Pretreatment Of Rats Research Articles

Exploring the effects of edaravone in rats with contrast-induced acute kidney injury

AimsOxidative stress and inflammatory response play a vital role in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). This study investigated the effects of edaravone in rats with CI-AKI. Main methodsMale Sprague Dawley rats were randomly assigned into four groups (n = 11–14/group): control, edaravone (30 mg/kg/day intraperitoneally (IP)), CI-AKI, and edaravone with CI-AKI. The induction of CI-AKI was performed by dehydration and the administration of contrast media (iohexol) and inhibitors of prostaglandin (indomethacin) and nitric oxide synthesis (L-NAME: N-nitro L-arginine methyl ester). Edaravone was administered for two weeks before the induction of CI-AKI. Serum creatinine and urea, renal oxidative stress and inflammatory biomarkers, and histopathological alterations were evaluated after 48 h of contrast exposure. Key findingsRats with CI-AKI showed a significant increase in serum creatinine and urea. The levels of antioxidant biomarkers including glutathione peroxidase, superoxide dismutase and reduced glutathione were significantly decreased in CI-AKI group versus control. Pre-treatment of rats with edaravone normalized kidney function and protected the kidney from oxidative damage as demonstrated by normalization of previous biomarkers. Furthermore, edaravone partially ameliorated renal histopathological alterations relative to the CI-AKI group, notably in the nephrons. No changes were observed in inflammatory biomarkers including tumour necrosis factor-alpha and interleukin-6 among all groups. SignificanceThe current findings suggest that edaravone could be a potential strategy to ameliorate developing CI-AKI possibly by improving renal antioxidant capacity. Further studies are warranted to expand the current understanding of the use of edaravone in the various models of AKI.

Characteristics of the gut microbiota in Bifidobacterium catenulatum LI10 pretreated rats with lower levels of D-galactosamine-induced liver damage.

Liver damage has caused great illness in human beings. Bifidobacterium catenulatum LI10 has been determined with protective effect against D-galactosamine-induced liver damage. However, due to the sample limitation, the individual difference in its protective effect was not determined. The current study was designed to characterize the gut microbiota of LI10-pretreated rats with lower levels of liver damage. A series of experiments and bioinformatic analyses were carried out. Two rat cohorts with different levels of liver damage were determined, that is, Non-Severe and Severe cohorts. Six out of the seven measured liver function variables were lower in the Non-Severe cohort, while four cytokine variables also yielded differences between the two cohorts. The Non-Severe and Severe cohorts were determined with distinct gut microbiota, among which ASV14_Parabacteroides and ASV7_Bacteroides were most associated with Non-Severe and Severe cohorts, respectively. Five phylotypes were determined as structural gatekeepers in the microbiota network of Non-Severe cohort, ASV135_Lachnospiraceae_NK4A136 of which contributed most to the stability of the network. The relevant findings suggest that some gut bacteria could benefit the protective effect of LI10 on lowering the severity of rat liver damage. The bacteria benefiting the protective effects of potential probiotics could be further investigated for future clinical application.

EFFECT OF NANONIZED CHRYSIN ON FEXOFENADINE PHARMACOKINETICS MEDIATED BY P-GLYCOPROTEIN IN RATS

Chrysin(CHR) is an abundant flavonoid in nature and has been found to possess P-glycoprotein (P-gp) inhibition activity in vitro, which may have the potential to alter bioavailability of P-gp substrates. The main objective of this study was to investigate the effect of nanonized chrysin (NCH) on the intestinal absorption and pharmacokinetics of P-gp probe substrate; fexofenadine in rats. NCH was prepared by antisolvent precipitation method and characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and in vitro dissolution testing. The influence of CHR and NCH on fexofenadine intestinal transport and permeability were evaluated by in vitro non-everted sac and in situ single pass intestinal perfusion (SPIP) studies. These findings were further confirmed by an in vivo pharmacokinetic study in which fexofenadine was administered (10 mg/kg, p.o) to CHR and NCH (50 mg/kg, p.o.) pretreated (10 days) rats and its plasma concentrations were determined by HPLC analysis. The intestinal transport and apparent permeability (Papp) of fexofenadine were significantly increased in duodenum, jejunum and ileum of CHR and NCH pretreated group as compared with the control. Similarly effective permeability (Peff) of fexofenadine was increased significantly in ileum of CHR and NCH pretreated group as compared with control. Cmax, AUC0-t and AUC0- ∞ of fexofenadine were found to be increased in CHR and NCH pretreated groups. Further, the CL/F and Vd/F of fexofenadine were significantly decreased. NCH enhances the oral bioavailability of fexofenadine by inhibition of P-gp mediated drug efflux during the intestinal absorption.

Crassocephalum rubens extract and fractions: Hypolipidemic and cardioprotective activities

Globally, cardiovascular diseases are becoming the major cause of death. Crassocephalum rubens is an indigenous vegetable used traditionally in the treatment of several disease conditions including stomach upset, wounds, and high blood pressure. However, there are limited literature reports on its hypolipidemic and cardioprotective activities, hence this study investigated the effects of leaf methanol extract and fractions of C. rubens on lipid profile, liver, cardiac marker enzymes; alanine (ALT), and aspartate (AST) aminotransferases, and cardiac tissue integrity in Isoproterenol-induced myocardial infarction (MI) in rats. Forty-five male Wistar rats were randomly divided into nine groups and administered different doses (100 & 150 mg/kg) of the plant extract and fractions for 14 days while normal control and MI control received phosphate buffer saline. C. rubens leaf methanol extract and fractions significantly (p<0.05) reduced TC (75.45 ± 2.44 - 96.09 ± 1.65 mg/dL), TG (84.04 ± 1.79 - 127.00 ± 0.47 mg/dL), VLDL-C (16.81 ± 0.36 - 25.42 ± 0.10 mg/dL), LDL-Cholesterol (03.49 ± 1.03 - 26.04 ± 1.64 mg/dL), and AST of the pretreated myocardial infarcted rats versus MI control (168.70 ± 9.85 mg/dL, 146.60 ± 1.74 mg/dL, 29.31 ± 0.34 mg/dL, 77.73 ± 9.67 mg/dL, respectively), while plasma HDL-C was increased. The crude extract and fractions of C. rubens showed significant cardioprotective activities on the integrity of the heart tissues of the experimental rats. The findings reveal antihyperlipidemic and cardioprotective potentials and provide a possible lead for isolation of bioactive compounds from C. rubens in the management of hyperlipidemia and its associated ailments.

JAK2/STAT3 pathway mediates beneficial effects of pterostilbene on cardiac contractile and electrical function in the setting of myocardial reperfusion injury

Contractile dysfunction and fatal arrhythmias are the hallmarks of myocardial ischemia/reperfusion (I/R) injury. Pterostilbene has notable cardioprotective effects, but its main mechanisms are not fully understood. Here, we investigated the effect of PTE on myocardial hemodynamics, arrhythmias, inflammatory/oxidative responses, and the causal role of the JAK2/STAT3 pathway in rats with acute myocardial I/R injury. Sixty male 7-8 months Sprague-Dawley rats (n=10/each group) experienced in vivo model of myocardial I/R injury through 40-min LAD coronary artery occlusion and subsequent 24-h reperfusion. PTE at concentrations of 5 and 25 mg/kg was intraperitoneally administered to rats five min before reperfusion. Cardiac hemodynamics, reperfusion-induced ventricular arrhythmias, infarct size, inflammatory cytokines, oxidative stress markers, the activity of the JAK2/STAT3 pathway were measured as the endpoints. Administration of PTE to I/R-injured rats recovered myocardial contractile function and reduced infarct size and ventricular arrhythmias counts and incidence in a dose-dependent manner. PTE at 25 mg/kg significantly and more potently reduced the levels of inflammatory mediators NF-?B, TNF-?, and IL-1?, suppressed intracellular ROS production, augmented the activity of glutathione, and manganese-superoxide dismutase, and upregulated the JAK2 and STAT3 phosphorylation. Importantly, pretreatment of rats with Ag490 as a JAK2 inhibitor significantly abolished the cardioprotective and signaling effects of PTE in I/R rats. PTE exerts significant protective effects on reducing arrhythmias and myocardial infarction and enhancing cardiac function by stimulating JAK2/STAT3-related suppression of inflammatory and oxidative reactions in the I/R injury setting.

Effectual Endeavors of Silk Protein Sericin against Isoproterenol Induced Cardiac Toxicity and Hypertrophy in Wistar Rats.

The silkworm cocoon has been used in the treatment of various ailments in different Asian countries. This research was designed to evaluate the effect of sericin on myocardial necrosis and hypertrophy in isoproterenol-challenged rats. The rats were administered with sericin (500 and 1000 mg/kg, p.o.) for 28 days, followed by administration of isoprenaline (85 mg/kg, s.c.) on the 29th and 30th days. The cardioprotective activity was assessed by various physical, enzymatic, and histopathological parameters along with apoptotic marker expression. The cardioprotective effect showed that pre-treatment of rats with sericin significantly increased the non-enzymatic antioxidants marker in serum and heart tissue (glutathione, vitamin E, and vitamin C). The results were the same in enzymatic antioxidant marker, mitochondrial enzymes, and protein. The grading of heart, heart/body weight ratio, gross morphology, cardiac markers, oxidative stress markers in serum and heart tissue, glucose, serum lipid profiling and Lysosomal hydrolases, heart apoptotic markers such as MHC expression by western blot, apoptosis by flow cytometry, total myocardial collagen content, fibrosis estimation, myocyte size were significantly decreased when compared with isoproterenol (ISG) group however histopathological studies showed normal architecture of heart in both control and treated rats. The pharmacological study reflects that sericin on both doses i.e., 500 mg/kg and 1000 mg/kg have potent cardioprotective action against the experimental model which was confirmed by various physical, biochemical, and histopathological parameters evaluated further research is required to examine the molecular mechanism of cardioprotective effect of sericin.

Acute toxicity profile and gastroprotective potential of ethanolic leaf extract of Manihot esculenta Crantz

The leaves of Manihot esculenta Crantz are used widely in traditional medicine to treat gastric ulcers. However, the safety and ethnopharmacological use of the plant as an anti-ulcer agent has not been validated in experimental studies. The study investigated the toxicity profile and anti-ulcer properties of ethanolic leaf extract of Manihot esculenta (MELE) in rats. A high dose of MELE (2000 mg/kg, p.o.) did not cause death in any of the rats. Moreover, no behavioural, haematological, or biochemical abnormalities could be attributed to the extract. The administration of acidified alcohol reduced rats’ luminal pH from 4.47 ± 1.39 (naïve control) to 1.95 ± 0.31 in the negative control rats. However, pre-treatment of rats with MELE (30, 100, and 300 mg/kg, p.o.) or omeprazole (10 mg/kg, p.o.) significantly (p < 0.05) elevated the luminal pH to 2.24 ± 0.19, 3.21 ± 0.18, 3.12 ± 0.40 and 2.63 ± 0.10 respectively. MELE (100 and 300 mg/kg) and omeprazole (10 mg/kg) caused a significant (p < 0.05) reduction in rats’ gastric ulceration with percentage inhibition of 71.05, 76.31 and 78.94% respectively. The extensive ulceration and erosion of the stomachs of rats in the negative control group were reversed by treatment with various doses of the extract and omeprazole. Elevated Ki67 immunoreactivity in the negative control group was also reduced by the MELE (30, 100 and 300 mg/kg) and the standard reference drug, omeprazole (10 mg/kg). The present study suggests that MELE produced no observed adverse effects and offered protection against acidified ethanol-induced gastric ulceration. Further studies should aim at isolating the active compounds responsible for the anti-ulcer effect as well as their possible mechanisms of action.

Bergapten mediated inflammatory and apoptosis through AMPK/eNOS/AKT signaling pathway of isoproterenol-induced myocardial infarction in Wistar rats.

Bergapten (BeG) is explored for its anti-inflammatory and antioxidant properties. Myocardial infarction (MI) is reported to be one of the leading cardiovascular diseases characterized by mitochondrial dysfunction and apoptosis. The main purpose of this study is to assess the cardiopreventive effects of BeG (50 mg/kg) in isoproterenol (ISO)-induced MI in Wistar rats. The increased infarct size after ISO induction was reduced simultaneously on treatment with BeG. Similarly, augmented levels of cardiac biomarkers, namely cardiac troponin T, creatine kinase (CK), cardiac troponin I, and CK-MB were also suppressed by BeG. The increased rate of lipid hydroperoxidesand thiobarbituric acid reactive substances owingto the oxidative stress caused by free radical generation in ISO-inducedrats were also inhibited by BeG. Antioxidants reduce oxidative stress by scavenging free radicals. ISO induction reduces these antioxidant enzymes glutathione peroxidase, catalase, superoxide dismutase, and glutathione, andlevels causing oxidative cardiac damage to the heart tissue. BeG supplementation improved these enzymes synthesis preventing potential damage to the myocardium. Inflammation caused by ISO pretreatment increased the secretion of proinflammatory cytokines in ISO-inducedrats. Pretreatment with BeG suppressed these inflammatory cytokines to a normal level in ISO + BeG-treated rats. The histopathological examination of the morphological characteristics showed that the intensity of cardiac damage caused by ISO induction was less in BeG pretreated rats with less inflammatory cells and no necrosis. BeG also showed promising results in the molecular alteration of AMP-activated protein kinase/endothelialnitric oxide synthase/protein kinase B signaling molecules. These observations emphasize the cardioprotective effects of BeG and its potential use as a drug in the near future.

Icariin and Competing Endogenous RNA Network: A Potential Protective Strategy Against Contrast-Induced Acute Kidney Injury.

BackgroundIcariin presents protective effect in several kidney diseases. However, the role of icariin in contrast-induced acute kidney injury (CIAKI) is still unclear. This study aimed to investigate the effect of icariin in CIAKI, as well as exploring the underlying mechanism from the aspect of interaction between protein-coding genes and non-coding RNAs.MethodsThe effect of icariin was evaluated in both in vivo and in vitro CIAKI models. Rat kidneys were collected for genome-wide sequencing. The differentially expressed genes (DEGs) were screened and visualized by R software. The function annotation of DEGs was analyzed by Metascape. By Cytoscape software, the competing endogenous RNA (ceRNA) network was constructed, and hub genes were selected. Expressions of hub genes were validated by PCR. Association of hub genes in the ceRNA network and renal function was also examined.ResultsIcariin protected against CIAKI in both in vivo and in vitro models. Based on DEGs in icariin pretreated CIAKI rats, lncRNA- and circRNA-associated ceRNA networks were constructed, respectively. Function annotation showed the ceRNA networks were enriched in ERK1 and ERK2 cascade, MAPK signaling and NF-κB signaling. Further, two circRNAs, six lncRNAs, four miRNAs and nine mRNAs were selected as hub genes of the ceRNA network. Among them, eight mRNAs (Acot1, Cbwd1, Ly6i, Map3k14, Mettl2b, Nyap1, Set and Utp20) were negatively correlated with renal function, while one mRNA (Tmem44) was positively correlated with renal function.ConclusionIcariin presented a protective effect against CIAKI. The ceRNA network, involving Acot1, Cbwd1, Ly6i, Map3k14, Mettl2, Nyap1, Set, Tmem44 and Utp20, might partially contribute to the underlying mechanism of icariin protection by regulation of ERK1 and ERK2 cascade, MAPK signaling and NF-κB signaling.

Effect of oxytocin pretreatment on the development of morphine tolerance and dependence in rats

Increased opioid synthesis and release, and enhanced alpha-2 adrenoceptor signaling have been suggested to mediate repeated oxytocin-induced long-lasting effects including elevated pain threshold in rats. This study evaluated whether oxytocin pretreatment would influence development of dependence and tolerance to the nociceptive and body temperature responses to morphine and enhance effects of alpha-2 adrenergic agonist clonidine on nociceptive threshold, body temperature and morphine withdrawal signs. Rats injected subcutaneously with saline or 1 mg/kg oxytocin for 5 days were implanted with placebo or morphine pellets 24 h after the treatment period. Body temperature and nociception were assessed, with nociception determined via by hot plate and tail immersion tests, before and 4, 24 and 48 h after pellet implantation, and following a challenge dose of morphine. Withdrawal signs were determined after naloxone administration. Oxytocin produced analgesia, as evidenced by increased paw withdrawal latency in the hot plate test. Morphine increased body temperature and nociceptive threshold which declined over time. Morphine challenge could not demonstrate tolerance to the body temperature response. Analgesic tolerance was observed in the hot plate test in saline and in both tests in oxytocin pretreated rats. Naloxone-precipitated withdrawal appeared to be less severe in oxytocin pretreatment. Clonidine was ineffective on the withdrawal signs but decreased body temperature and increased tail flick latency in the tail immersion test in oxytocin pretreated animals. These results, while producing evidence for a hyperresponsiveness in alpha-2 adrenoceptors, provide contrasting effects on morphine tolerance and dependence, and their partial mediation by opioidergic and adrenergic activation in repeated oxytocin treatment.

Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D2 and Histamine H3 Receptors: A PET Study in Healthy Rats.

Introduction: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between the dopaminergic and histaminergic systems suggest that dual-action pharmaceuticals like AG-0029 (D2/D3 agonist/H3 antagonist) could ameliorate both the motor and cognitive symptoms of PD. The current study aimed to demonstrate the interaction of AG-0029 with its intended targets in the mammalian brain using positron emission tomography (PET). Methods: Healthy male Wistar rats were scanned with a small-animal PET camera, using either the dopamine D2/D3 receptor ligand [11C]raclopride or the histamine H3 receptor ligand [11C]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [11C]raclopride PET data (60 min duration) were analyzed using the simplified reference tissue model 2 (SRTM2) with cerebellum as reference tissue and the nondisplaceable binding potential as the outcome parameter. Data from dynamic [11C]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution (VT) as the outcome parameter. Receptor occupancy was estimated using a Lassen plot. Results: Dopamine D2/3 receptor occupancies in the striatum were 22.6 ± 18.0 and 84.0 ± 3.5% (mean ± SD) after administration of 0.1 and 1 mg/kg AG-0029, respectively. In several brain regions, the VT values of [11C]GSK-189254 were significantly reduced after pretreatment of rats with 1 or 10 mg/kg AG-0029. The H3 receptor occupancies were 11.9 ± 8.5 and 40.3 ± 11.3% for the 1 and 10 mg/kg doses of AG-0029, respectively. Conclusions: Target engagement of AG-0029 as an agonist at dopamine D2/D3 receptors and an antagonist at histamine H3 receptors could be demonstrated in the rat brain with [11C]raclopride and [11C]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D2/D3 and moderate (submicromolar) affinity to H3 receptors.

Cytoprotective Effect of Methanol Extract of Laportea aestuans on Acidified Ethanol-induced Gastric Ulcer in Male Wistar Rats

Laportea aestuans (Urticaceae) plant is widely distributed in tropical rain forests and used as remedial agent for various diseases in Nigeria by herbal practitioners. Ethanol consumption is one of the common causes of gastric ulcer due to excessive generation of reactive oxygen species and erosion of gastric mucosal layer. This study investigated the cytoprotective effect of pretreatment with methanol extract of Laportea aestuans (MELA) for 7 days on ethanol-induced gastric ulcer in male Wistar rats using cimetidine as a standard drug. Ulcerogenic parameters, oxidative damage, inflammatory and apoptotic markers were evaluated. MELA showed a significant dose-dependent (p &lt; 0.01) decrease in ulcer score (US), ulcer index (UI) and peptic activity with an increase in mucus content and percentage inhibition compared to the ethanol group. Activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), Glutathione S-transferase (GST) and level of reduced glutathione (GSH) were also increased with concomitant decrease in malondialdehyde (MDA) level in MELA treated rats. Serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and activities of cytochrome c (Cyt c), caspases-3 and -9 (CASPS-3 and -9) were also reduced by administration of MELA. Taking together, this study shows that MELA protected the gastric mucosal against the assault induced by ethanol via upregulation of the antioxidant system, and downregulation of inflammatory and apoptotic processes.&#x0D; HIGHLIGHTS&#x0D; &#x0D; Oral administration of ethanol to Wistar rats induced gastric ulceration&#x0D; Oral administration of ethanol to Wistar rats caused ulcer by generation of ROS, inflammation and induce apoptosis&#x0D; Pretreatment of rats with methanol extract of Laportea aestuans (MELA) preserved the gastric mucosal integrityby boosting antioxidant defence system and inhibiting inflammatory and apoptotic processes&#x0D; &#x0D; GRAPHICAL ABSTRACT

Prelimbic medial prefrontal cortex has bidirectional control over the expression of behavioral sensitization to 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) depending on the context of drug administration

Behavioral sensitization to MDMA is observed in the vast majority of rats if tested in the same environment in which previous MDMA exposure occurred, but not if tested in a novel, unpaired context. Previous studies have revealed a critical role for the prelimbic region of medial prefrontal cortex (PL) in the expression of sensitization to MDMA, but these studies assessed sensitization only in MDMA-paired environments. Given that PL activity can both facilitate and suppress behavior depending on context, we tested the hypothesis that PL has bidirectional control over the expression of locomotor sensitization to MDMA depending on the context of drug administration. Rats were treated with either saline or MDMA (5.0 mg/kg) twice daily for 5 days, in either their home cages (unpaired groups) or the activity monitors that were used for tests of sensitization on challenge days (paired groups). Prior to MDMA challenge injections (2.5 mg/kg; at ∼ 2 weeks of withdrawal), rats received bilateral PL microinjections of either lidocaine (100 μg/0.5 μl/side) or physiological saline (0.5 μl/side). Locomotor activity in response to MDMA challenge was unaffected by PL inactivation in saline pretreated rats. However, PL inactivation caused a decrease in locomotion to the challenge injection in MDMA/paired rats and an increase in locomotion in MDMA/unpaired rats. These results establish a novel role for PL in suppressing the expression of behavioral sensitization when subjects are challenged in a drug-unpaired context, adding to the literature implicating PL activity in both the expression and inhibition of other drug-related behaviors.

Evaluation of antiobesity and hepatorenal protective activities of Salvia officinalis extracts pre-treatment in high-fat diet-induced obese rats.

The present study evaluated the effects of Hail Salvia officinalis total extract (SOTE) and its high flavonoid fraction (SOHFF) on the high-fat diet (HFD)-induced obesity and hepatorenal damage in rats. Salvia officinalisplants were collected from Hail region, Saudi Arabia. Rats were fed HFD and supplemented orally with SOTE (250mgkg-1) or SOHFF (100mgkg-1) or simvastatin (SVS; 10mgkg-1) every day for 8weeks. Compared to the controls, HFD-induced obesity led to significant increases in body weight, body weight gained, blood insulin, leptin, cardiac enzymes (LDH and CPK) activity, and atherogenic index (AI). HFD rats also showed higher levels of hepatic and renal function biomarkers (ALT, urea, and creatinine), as well as lower levels of PPARγ and Nrf2-gene expression and a disrupted lipid profile. Moreover, HFD rats had lower levels of hepatic and renal antioxidant biomarkers (CAT, GPx, SOD, GR, and GSH), accompanied by higher levels of hepatic and renal lipid peroxidation (LPO), nitric oxide (NO), and inflammatory mediators (interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)). In addition, histological examination of hepatic and renal tissues revealed histopathological changes that validated the biochemical findings. Compared to HFD group, SOTE and SOHFF treatment led to marked amelioration of all the aforementioned parameters. Collectively, supplementation with SOTE and SOHFF effectively reversed HFD-induced alterations through its antioxidant, hypolipidemic, and anti-inflammatory properties. Hence, SOTE and SOHFF have therapeutic potential in controlling obesity and related pathologies.

Neurobehavioural and Histological Alterations in Lead Acetate-Exposed Rats Pretreated with Aqueous Leaf Extract of Vernonia amygdalina

Lead is a systemic toxicant that affects virtually every organ system, primarily the central nervous system, through an increase in the production of reactive oxygen species (ROS). This increase in ROS overwhelms the natural antioxidant system of the body leading to oxidative stress. Some plants such as Vernonia amygdalina have been reported to possess antioxidant activity which counteracts the damage induced by free radicals. Accordingly, this study was designed to investigate the possible protective activity of aqueous Vernonia amygdalina leaf extract against lead-induced neurotoxicity in adult Wistar rats. Thirty Wistar rats were randomised into six groups (A-F) consisting of five rats each for a study period of 28 days. Group A served as the control group, Group B was administered with 100mg/kg body weight of lead only, Groups C and D were pretreated with 200mg/kg and 400mg/kg bodyweight of aqueous Vernonia amygdalina leaf extract and 100mg/kg body weight of lead respectively. Groups E and F were administered with 200mg/kg and 400mg/kg body weight of aqueous Vernonia amygdalina leaf extract only. The Open field and Novel Object Recognition tests were assessed and thereafter, the cerebellum, cerebrum and hippocampus were harvested for histological examination. Results showed a significant decrease in the body and brain weights, ambulation, rearing and discrimination index as well as a conversely significant increase in grooming and immobility in lead-treated rats. Histological examination of lead-alone treated groups showed loss of some Purkinje cells in the cerebellum, degenerating pyramidal cells in the cerebrum and altered morphology with pyknotic nuclei in the hippocampus. Pretreatment of rats with Vernonia amygdalinaattenuated lead-induced alterations to body and brain weights, neurobehavioural activities and tissue histomorphology, thus indicating a potent protective activity. These findings provide the first research evidence that Vernonia amygdalina protects against lead-induced neurotoxicity in Wistar rats.

Antihypertensive effect and the underlying mechanisms of action of phytolaccagenin in rat models

ABSTRACT Background Phytolaccagenin, a natural triterpenoid, is reported for various biological activities that indicate its potential role in the management of hypertension. Methods Phytolaccagenin was evaluated for its antihypertensive activity in rat models via in vivo and in vitro experiments using polyethylene tubings for cannulation, organ bath bubbled with carbogen gas, and a pressure transducer connected to a PowerLab data acquisition system. Results Intravenous administration of phytolaccagenin decreased mean arterial pressure (MAP), significantly, in normotensive and hypertensive anesthetized rats. Pretreatment of rats with atropine (2 mg/kg) partially reversed the decrease in blood pressure due to phytolaccagenin at first tested doses. However, Nω-nitro-L-arginine methyl ester (L-NAME) (100 mg/kg) pretreatment modified the effect of phytolaccagenin on blood pressure with greater response. In isolated rat aortic rings precontracted with phenylephrine, cumulative addition of phytolaccagenin induced relaxation that is ablated (50%) with denudation and pre-incubation with atropine (1 μM) and L-NAME (10 μM). Phytolaccagenin also partially inhibited high K+ precontraction at initial doses, while an inhibitory effect was observed at higher concentrations, confirming its effect on voltage-dependent calcium channels. In isolated spontaneously beating rat atrial strips, phytolaccagenin suppressed the atrial tone that was reduced with isoprenaline and atropine pre-incubation, suggesting the role of cardiac adrenergic and muscarinic receptors. Interestingly, atenolol (1 μM) pretreatment also ablated the cardiac effects of phytolaccagenin. Conclusion The antihypertensive effect of phytolaccagenin is due to a decrease in vascular resistance and cardiac depressant effects. These effects are mediated via muscarinic receptors-linked NO pathway, inhibitory effect on Ca2+ movements (vascular), and activation of cardiac muscarinic and blockade of β-adrenergic receptors.

Ficus exasperata Attenuates Acetaminophen-Induced Hepatic Damage via NF-κB Signaling Mechanism in Experimental Rat Model.

Ficus exasperata has been used to treat ulcer, diabetes, fever, and a variety of stress-related disorders. Acetaminophen (APAP) overdose is the most common cause of drug-induced acute liver injury. In this study, we evaluated the hepatoprotective effect and antioxidant capacity of ethanolic extract of F. exasperata (EFE) on acetaminophen-induced hepatotoxicity in albino rats. Rats were pretreated with EFE (150, 250, 500 mg/kg) and thereafter received 250 mg/kg APA intraperitoneally (i.p.). The normal control group received distilled water, while the negative control group received 250 mg/kg APAP, respectively. Hepatotoxicity and oxidative stress-antioxidant parameters were then assessed. Flavonoids, saponins, steroids, and glycosides, but not phenolics were detected by EFE phytochemical analysis. No mortality was recorded on acute exposure of rats to varying concentrations of APAP after 24 h; however, a dose-dependent increase in severity of convulsion, urination, and hyperactivity was observed. APAP overdose induced high AST, ALT, ALP, and total bilirubin levels in the serum, invoked lipid peroxidation, depleted GSH, decreased CAT, SOD, and GST levels, respectively. Nitric oxide (NO) level, myeloperoxidase activity, TNF-α, IL-1β, NF-κB, COX-2, MCP-1, and IL-6 were also increased. Importantly, pretreatment of rats with EFE before acetaminophen ameliorated and restored cellular antioxidant status to levels comparable to the control group. Our results show and suggest the hepatoprotective effect of F. exasperata and its ability to modulate cellular antioxidant status supports its use in traditional medicine and renders it safe in treating an oxidative stress-induced hepatic injury.

Postinjury Inhibition of Endothelin‐1 Dependent Renal Vasoregulation Mitigates Rhabdomyolysis‐Induced Acute Kidney Injury

Rhabdomyolysis is a life‐threatening condition resulting from the breakdown of skeletal muscle fibers leading to the release of myoglobin into the blood. Increased circulating myoglobin can cause kidney damage, and acute kidney injury (AKI) occurs in 33‐50% of patients with myoglobinuria. Persistent constriction of the renal microvessels, which reduces renal blood flow (RBF) and glomerular filtration rate (GFR), contributes to rhabdomyolysis‐induced AKI. Since activation of G‐protein‐coupled receptors (GPCR) and ion channels regulate renal vascular resistance (RVR), rhabdomyolysis may likely modulate RVR via GPCR and vascular ion channel mechanisms. Pretreatment of rats with an endothelin receptor antagonist has been shown to alleviate rhabdomyolysis‐induced AKI. However, the downstream and upstream links between rhabdomyolysis and increased ET‐1 synthesis are unknown. The downstream effectors of ET‐1‐induced vasoconstriction are smooth muscle cell (SMC) Ca2+‐permeable ion channels. Yet, the ion channel mechanisms that trigger renal vasoconstriction in rhabdomyolysis‐induced AKI remain unknown. Also, most cases of rhabdomyolysis‐induced AKI cannot be predicted. Whether post‐injury inhibition of the vascular mechanisms of ET‐1 ameliorates, rhabdomyolysis‐induced AKI is unknown. This study investigates post‐injury renal production and vascular regulation of the ET system in rhabdomyolysis‐induced AKI. Six h of rhabdomyolysis increased peptidase endothelin converting enzyme (ECE‐1)‐dependent biosynthesis of ET‐1 in the kidneys. Rhabdomyolysis‐induced AKI was not sex‐dependent. At 24 h, rhabdomyolysis also increased renal reactive oxygen species (ROS), ECE‐1, and ET‐1 levels. Furthermore, ET‐1 activated rat renal vascular smooth muscle cell TRPC3 leading to a reduction in RBF and increased RVR. Protein expression levels of the ET receptors (ETA and ETB) and TRPC3 channels in renal microvessels were unaltered. However, postinjury inhibition of ECE1, ET Receptors, and TRPC3 mitigated rhabdomyolysis‐induced GFR impairment, renal hypoperfusion, AKI biomarker elevation, and morphological kidney damage. To further explore the role of TRPC3 ion channels in rhabdomyolysis‐induced AKI, we subjected TRPC3 knock‐out (KO) rats to rhabdomyolysis. Compared to their wild‐type counterparts, KO rats show protection against rhabdomyolysis‐induced AKI. Our findings suggest that ECE‐driven proteolytic ET‐1 production contributes to rhabdomyolysis‐induced AKI. Downstream, ET‐derived DAG activates renal vascular smooth muscle cell TRPC3 channels leading to extracellular calcium entry, vasoconstriction, increased RVR, and reduced GFR.

Parquetina nigrescens and Spondias mombin protects against neurochemical alterations in the scopolamine model of cognitive dysfunction.

Natural plants which are effective in Alzheimer's disease (AD) management are of pharmacological importance, though there is little or no scientific proof for most of their claims. This study sought to evaluate the effect of Hog plum (Spondias mombin) and Ogbo (Parquetina nigrescens) leaves extracts on antioxidant levels and activities of key enzymes linked to cognitive function in scopolamine-induced cognitive dysfunctioned rats. Rats were pretreated with S. mombin (SM) and P. nigrescens (PN) leaves extracts (50 and 100 mg/kg), donepezil (5mg/kg) for 2 weeks via oral administration before induction of memory impairment via single i.p. administration of scopolamine (3mg/kg body weight). Experimental rats were subjected to behavioral tests to check for cognitive performance before experiment termination. The activities of hippocampal key enzymes linked to cognitive function were determined. Results showed that pretreatment with SM and PN prevented the cognitive impairment induced by scopolamine. Furthermore, increased cholinesterases, adenosine deaminase (ADA), ATP hydrolysis, monoamine oxidase (MAO), and arginase activities induced by scopolamine were significantly reduced in rats treated with SM and PN leaves extract. Additionally, elevated malondialdehyde (MDA) and reactive oxygen species (ROS) levels observed in scopolamine-induced rats were reduced significantly in SM- and PN- pretreated rats. Decreased AMP hydrolysis, and nitric oxide and antioxidant level induced by scopolamine were prevented in pretreated rats. This study concluded that SM and PN leave extract effectiveness in cognitive management may be due to their high antioxidant activities and neuromodulatory effects on key enzymes linked to AD. PRACTICAL APPLICATIONS: The use of natural products in the treatment and management of neurodegenerative diseases in Africa is becoming pertinent as the continent is blessed with medicinal plants while the price of synthetic drugs has been observed to be an economic burden on the continent. Parquetina nigrescens and Spondias mombin are examples of such medicinal plants that have been explored in folklore for the management of neurodegenerative diseases but there is a dearth of scientific validation for their use while there is no present data to evaluate possible mechanisms of action employed by these medicinal plants to mediate the therapeutic potential observed in folklore. Therefore, the present study seeks to validate the therapeutic use of P. nigrescens and S. mombin as observed in folklore as well as explore the possible mechanism of actions the plants may employ in mediating the proposed therapeutic potentials in neurodegenerative disease conditions while considering its toxicological effects in experimental animals.

Prazosin Treatment Protects Brain and Heart by Diminishing Oxidative Stress and Apoptotic Pathways After Renal Ischemia Reperfusion.

Acute kidney injury (AKI) is a major medical challenge caused from renal ischemia-reperfusion (IR) injury connected with different cellular events in other distant organs. Renal IR-related oxidative stress and inflammation followed by cell apoptosis play a crucial role in IR-induced distant organ pathological damages. Prazosin has shown protective effects against IR-injuries. Thus, the current study intended to investigate the possible protective role of prazosin against the consequents of renal IR in the heart and brain tissues. To reach this goal, rats were randomly divided into 3 groups (n=7): Sham, IR and prazosin pretreatment-IR animals (1 mg/kg intraperitoneally injection of prazosin 45 min before IR induction). After 6 h reperfusion, lipid peroxidation and antioxidant markers levels were evaluated in the both, brain and heart tissue. Moreover, apoptotic pathway in the heart and brain tissues were assessed by western blotting. Accordingly, prazosin pretreatment in IR model rats could significantly increase the antioxidant capacity and attenuate apoptotic pathways by increasing the bcl-2 levels and decreasing the expression of Bax and caspase 3 enzymes (P<0.05). Thus, prazosin suppressed cellular damages of heart and brain tissues post kidney IR by anti-oxidative and anti-apoptotic effects, which suggests the plausible use of prazosin in improving the clinical outcomes during AKI after further investigations.