats.

PURPOSE: This work investigates the possible renoprotective effects of date palm fruits and seeds extract against renal ischemia and their underlying mechanisms. METHODS: 108-Sprague Dawle male rats were randomly allocated into 6 equal groups differently receiving aqueous or methanolic fruit and seed extracts. Assay of serum creatinine, BUN and TNF-α, morphological examination of the left kidney, markers of the redox state (MDA, CAT, and GSH), the expression of TNFα and Nrf2 genes at the level of mRNA, the expression of caspase-3 and TGF-ß proteins by immunohistochemistry were performed. RESULTS: 45-min renal I/R caused significant deterioration of kidney functions (increase in serum creatinine and BUN) and morphology (P < 0.001) and significant reduction in CAT activity and GSH levels with significant increase in serum TNF-α and MDA concentration and the expression of Nrf2, caspase-3, TNF-α, and TGF-ß in kidney tissues. Pre-treatment with either date palm fruit or seed extracts significantly improved kidney functions and morphology (P ≤ 0.001) with a significant increase in the expression of Nrf2 and CAT activity, and GSH concentration and a reduction in serum TNF-α and expression of caspase-3, TNF-α, and TGF-ß (P < 0.001). CONCLUSIONS: Administration of date palm extracts exhibited a renoprotective effect against renal I/R injury.This renoprotective action might be due to their antioxidants, anti-apoptotic and anti-inflammatory actions. Moreover, aqueous fruit extracts offered powerful renoprotective effect than aqueous seed extracts, and aqueous fruit and seed extracts were generally more effective than methanolic extracts.

Exercise and Stevia Rebaudiana (R) Extracts Attenuate Diabetic Cardiomyopathy in Type 2 Diabetic Rats: Possible Underlying Mechanisms.

BACKGROUND AND AIMS: In the current work, we studied the effects of exercise and stevia rebaudiana (R) extracts on diabetic cardiomyopathy (DCM) in type 2 diabetic rats and their possible underlying mechanisms. METHODS: Thirty-two male Sprague Dawley rats were randomly allocated into 4 equal groups; a) normal control group, b) DM group, type 2 diabetic rats received 2 ml oral saline daily for 4 weeks, c) DM+ Exercise, type 2 diabetic rats were treated with exercise for 4 weeks and d) DM+ stevia R extracts: type 2 diabetic rats received methanolic stevia R extracts. By the end of the experiment, serum blood glucose, HOMA-IR, insulin and cardiac enzymes (LDH, CK-MB), cardiac histopathology, oxidative stress markers (MDA, GSH and CAT), myocardial fibrosis by Masson trichrome, the expression of p53, caspase-3, α-SMA and tyrosine hydroxylase (TH) by immunostaining in myocardial tissues were measured. RESULTS: T2DM caused a significant increase in blood glucose, HOMA-IR index, serum CK-MB and LDH, myocardial damage and fibrosis, myocardial MDA, myocardial α-SMA, p53, caspase-3, Nrf2 and TH density with a significant decrease in serum insulin and myocardial GSH and CAT (p< 0.05). On the other hand, treatment with either exercise or stevia R extracts significantly improved all studied parameters (p< 0.05). Moreover, the effects of stevia R was more significant than exercise (p< 0.05). CONCLUSION: Both exercise and methanolic stevia R extracts showed cardioprotective effects against DCM and Stevia R offered more cardioprotective than exercise. This cardioprotective effect of these lines of treatment might be due to attenuation of oxidative stress, apoptosis, sympathetic nerve density and fibrosis and upregulation of the antioxidant transcription factor, Nrf2.

Effects of exercise and stevia on renal ischemia/reperfusion injury in rats.

BACKGROUND: The present work was designed to study the effects of methanolic stevia extracts and aerobic exercise and combination of both on renal I/R injury in male rats. METHODS: 60 adult male Sprague-Dawley rats were subdivided into five equal groups as sham, control, exercise, stevia, and stevia plus exercise group. After 5 weeks of exercise and stevia, animals were exposed to 45 min of left renal ischemia and right nephrectomy followed by reperfusion. Serum creatinine, creatinine clearance, fractional Na excretion (FENa+), malondialdehyde (MDA), reduced glutathione (GSH) and catalase (CAT) levels in kidney tissues were measured. Also, renal histopathology and the expression of caspase-3 by immunohistochemical examination were done. RESULTS: The results showed that stevia, exercise or combination of stevia and exercise caused a significant decrease in serum level of creatinine (p < 0.001) and FENa+ (p < 0.001) and an increase in creatinine clearance (p < 0.001). Moreover, this caused a significant decrease in (MDA; p < 0.046) and an increase in GSH (p < 0.01) and CAT (p < 0.01), as well as causing a significant decrease in caspase 3 expression compared to the control group. CONCLUSIONS: Pretreatment with either stevia or exercise of combination of both seem to have protective effects on renal I/R injury. However, the protective effect of exercise against renal I/R injury seems to be less than stevia. These effects might be due to attenuation of oxidative stress and apoptosis in kidney tissues.

Attenuation of metabolic dysfunctions in the skeletal muscles of type 1 diabetic rats by Stevia rebaudiana extracts, via AMPK upregulation and antioxidant activities.

BACKGROUND: Stevia rebaudiana Bertoni leaves are well-known for their sweetness and have been used as a non-caloric sweetener in several countries. It has numerous therapeutic properties which have been proven safe and effective over hundreds of years. In the present study, we aimed to evaluate the possible antioxidant effects of stevia extracts and their role in regulating AMPK in type-1 diabetic rats. METHODS: Fifty male Sprague Dawely rats were divided into: (1) normal control (NC) group; normal rats receiving 0.5 ml normal saline, (2) DM group; diabetic rats receiving 0.5 ml normal saline, (3) DM + MSE group; DM rats receiving 200 mg/kg of methanolic extract of stevia, (4) DM + S group; DM rats receiving 2 mg/kg of pure stevioside, and (5) DM + CGA group; DM rats receiving 10 mg/kg of pure chlorogenic acid. Four weeks after treatment, AMPK activity, GLUT4 mRNA and oxidative stress markers were measured in frozen muscles. Also, fasting blood glucose in serum, insulin and HbA1c were measured at the end of experiment. RESULTS: DM caused a significant increase in serum fasting glucose, HbA1c and muscle MDA with significant reduction in serum insulin, muscle SOD, catalase, GPx, AMPK activity and GLUT4 expression (p < 0.05). Treatment with stevia extract, pure stevioside and chlorogenic acid caused significant improvements in the studied parameters (p < 0.05). CONCLUSIONS: We concluded that stevia extracts and derivatives may improve metabolic dysfunction in skel- etal muscles via upregulation of AMPK and GLUT4 and suppression of oxidative stress.

l-Carnitine Modulates Epileptic Seizures in Pentylenetetrazole-Kindled Rats via Suppression of Apoptosis and Autophagy and Upregulation of Hsp70.

l-Carnitine is a unique nutritional supplement for athletes that has been recently studied as a potential treatment for certain neuropsychiatric disorders. However, its efficacy in seizure control has not been investigated. Sprague Dawley rats were randomly assigned to receive either saline (Sal) (negative control) or pentylenetetrazole (PTZ) 40 mg/kg i.p. × 3 times/week × 3 weeks. The PTZ group was further subdivided into two groups, the first received oral l-carnitine (l-Car) (100 mg/kg/day × 4 weeks) (PTZ + l-Car), while the second group received saline (PTZ + Sal). Daily identification and quantification of seizure scores, time to the first seizure and the duration of seizures were performed in each animal. Molecular oxidative markers were examined in the animal brains. l-Car treatment was associated with marked reduction in seizure score (p = 0.0002) that was indicated as early as Day 2 of treatment and continued throughout treatment duration. Furthermore, l-Car significantly prolonged the time to the first seizure (p < 0.0001) and shortened seizure duration (p = 0.028). In addition, l-Car administration for four weeks attenuated PTZ-induced increase in the level of oxidative stress marker malondialdehyde (MDA) (p < 0.0001) and reduced the activity of catalase enzyme (p = 0.0006) and increased antioxidant GSH activity (p < 0.0001). Moreover, l-Car significantly reduced PTZ-induced elevation in protein expression of caspase-3 (p < 0.0001) and ß-catenin (p < 0.0001). Overall, our results suggest a potential therapeutic role of l-Car in seizure control and call for testing these preclinical results in a proof of concept pilot clinical study.

Effects of aluminum oxide (Al2O3) nanoparticles on ECG, myocardial inflammatory cytokines, redox state, and connexin 43 and lipid profile in rats: possible cardioprotective effect of gallic acid.

The objectives of present study were to examine the effects of aluminum oxide (Al2O3) nanoparticles on myocardial functions, electrical activities, morphology, inflammation, redox state, and myocardial expression of connexin 43 (Cx43) and the effect of gallic acid (GA) on these effects in a rat animal model. Forty male albino rats were divided into 4 equal groups: the control (normal) group; the Al2O3 group, rats received Al2O3 (30 mg·kg(-1), i.p.) daily for 14 days; the nano-alumina group, rats received nano-alumina (30 mg·kg(-1), i.p.) daily for 14 days; and the nano-alumina + GA group, rats received GA (100 mg·kg(-1) orally once daily) for 14 days before nano-alumina administration. The results showed disturbed ECG variables and significant increases in serum levels of LDH, creatine phosphokinase (CPK), CK-MB, triglycerides (TGs), cholesterol and LDL, nitric oxide (NO), and TNF-α and myocardial concentrations of NO, TNF-α, and malondialdehyde (MDA), with significant decreases in serum HDL and myocardial GSH, SOD, catalase (CAT), and Cx43 expression in the nano-alumina group. Pretreatment with GA improved significantly all parameters except serum and myocardial NO. We concluded that chronic administration of Al2O3 NPs caused myocardial dysfunctions, and pretreatment with GA ameliorates myocardial injury induced by nano-alumina, probably through its hypolipidaemic, anti-inflammatory, and antioxidant effects and upregulation of Cx43 in heart.