Risperidone Toxicity on Human Blood Lymphocytes in Nano molar Concentrations.

Risperidone is an atypical antipsychotic drug used for the pharmacotherapy of psychiatric disorders. Some reports indicate that risperidone is toxic to various systems of the body, including the immune system. This study evaluated the toxicity effect of risperidone on human blood lymphocytes. To achieve this aim, lymphocytes were isolated using Ficoll paque plus. The results showed that risperidone (12, 24 and 48 nM) causes toxicity in human blood lymphocytes by increasing the level of intracellular reactive oxygen species (ROS), damage to lysosomal membrane, the collapse of the mitochondrial membrane potential (MMP), and increased extracellular oxidized glutathione (GSSG). Also, exposure of human blood lymphocytes to risperidone is associated with a decrease in intracellular glutathione (GSH) levels. Finally, it could be concluded that oxidative stress is one of the mechanisms of risperidone-induced toxicity in human blood lymphocytes.

Rhus coriaria L., a new candidate for controlling metabolic syndrome: a systematic review.

OBJECTIVES: Rhus coriaria L. (RC) is a deciduous shrub with several pharmacological activities. Evidence of the effects of RC on weight, hyperlipidaemia, hypertension and diabetes mellitus have been presented in this study. Books, thesis and internet-based resources such as PubMed, Web of Science, Scopus, EMBASE, Cochrane, Ovid and Google Scholar were searched for the English, Arabic and Persian literature from 1966 to 2020 (December). The keywords were Rhus coriaria L., Sumac, metabolic syndrome and all its medical conditions (hyperlipidaemia, hypertension, obesity and diabetes mellitus). The inclusion criteria were full-text animal and human studies conducted on RC to evaluate its efficacy on any components of metabolic syndrome (MetS). Jadad scale was used to assess the quality of evidence. KEY FINDINGS: Reviewing 23 relevant studies demonstrated that RC is able to decrease the level of blood glucose, glycated haemoglobin, serum insulin and insulin resistance. Studies on hyperlipidaemia and obesity have very contradicting results, and there is no definite conclusion on the effect of RC on lipid profile. However, the hypotensive and effect of RC was confirmed in the existing studies. SUMMARY: According to the literature, RC can be considered as a promising curative candidate for MetS. However, further studies with larger sample size and higher methodological quality are needed.

Protective Effect of Crocin against Mitochondrial Damage and Memory Deficit Induced by Beta-amyloid in the Hippocampus of Rats.

Alzheimer's disease is the most common form of dementia among the elderly. This progressive neurodegenerative disorder affects brain regions that control cognition, memory, language, speech, and awareness. As a potent antioxidant, crocin has been proposed to effectively manage the neurodegenerative disease. In this study, the recovery effects of crocin on the memory deficits caused by the intra-hippocampal injection of amyloid beta1-42 (Aß1-42) were evaluated in rats. We also considered the protective effects of crocin on the mitochondrial damage caused by Aß1-42. We examined the memory deficits of rats with the help of the Morris water maze. Then, we determined different mitochondrial toxicity endpoints caused by Aß1-42, including mitochondrial ROS formation, lipid peroxidation, mitochondrial membrane potential collapse, mitochondrial outer membrane integrity, and cytochrome c release. Our results demonstrated that the behavioral signs of memory deficiency caused by Aß1-42 significantly (P < 0.01) reduced by both pretreatment and post-treatment with crocin (30 mg/kg). Furthermore, crocin prevented all the Aß1-42 induced above referenced mitochondrial upstream toxic events leading to neuronal apoptosis. These results demonstrated that crocin is a promising preventive candidate for the potential treatment of Alzheimer's disease. Furthermore, it seems that the antioxidant and neuroprotective effects of crocin are better seen when the compound is pretreated beforehand rather than introduced afterward in Aß1-42 exposed mitochondria.

Beneficial Medicinal Plants for Memory and Cognitive Functions Based on Traditional Persian Medicine.

Alzheimer's disease (AD) is one of the most important causes of dementia, especially in the elderlies. Due to the failures of recent clinical trials in finding effective medications, it appears the use of complementary therapies such as Traditional Persian Medicine (TPM) and the rich sources of effective herbs as well as their constituents for improving memory function could be beneficial. The aim of this study was to evaluate the recommended natural remedies in the TPM and examine their pharmacological properties. For this purpose, the data were collected by searching the recommended prescriptions of the seminal TPM textbooks. Then, the names of the most freuqently mentioned plants were extracted from the natural remedies and evaluated for their pharmacological properties. The sources included recently published articles cited in the major scientific databases. A total of 262 plants were identified in 96 evaluated prescriptions; 20 plants were identified with the most frequency of report (i.e. more than 10 times). Their neuroprotective effects, antioxidant features, and anti-AD properties were discussed. Based on our results, TPM has introduced many effective treatments for AD. Hence, more clinical studies are warranted to verify their efficacy and safety.

A review on phytochemical and therapeutic potential of Iris germanica.

OBJECTIVES: Iris germanica L. is a medicinal plant, which has a long history of uses, mainly in medieval Persia and many places worldwide for the management of a wide variety of diseases. In this study, we aimed to review ethnopharmacological applications in addition to phytochemical and pharmacological properties of I. germanica. KEY FINDINGS: Ethnomedical uses of I. germanica have been reported from many countries such as China, Pakistan, India, Iran and Turkey. The medicinal part of I. germanica is the rhizome and the roots. Based on phytochemical investigations, different bioactive compounds, including flavonoids, triterpenes, sterols, phenolics, ceramides and benzoquinones, have been identified in its medicinal parts. Current pharmacological studies represent that the plant possesses several biological and therapeutic effects, including neuroprotective, hypoglycaemic, hypolipidaemic, antimicrobial, antioxidant, antiproliferative, anti-inflammatory, antiplasmodial, antifungal, immunomodulatory, cytotoxic and antimutagenic effects. SUMMARY: Although the majority of preclinical studies reported various pharmacological activities of this plant, however, sufficient clinical trials are not currently available. Therefore, to draw a definitive conclusion about the efficacy and therapeutic activities of I. germanica and its bioactive compounds, further clinical and experimental studies are required. Moreover, it is necessary to focus on the pharmacokinetic and safety studies on the extracts of I. germanica.

Health Benefits of Turmeric and Curcumin Against Food Contaminants.

Food contaminants are one of the most important and concerning issues worldwide. Protecting the public from the harm of contaminated foods has become a daunting task. On the other hand, the elimination of these contaminants from food seems impossible. Therefore, one of the best solutions is to recommend inexpensive and publicly available food additives like many spices used in food as flavoring and coloring. Curcuma longa or turmeric is one of the well-known spice, which confers many medicinal properties. Curcumin is the main active ingredient in turmeric, which has many health benefits. Recent research has revealed that turmeric/curcumin has protective effects against toxicants, mostly natural and chemical toxins. In this review article, we reviewed studies related to the protective effects of turmeric and its active ingredient against food contaminants.

The antioxidant and neuroprotective effects of Zolpidem on acrylamide-induced neurotoxicity using Wistar rat primary neuronal cortical culture.

Zolpidem is an introduced medication for the therapy of sleeping disorders. Its pharmacological effects are consequently characterized by a quick onset and a half-life of 2.4 h. Previous studies revealed the antioxidant and neuroprotectant effects of zolpidem. In this research, we wanted to demonstrate the exact sub-cellular/molecular mechanism of this medication using the primary neuronal cortical culture. For this purpose, firstly, the cortical neurons were isolated from the postnatal Wistar rat pups. Thereafter, different neural toxicity endpoints caused by acrylamide including ROS formation, lipid peroxidation, mitochondrial membrane potential collapse, lysosomal membrane integrity, and apoptosis were determined. All of these parameters are upstream events of cellular apoptosis which justifies neurodegeneration involved in many diseases such as Alzheimer's and Parkinson's. Our results demonstrated that zolpidem at concentrations of 1 and 2 mM prevented all the acrylamide-induced above referenced neural toxic events leading to neuronal apoptosis. These results revealed that zolpidem has the antioxidant and neuroprotectant properties that make it a promising prophylactic agent for preventing neurodegenerative complications. Considering the important role of oxidative stress in the development or progression of diseases, if the medication used as a treatment of a disease has antioxidant properties at the same time, it will certainly have much greater healing effects.

Effect of Intravenous Lipid Emulsion on Clozapine Acute Toxicity in Rats.

OBJECTIVES: Many studies have been reported the efficacy of intravenous lipid emulsion (ILE) as an antidote on acute lipophilic drug toxicity. Clozapine, highly lipophilic dibenzodiazepine neuroleptics, is an important medication in the schizophrenia therapy regimen. Acute intoxication with antipsychotics is one of the main reasons for the referral of poisoned patients to the hospital. We expected that ILE could be used for the therapy of acute clozapine intoxicated patients. METHODS: We used two groups of consisting of six male rats. Both groups received a toxic dose of clozapine (40 mg/kg) intravenously, via the tail vein. After 15 minutes, they were treated with intravenous infusion of 18.6 mg/kg normal saline (NS group), or 18.6 mg/kg ILE 20% (ILE group). We evaluated blood pressure (BP) and heart rate by power lab apparatus through the tail artery, ataxia by a rat rotary circle, seizure scores and death in multiple times after starting clozapine administration. For biochemical and pathological evaluations the samples of tissue and blood were taken. RESULTS: Our results demonstrated that ILE 20% could return hypotension-induced clozapine better than normal saline. Furthermore, ataxia and seizure have rectified more rapidly and deaths reduced. Clozapine administration causes pancreatitis and lung injury but fat emulsion did not show an optimal effect on tissue damages caused by clozapine toxicity. CONCLUSION: In conclusion, ILE can remove toxic signs of clozapine same as other lipophilic medicines, however, clinical uses of ILE for this intention requires more appraisement to determine the precise implication and safety.

Anticonvulsant Activity of Viola tricolor against Seizures Induced by Pentylenetetrazol and Maximal Electroshock in Mice.

BACKGROUND: Recently, there has been much more interest in the use of medicinal plants in search of novel therapies for human neurodegenerative diseases such as epilepsy. In the present study, we investigated the anticonvulsant effects of Viola tricolor (V. tricolor) on seizure models induced by pentylenetetrazol (PTZ) and maximal electroshock stimulation (MES). METHODS: Totally, 260 mice were divided into 26 groups (n=10). Thirty minutes after treatment with the hydroalcoholic extract of V. tricolor (VHE 100, 200, and 400 mg/kg) and its ethyl acetate (EAF 50, 100, and 200 mg/kg) and n-butanol (NBF 50, 100, and 200 mg/kg) fractions as well as diazepam (3 mg/kg), seizure was induced by PTZ (100 mg/kg) or by MES (50 Hz, 1 s and 50 mA). Analysis was performed via ANOVA with the Tukey-Kramer post-hoc test using GraphPad Prism 6.01 (La Jolla, CA). RESULTS: The VHE (400 mg/kg) significantly enhanced latency to the first generalized tonic-clonic seizures (GTCs) induced by PTZ in comparison to the control group (P<0.001). All 3 concentrations of the EAF (50, 100, and 200 mg/kg) significantly prolonged the latency of PTZ-induced seizures compared to the control group. Additionally, all the concentrations of the NBF (50, 100, and 200 mg/kg) made a significant increment in GTCs latency induced by PTZ in comparison to the control group. On the other hand, all the concentrations of the VHE, EAF, and NBF significantly reduced the incidence of hind-limb tonic extension (HLTE) induced by MES, when compared to the control group. CONCLUSION: The present study showed that V. tricolor and its ethyl acetate and n-butanol fractions possessed anticonvulsant effects as confirmed by the prolongation of latency to the first GTCs induced by PTZ and decrement in the incidence of HLTE induced by MES.

Crocin Prevents Sub-Cellular Organelle Damage, Proteolysis and Apoptosis in Rat Hepatocytes: A Justification for Its Hepatoprotection.

Crocin, the main constituent of saffron (Crocus sativus L.), is a natural carotenoid which is known for its antioxidant activity. Liver as the organ that metabolizes many chemicals is one of the first position that is at risk of environmental pollutants. It is clear that compounds that exhibit antioxidant properties, scavenging of free radicals and inhibition of lipid peroxidation are expected to show hepatoprotective effects. Previous studies have proven the protective effect of crocin on the liver. The aim of this study is to find out the exact hepatoprotective mechanisms of this compound. In the present study, the protective effects of various concentrations of crocin (5, 10, 25, 50 and 100 µg/mL) were examined against oxidative stress toxicity induced by cumene hydroperoxide (CHP) on isolated rat hepatocytes. To find out the exact protective activity of crocin, we evaluated cell lysis, lipid peroxidation, reactive oxygen species (ROS) generation, GSH/GSSG, collapse of mitochondrial membrane potential, lysosomal membrane damage, the release of cytochrome c, and cellular proteolysis. Crocin (50 and 100 µg/mL) reduces cell lysis, lipid peroxidation, ROS generation, collapse of mitochondrial membrane potential, lysosomal membrane damage, cytochrome c release, and cellular proteolysis. It also increase GSH/GSSG. Crocin (50 and 100 µg/mL) reduced liver toxicity not only as an antioxidant but also by protecting the mitochondria and lysosome. Our data demonstrated that crocin is a promising candidate for preventing liver injury associated with oxidative stress. These findings pave the way to further studies evaluating the clinical protective effect of crocin.

The mechanism of protective effect of crocin against liver mitochondrial toxicity caused by arsenic III.

In this study, we want to understand whether crocin could prevent mitochondrial damage caused by As III. For this purpose, we determined different mitochondrial toxicity endpoints caused by As III. We evaluated mitochondrial ROS formation, lipid peroxidation, mitochondrial membrane potential (MMP) collapse, mitochondrial outer membrane integrity and cytochrome c release. Our results showed that pretreatment with crocin at a concentration of 25 µg/ml significantly (p < 0.001) reduced As III-induced mitochondrial ROS formation, lipid peroxidation, MMP collapse and mitochondrial swelling. Crocin also protected the mitochondria by decreasing the mitochondrial outer membrane damage that leads to reduce the amount of cytochrome c release. These results demonstrated that crocin is a promising antidotal candidate by ameliorating As III-induced oxidative stress through mitochondrial targeting.

Inhibition of glucose-6-phosphate dehydrogenase protects hepatocytes from aluminum phosphide-induced toxicity.

Aluminum phosphide (AlP) poisoning is a severe toxicity with 30-70% mortality rate. However, several case reports presented AlP-poisoned patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and extensive hemolysis who survived the toxicity. This brought to our mind that maybe G6PD deficiency could protect the patients from severe fatal poisoning by this pesticide. In this research, we investigated the protective effect of 6-aminonicotinamide (6-AN)- as a well-established inhibitor of the NADP+- dependent enzyme 6-phosphogluconate dehydrogenase- on isolated rat hepatocytes in AlP poisoning. Hepatocytes were isolated by collagenase perfusion method and incubated into three different flasks: control, AlP, and 6-AN+ALP. Cellar parameters such as cell viability, reactive oxygen species (ROS) formation, mitochondria membrane potential collapse (MMP), lysosomal integrity, content of reduced (GSH) and oxidized glutathione (GSSG) and lipid peroxidation were assayed at intervals. All analyzed cellular parameters significantly decreased in the third group (6-AN+AlP) compared to the second group (AlP), showing the fact that G6PD deficiency induced by 6-AN had a significant protective effect on the hepatocytes. It was concluded that G6PD deficiency significantly reduced the hepatotoxicity of AlP. Future drugs with the power to induce such deficiency may be promising in treatment of AlP poisoning.

In vitro toxicity of perfluorooctane sulfonate on rat liver hepatocytes: probability of distructive binding to CYP 2E1 and involvement of cellular proteolysis.

Perfluorooctanesulfonate (PFOS), an anthropogenic fluorosurfactant, is one of the most common global pollutants. PFOS is used in various consumer products to provide soil, oil, and water resistance to materials used in clothing, upholstery, and food packaging. PFOS is persistent, bioaccumulative, and toxic to mammalian species. In this study, the cellular mechanisms involved in PFOS hepatotoxicity were evaluated. For this purpose, we determined oxidative stress markers including cell lysis, ROS generation, lipid peroxidation, glutathione depletion, mitochondrial membrane potential decrease, lysosomal membrane leakiness, and cellular proteolysis. Our results demonstrated that PFOS liver cytotoxicity was associated with reactive oxygen species (ROS) formation and lipid peroxidation in isolated rat hepatocytes. Incubation of hepatocytes with PFOS caused rapid depletion of hepatocyte glutathione (GSH), an important marker of cellular oxidative stress. Most of the PFOS-induced GSH depletion could be attributed to the expulsion of glutathione disulfide (GSSG). PFOS hepatotoxicity was inhibited by antioxidants and ROS scavengers, mitochondrial permeability transition (MPT) pore sealing agents, and endocytosis inhibitors. Our results suggest that PFOS hepatotoxicity might be the result of oxidative stress-induced lysosomal membrane leakiness and cellular proteolysis in rat hepatocytes.

Protective effect of rutin on hexachlorobutadiene-induced nephrotoxicity.

Hexachlorobutadiene (HCBD) is a potent nephrotoxin which nowadays contaminates human foods and water. On the other hands, it has been reported that rutin is a chemopreventive flavonoid which exerts some protective effects on the kidney. Therefore, in this work, the possible effect of rutin on HCBD-induced nephrotoxicity was investigated in female rats. The animals were divided into five groups. Groups 1 and 2 were treated with vehicle and HCBD (100 mg/kg, i.p.), respectively. Groups 3-5 were pretreated with rutin (100, 500 and 1000 mg/kg, i.p.) 1 h before HCBD injection. The level of serum urea and creatinine as well as urinary glucose and protein were measured. Total thiol content and lipid peroxidation level were also determined in the kidney homogenate. When compared to control group, a significant increase in the level of serum creatinine and urea (p < 0.001) as well as urine glucose and protein (p < 0.001) were observed after 24 h of HCBD administration. HCBD also caused a significant decrease in total thiol content (p < 0.001) and a significant increase in lipid peroxidation level (p < 0.001). Pretreatment with rutin could decrease serum creatinine (p < 0.001) and urea (p < 0.001) as well as urine protein (p < 0.001) concentrations when compared with HCBD treated rats. No significant modification on urine glucose was seen (p > 0.05). Rutin also reversed the HCBD-induced depletion in thiol content (p < 0.001) and elevation in lipid peroxidation (p < 0.001) in the kidney. The results of present study showed that rutin clearly attenuated HCBD-induced nephrotoxicity and has the potential to be considered as a nephroprotective agent.