Piperine: A review of its biological effects.

Medicinal plants have been used for years as a source of food, spices, and, in traditional medicine, as a remedy to numerous diseases. Piper nigrum, belonging to the family Piperaceae is one of the most widely used spices all over the world. It has a distinct sharp flavor attributed to the presence of the phytochemical, piperine. Apart from its use as a spice, P. nigrum is frequently used for medicinal, preservation, and perfumery purposes. Black pepper contains 2-7.4% of piperine, varying in content is associated with the pepper plant. Piperine displays numerous pharmacological effects such as antiproliferative, antitumor, antiangiogenesis, antioxidant, antidiabetic, anti-obesity, cardioprotective, antimicrobial, antiaging, and immunomodulatory effects in various in vitro and in vivo experimental trials. Furthermore, piperine has also been documented for its hepatoprotective, anti-allergic, anti-inflammatory, and neuroprotective properties. This review highlights and discusses the medicinal and health-promoting effects of piperine, along with possible mechanisms of its action in health promotion and disease prevention. In addition, the present review summarizes the recent literature related to piperine as a therapeutic agent against several diseases.

Nanotechnology enabled the enhancement of antitrypanosomal activity of piperine against Trypanosoma evansi.

Nanoencapsulation is the promising approach to enhance the therapeutic potential of a drug. In the present investigation, piperine-loaded nanocapsules (NCs) was prepared and evaluated for antitrypanosomal activity against the parasite Trypanosoma evansi, a causative agent of trypanosomiasis. Piperine, a bioactive compound was selected as an alternative for drugs that have been used for the treatment of the disease from decades to overcome the toxic effects or drug resistance effect. Moreover, piperine has reported to possess therapeutic potential against other Trypanosoma spp. and has also been reported to cause reactive oxygen species (ROS) mediated effect in cancer cells that was the other reason for the selection. To date, piperine and its nanoformulations have not been evaluated for their growth inhibitory effect against T. evansi. Piperine-loaded NCs exhibited more significant antitrypanosomal effect at approximately three-times less IC50 value 5.04 µM as compared to piperine (IC50-14.45 µM). Moreover, increased production of reactive oxygen species observed in the case of piperine-loaded NCs as that of pure piperine in the axenic culture of T. evansi. Furthermore, different concentrations of piperine-loaded NCs showed less cytotoxicity on horse peripheral blood mononuclear cells as liken to pure piperine. In conclusion, our results demonstrated that piperine-loaded NCs induced more generation of ROS that contributed inhibitory effect on the growth of Trypanosoma evansi as compared to pure drug.

Neurotoxic effects of high-dose piperine on hippocampal synaptic transmission and synaptic plasticity in a rat model of memory impairment.

In recent years, piperine has attracted much attention due to its various biological effects as a neuroprotective agent. Therefore, clarification of the possible side effects of piperine is important to identify its potential pharmacological action. Thus, the effects of piperine on the long-term plasticity of perforant pathway to dentate gyrus synapses were studied in hippocampus of an animal model of Alzheimer's disease (AD). Adult male rats were injected with intracerebroventricular (ICV) streptozotocin (STZ) bilaterally, on days 1 and 3 (3 mg/kg). The STZ-injected rats were treated with different doses of piperine for 4 weeks before being used in behavioral, electrophysiological and histopathological experiments. The passive-avoidance test was conducted on all animals in order to determine the cognitive performance. Rats were placed in a stereotaxic frame to implant a recording electrode in the hippocampal dentate gyrus and a stimulating electrode in the perforant path. Additionally, we assessed the density of survived neurons stained by cresyl violet. In this study, chronic administration of piperine low dose improved the ICV-STZ induced learning and long-term potentiation (LTP) impairments with no significant effect on baseline synaptic activity. In contrast, remarkable learning and long-term plasticity impairments were observed in rats treated by high dose of piperine in comparison to the other groups. Interestingly, this impaired hippocampal LTP was accompanied by an obvious alteration in baseline activity and significantly decreased neuronal numbers within the hippocampus. Therefore, our data provides a new understanding of the piperine supplementation effects on hippocampal electrophysiological profile although the consequences may be either beneficial or detrimental.

Reproductive toxicity of the hydroethanolic extract of the flowers of Acmella oleracea and spilanthol in zebrafish: In vivo and in silico evaluation.

Hydroethanolic preparations of Acmella oleracea is used in the north of Brazil as a female aphrodisiac. Thus, the objective of this study was to evaluate the action of the hydroethanolic extract of Acmella oleracea (EHFAo) flowers (21.873 and 44.457 mg/kg) and spilanthol (3 mg/kg) administered orally on reproductive performance and effects on the embryonic development of zebrafish F1 generation. It was observed that in the groups in which males and females received EHFAo and spilanthol, the spawning was interrupted, whereas in the groups in which only the females were treated, spawning occurred during the 21 days. Thus, in the histopathological evaluation of the gonads, it was possible to observe that the percentage of mature cells in the spermatozoa and females was significantly reduced. Only the embryo groups in which parental generation was treated with EHFAo showed lethal and teratogenic effects. On the other hand, the parental groups treated with the spilanthol presented only the lethality. Spilanthol and some metabolites showed good oral availability and important toxicological properties. Thus, it is suggested that the treatment of parental generation of zebrafish with EHFAo and spilanthol caused severe changes in the gonads and on fertility. However, on the embryo, the most striking effects in the development were recorded in the groups in which the parental generation was treated with the EHFAo, while the spilanthol influenced the lethality of the embryos.

Biophysical and biomechanical properties of neural progenitor cells as indicators of developmental neurotoxicity.

Conventional in vitro toxicity studies have focused on identifying IC50 and the underlying mechanisms, but how toxicants influence biophysical and biomechanical changes in human cells, especially during developmental stages, remain understudied. Here, using an atomic force microscope, we characterized changes in biophysical (cell area, actin organization) and biomechanical (Young's modulus, force of adhesion, tether force, membrane tension, tether radius) aspects of human fetal brain-derived neural progenitor cells (NPCs) induced by four classes of widely used toxic compounds, including rotenone, digoxin, N-arachidonoylethanolamide (AEA), and chlorpyrifos, under exposure up to 36 h. The sub-cellular mechanisms (apoptosis, mitochondria membrane potential, DNA damage, glutathione levels) by which these toxicants induced biochemical changes in NPCs were assessed. Results suggest a significant compromise in cell viability with increasing toxicant concentration (p < 0.01), and biophysical and biomechanical characteristics with increasing exposure time (p < 0.01) as well as toxicant concentration (p < 0.01). Impairment of mitochondrial membrane potential appears to be the most sensitive mechanism of neurotoxicity for rotenone, AEA and chlorpyrifos exposure, but compromise in plasma membrane integrity for digoxin exposure. The surviving NPCs remarkably retained stemness (SOX2 expression) even at high toxicant concentrations. A negative linear correlation (R2 = 0.92) exists between the elastic modulus of surviving cells and the number of living cells in that environment. We propose that even subtle compromise in cell mechanics could serve as a crucial marker of developmental neurotoxicity (mechanotoxicology) and therefore should be included as part of toxicology assessment repertoire to characterize as well as predict developmental outcomes.

Absence of adverse effects following administration of piperine in the diet of Sprague-Dawley rats for 90 days.

Piperine (E,E-) is a naturally occurring pungent and spicy constituent of black pepperand is also used as an added flavoring ingredient to foods and beverages. Piperine has been determined safe under conditions of intended use as a flavoring substance by regulatory and scientific expert bodies. While concurring with the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and Flavor and Extract Manufacturers Association (FEMA) Expert Panel on the safety of piperine, the European Food Safety Authority (EFSA) requested additional toxicological data. The results of a 90-day GLPcompliant dietary study, conducted in Sprague-Dawley rats at target doses of 0, 5, 15, or 50 mg/kg bw/day, to respond to this request are presented herein. No adverse effects were found attributable to ingestion of piperine. Statistically significant changes in food consumption, body weight gain, and plasma cholesterol levels were not considered adverse as discussed in this paper. Therefore, the oral no-observed-adverse-effect level (NOAEL) was determined to be the highest dose tested of 50 mg/kg bw/day. EFSA derived a lower NOAEL of 5 mg/kg bw/day based on increased plasma cholesterol levels which still affords an adequate margin of safety of over 48,000 and concluded that piperine is not of safety concern.

Evidences for Piperine inhibiting cancer by targeting human G-quadruplex DNA sequences.

Piperine, a naturally occurring alkaloid, is well known as anti-oxidant, anti-mutagenic, anti-tumor and anti-proliferative agent. Piperine exerts such pharmacological activities by binding or interacting with various cellular targets. Recently, the first report for Piperine interaction with duplex DNA has been published last year but its interaction with G-quadruplex structures has not been studied yet. Herein, we report for the first time the interaction of Piperine with various DNA G-quadruplex structures. Comprehensive biophysical techniques were employed to determine the basis of interaction for the complex formed between Piperine and G-quadruplex DNA sequences. Piperine showed specificity for G-quadruplex DNA over double stranded DNA, with highest affinity for G-quadruplex structure formed at c-myc promoter region. Further, in-vitro studies show that Piperine causes apoptosis-mediated cell death that further emphasizes the potential of this natural product, Piperine, as a promising candidate for targeting G-quadruplex structure and thus, acts as a potent anti-cancer agent.

Delivery of Dual Drug Loaded Lipid Based Nanoparticles across the Blood-Brain Barrier Impart Enhanced Neuroprotection in a Rotenone Induced Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is the most widespread form of dementia where there is an age related degeneration of dopaminergic neurons in the substantia nigra region of the brain. Accumulation of α-synuclein (αS) protein aggregate, mitochondrial dysfunction, oxidative stress, and neuronal cell death are the pathological hallmarks of PD. In this context, amalgamation of curcumin and piperine having profound cognitive properties, and antioxidant activity seems beneficial. However, the blood-brain barrier (BBB) is the major impediment for delivery of neurotherapeutics to the brain. The present study involves formulation of curcumin and piperine coloaded glyceryl monooleate (GMO) nanoparticles coated with various surfactants with a view to enhance the bioavailability of curcumin and penetration of both drugs to the brain tissue crossing the BBB and to enhance the anti-parkinsonism effect of both drugs in a single platform. In vitro results demonstrated augmented inhibition of αS protein into oligomers and fibrils, reduced rotenone induced toxicity, oxidative stress, and apoptosis, and activation of autophagic pathway by dual drug loaded NPs compared to native counterpart. Further, in vivo studies revealed that our formulated dual drug loaded NPs were able to cross BBB, rescued the rotenone induced motor coordination impairment, and restrained dopaminergic neuronal degeneration in a PD mouse model.

Intranasal Piperine-Loaded Chitosan Nanoparticles as Brain-Targeted Therapy in Alzheimer's Disease: Optimization, Biological Efficacy, and Potential Toxicity.

Piperine (PIP) is a phytopharmaceutical with reported neuroprotective potential in Alzheimer's disease (AD). Oral PIP delivery suffers from its hydrophobicity and pre-systemic metabolism. In this article, mono-disperse intranasal chitosan nanoparticles (CS-NPs) were elaborated for brain targeting of PIP. Formula optimization was based on particle size (PS), zeta potential (ZP), polydispersity index (PDI), % entrapment efficiency (% EE), release studies, and transmission electron microscopy. AD was induced in 48 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor for inflammation. Spherical NPs with optimum % EE (81.70), PS (248.50 nm), PDI (0.24), and ZP (+56.30 mV) were elaborated. PIP-NPs could significantly improve cognitive functions as efficient as standard drug (donpezil injection) with additional advantages of dual mechanism (Ach esterase inhibition and antioxidant effect). CS-NPs could significantly alleviate PIP nasal irritation and showed no brain toxicity. This work was the first to report additional mechanism of PIP in AD via anti-apoptosis and anti-inflammatory effects. To conclude, mucoadhesive CS-NPs were successfully tailored for effective, safe, and non-invasive PIP delivery with 20-folds decrease in oral dose, opening a gate for a future with lower AD morbidity.

Effect of piperine on liver function of CF-1 albino mice.

BACKGROUND: Piperine is isolated from Piper nigrum popularly known as black pepper. Previous studies have demonstrated the beneficial effects of piperine in various health conditions. Additionally, it is a powerful bioenhancer for many drugs. Piperine extract is believed to potentiate the effect of drugs by several folds. The present study is focused on its individual effect on liver function. MATERIALS AND METHODS: A total of 30 CF-1 albino mice obtained from the animal house of faculty of Medicine, Benghazi University, Benghazi, Libya were included in the study. These mice were fed with high cholesterol diet and divided into 2 groups. Twenty mice were administered piperine at a dose of 5mg/kg body weight. Piperine was isolated in Department of Pharmacognosy, Faculty of Pharmacy, Benghazi University, Benghazi and 10 mice were not administered piperine but fed with high fat diet. These mice were anesthetized with ketamine and halothane and blood was drawn from each mouse before the study and after three weeks by cardiocentesis. Serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), alkaline phosphatase and total protein were measured by authenticated methods. RESULTS: Serum alanine amino transferase was significantly elevated (p=0.0002) in group A mice after the administration of Piperine extract for three weeks compared to those of group B mice. Serum aspartate amino transferase was elevated significantly (p=0.046) and alkaline phosphatase (p= 0.0001) also was significantly increased after the administration of piperine. Serum total protein (p= 0.011) values were significantly decreased after the use of piperine for three weeks in group A mice. CONCLUSION: This study showed that there might have been a considerable damage to liver with piperine extract. Further research may be required to prove this damage to liver function.

Effect of piperine on inhibition of FFA induced TLR4 mediated inflammation and amelioration of acetic acid induced ulcerative colitis in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Piperine, a main component of Piper longum Linn. and Piper nigrum Linn., is a plant alkaloid with a long history of medicinal use. Piperine exhibits antidepressant, hepatoprotective, anti-metastatic, anti-thyroid, immunomodulatory, antitumor and anti-inflammatory activities, However its therapeutic potential in amelioration of ulcerative colitis and the underlying mechanism for anti-inflammatory activity remains unknown.The objective of the present investigation was to unravel the therapeutic potential of piperine on amelioration of IBD using acetic acid induced experimental animal model for ulcerative colitis and to determine the role of TLR4 receptor in signalling pathway of inflammatory gene expression in ulcerative colitis. MATERIALS AND METHODS: We induced colitis using acetic acid (150µl of 5% once, intrarectally) in mice and estimated disease activity index (DAI), which took into account weight loss, stool consistency, and occult/gross bleeding. Colon length, spleen weights, ulcer area and ulcer index were measured; histological changes were observed by H&E staining. Effect of piperine on various antioxidant parameter of mice colon such as tissue myeloperoxidase (MPO) accumulation, SOD concentrations, reduced GSH and lipid peroxidation were determined. Pro-inflammatory mediators, namely, nitric oxide (NO), tumour necrosis factor-α (TNF-α) were determined by a TNF-α ELISA kit obtained from Thermo fisher scientific India Pvt. Ltd. Effect of piperine on haematological parameters of mice in acetic acid induced IBD was also determined which involves the estimation of FFA using a commercial free fatty acid fluorometric assay kit. RESULT: Piperine significantly attenuated acetic acid induced DAI score which implies that it suppresses weight loss, diarrhoea, gross bleeding and infiltration of immune cells. Piperine administration also effectively and dose dependently prevented shortening of colon length and enlargement of spleen size. Histological examination indicated that piperine reduces oedema in sub-mucosa, cellular infiltration, reduced haemorrhages and ulceration as compare to acetic acid induced colitis in mice. Furthermore piperine inhibited abnormal secretion of pro-inflammatory mediators namely NO, cytokines TNF-α and reduces FFA induced TLR4 mediated inflammation. CONCLUSION: These results suggest that piperine has an anti-inflammatory effect at colorectal sites that is due to down- regulations of the productions and expression of inflammatory mediators and it also reduces FFA induced TLR4 mediated inflammation. Thus it may have therapeutic potential on amelioration of IBD.

Black pepper constituent piperine: genotoxicity studies in vitro and in vivo.

Piperine is responsible for the hot taste of black pepper. Publications on genotoxicity of piperine are reported: negative Ames Tests and one in vitro micronucleus test (MNT). In vivo tests were mainly negative. In the majority of the data the administered dose levels did not follow the dose selection requirements of regulatory guidelines of having dose levels up to the maximum tolerated dose (MTD). The only oral high dose studies were a positive in vivo MNT in mice in contrast to a negative in vivo chromosome aberration test in rats. Thus, conflicting results in genotoxicity testing are published. To investigate this further, we administered piperine to mice up to the MTD and determined micronuclei-frequency. Piperine reduces core body temperature and interferes with blood cells both being known to result in irrelevant positive in vivo MNTs. Therefore we added mechanistic endpoints: core body temperature, haematology, erythropoietin level, and organ weights. Additionally an in vitro MNT in Chinese hamster ovary cells was performed. Piperine was negative in the in vitro MNT. It caused significant reduction of core body temperature, decrease of white blood cells and spleen weights but no increase in the micronucleus-frequency. Thus, in our studies piperine was not genotoxic.

Piperine inhibits the proliferation of human prostate cancer cells via induction of cell cycle arrest and autophagy.

Piperine, an alkaloid from black and long peppers (Piper nigrum Linn & Piper longum Linn), has been reported to exhibit antitumor activities in vitro and in vivo. To further understand the antitumor mechanism of piperine, we investigated the growth inhibitory effects of piperine on human prostate cancer DU145, PC-3 and LNCaP cells. Piperine treatment resulted in a dose-dependent inhibition of the proliferation of these cell lines. Cell cycle arrest at G0/G1 was induced and cyclin D1 and cyclin A were downregulated upon piperine treatment. Notably, the level of p21(Cip1) and p27(Kip1) was increased dose-dependently by piperine treatment in both LNCaP and DU145 but not in PC-3 cells, in line with more robust cell cycle arrest in the former two cell lines than the latter one. Although piperine induced low levels of apoptosis, it promoted autophagy as evidenced by the increased level of LC3B-II and the formation of LC3B puncta in LNCaP and PC-3 cells. The piperine-induced autophagic flux was further confirmed by assaying LC3-II accumulation and LC3B puncta formation in the presence of chloroquine, a well-known autophagy inhibitor. Taken together, these results indicated that piperine exhibited anti-proliferative effect in human prostate cancer cells by inducing cell cycle arrest and autophagy.

Influence of serum and albumin on the in vitro anandamide cytotoxicity toward C6 glioma cells assessed by the MTT cell viability assay: implications for the methodology of the MTT tests.

Anandamide (AEA), an endogenous ligand of cannabinoid CB1 and CB2 receptors, which also binds transient receptor potential vanilloid type 1 receptor (TRPV1), has been shown to display substantial selective cytotoxicity toward some cancer cell lines in vitro, although the relevant data are not consistent. In the present study, we employed the MTT test to assess short-term cytotoxicity of AEA on C6 rat glioma cell culture. When anandamide was administered to the culture medium with foetal bovine serum (FBS), no cytotoxic effect was observed following 24 h exposure of the glioma cells to micromolar concentrations of AEA. However, if no serum was present in the medium, micro-to-submicromolar concentrations of AEA induced dose-dependent cytotoxicity clearly detectable after 24 h. Control experiments made it possible to exclude significant interference of serum with the MTT test per se. Bovine serum albumin mimicked the effect of FBS. We conclude that the apparent inhibition of short-term cytotoxicity of AEA toward C6 rat glioma cells in vitro is caused by binding AEA to serum proteins such as albumin. Taking into account that blood serum or albumin is practically always present in cell culture media, we discuss implications of binding substances to serum proteins for methodology and interpretation of in vitro cytotoxicity testing.

Manumycin A inhibits triple-negative breast cancer growth through LC3-mediated cytoplasmic vacuolation death.

Therapy resistance can be attributed to acquisition of anti-apoptotic mechanisms by the cancer cells. Therefore, developing approaches that trigger non-apoptotic cell death in cancer cells to compensate for apoptosis resistance will help to treat cancer effectively. Triple-negative breast cancers (TNBC) are among the most aggressive and therapy resistant to breast tumors. Here we report that manumycin A (Man A), an inhibitor of farnesyl protein transferase, reduces cancer cell viability through induction of non-apoptotic, non-autophagic cytoplasmic vacuolation death in TNBC cells. Man A persistently induced cytoplasmic vacuolation and cell death through the expression of microtubule-associated protein 1 light chain 3 (LC3) and p62 proteins along with endoplasmic reticulum (ER) stress markers, Bip and CHOP, and accumulation of ubiquitinated proteins. As inhibitors of apoptosis and autophagy failed to block cytoplasmic vacuolation and its associated protein expression or cell death, it appears that these processes are not involved in the death induced by Man A. Ability of thiol antioxidant, NAC in blocking Man A-induced vacuolation, death and its related protein expression suggests that sulfhydryl homeostasis may be the target of Man A. Surprisingly, normal human mammary epithelial cells failed to undergo cytoplasmic vacuolation and cell death, and grew normally in presence of Man A. In conjunction with its in vitro effects, Man A also reduced tumor burden in vivo in xenograft models that showed extensive cytoplasmic vacuoles and condensed nuclei with remarkable increase in the vacuolation-associated protein expression together with increase of p21, p27, PTEN and decrease of pAkt. Interestingly, Man A-mediated upregulation of p21, p27 and PTEN and downregulation of pAkt and tumor growth suppression were also mimicked by LC3 knockdown in MDA-MB-231 cells. Overall, these results suggest novel therapeutic actions by Man A through the induction of non-apoptotic and non-autophagic cytoplasmic vacuolation death by probably affecting ER stress, LC3 and p62 pathways in TNBC but not in normal mammary epithelial cells.

Piperine inhibits cytokine production by human peripheral blood mononuclear cells.

Piperine, an amide isolated from Piper species (Piperaceae), has been reported to exhibit central nervous system depression, anti-pyretic and anti-inflammatory activity. Immunomodulatory and anti-tumor activity of piperine has been demonstrated in mouse carcinomas. However, there is little information available concerning the effect of piperine on humans. We evaluated the immunopharmacological activity of this compound in human immune cells. Human peripheral blood mononuclear cells (PBMCs) were exposed to piperine, and cell proliferation was determined by the MTS assay. Piperine significantly inhibited phytohemagglutinin-stimulated human PBMC proliferation after exposure for 72 h. This compound inhibited PBMC activity, with an IC(50) of 100.73 ± 11.16 µg/mL. Production of interleukin-2 (IL-2) and interferon-γ (IFN-γ) was measured using an ELISA assay and RT-PCR. Piperine inhibited IL-2 and IFN-γ production in the PBMCs. RT-PCR data indicated that IL-2 and IFN-γ mRNA expression in PBMCs is suppressed by piperine. This compound significantly inhibited the production of these two cytokines by activated PBMCs in a dose-dependent manner. In conclusion, piperine appears to have potential as an immunomodulatory agent for immune system suppression.

Involvement of transient receptor potential vanilloid type 1 channels in the pro-convulsant effect of anandamide in pentylenetetrazole-induced seizures.

Anandamide, an endogenous agonist of CB(1) receptors, also activates TRPV1 but at a higher concentration. Studies demonstrate the anticonvulsant activity of anandamide via CB(1) receptors, while its action through TRPV1 is still ambiguous. Thus, the present study investigated the influence of anandamide on pentylenetetrazole-induced seizures in mice pretreated with TRPV1 or CB(1) receptor antagonists. Acute intracerebroventricular administration of low doses of anandamide (10, 20, or 40µg/mouse) produced anticonvulsant effect, while the pro-convulsant effect was evident at high doses (80 or 100µg/mouse). Interestingly, AM251 (2µg/mouse), a CB(1) antagonist pretreatment blocked the anticonvulsant effect, but augmented the pro-convulsant effect. Conversely, in the presence of inactive dose of capsazepine (1µg/mouse), a TRPV1 antagonist, anandamide exhibited significant anticonvulsant effect even at high doses with no change in its anticonvulsant effect. Moreover, mice treated with capsaicin, a TRPV1 agonist (10, or 100µg/mouse) exhibited pro-convulsant activity that was blocked by capsazepine pretreatment. However, capsazepine, per se at doses 10 or 100µg/mouse exhibited anticonvulsant effect. Like anandamide, the agents (AM404 and URB597), which increase its synaptic concentrations produced similar biphasic effects. Thus, these results indicate that anandamide exhibits both pro- and anticonvulsant activities by activating TRPV1 and CB(1) receptor respectively.

Safety evaluation of Trikatu, a generic Ayurvedic medicine in Charles Foster rats.

Chemical characterization and acute and sub-acute toxicity study of Trikatu, a generic herbal formulation of Indian system of medicine, was carried out in Charles Foster (CF) rats for safety profiling. In acute toxicity experiment, Trikatu at 2,000 mg/kg body weight once orally was well tolerated by the experimental animals (both male and female) and no changes were observed in mortality, morbidity, gross pathology, gain in weight, vital organ weight, hematological (total white blood cells (WBC) and red blood cells (RBC) count), biochemical parameters such as serum creatinine, serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), serum lipid profile and tissue biochemical parameters such as reduced glutathione and malonaldehyde content as oxidative stress markers. In sub-acute experiment, Trikatu was administered at 5, 50 and 300 mg/kg body weight once daily for 28 days in female CF rats, and non-significant changes were found in most of the parameters studied such as acute experiment except significant increase in low density lipoprotein (LDL) cholesterol level at 50 and 300 mg/kg body weight, decrease in high density lipoprotein (HDL) cholesterol level at 300 mg/kg body weight, increase in SGPT activity at 50 mg/kg body weight and decrease in WBC count at 300 mg/kg body weight on 28(th) day post treatment.

The role of the endocannabinoid system in gametogenesis, implantation and early pregnancy.

Maternal use of marijuana, in which the exocannabinoid Delta(9)-tetrahydrocannabinol is the most active psychoactive ingredient, is known to have adverse effects on various aspects of reproduction including ovulation, spermatogenesis, implantation and pregnancy duration. Endogenous cannabinoids of which Anandamide is the prototype are widely distributed in the body especially in the reproductive tract and pregnancy tissues and act through the same receptors as the receptor as Delta(9)-tetrahydrocannabinol. Anandamide, has been reported to have pleiotropic effects on human reproduction and in experimental animal models. It appears to be the important neuro-cytokine mediator synchronizing the embryo-endometrial development for timed implantation, the development of the embryo into the blastocyst and transport of the embryo across the fallopian tubes. The mechanisms by which it exerts these effects are unclear but could be via direct actions on the various sites within the reproductive system or its differential actions on vascular tone dependent. In this review article we bring together the current knowledge on the role of endoccanabinoids in reproduction and postulate on the potential mechanisms on how these affect reproduction. In addition, we examine its role on the endothelium and vascular smooth muscle as a potential mechanism for adverse pregnancy outcome.

Temporal interactions between oral irritants: piperine, zingerone, and capsaicin.

Sequential presentation of 2 irritants may produce cross-sensitization or cross-adaptation effects upon introduction of the second irritant. In Experiment 1, subjects were given either 34 min of stimulation with zingerone, capsaicin, or piperine or one of those irritants for 23 min followed by blanks for 23 min. In Experiment 2, subjects received one irritant for 23-min irritants, followed immediately by another for 23 min (piperine --> zingerone, piperine --> capsaicin, zingerone --> piperine, or zingerone --> capsaicin). Cross-sensitization was observed for the piperine --> zingerone, zingerone --> piperine, and piperine --> capsaicin groups; cross-adaptation was observed for the zingerone --> capsaicin group. Cross-adaptation and cross-sensitization were predicted by adding the independent time courses of the respective irritants, starting the second at the offset of the first. These responses were also predicted by a mathematical model of central processing of primary afferent responses.