piperine and Disease-Models--Animal

Eighty percent (80%) aqueous acetone extract from fruit of Piper chaba (Piperaceae) was found to have a hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. Among the isolates, several amide constituents inhibited D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes, and the following structural requirements were suggested: i) the amide moiety was essential for strong activity; ii) the 1,9-decadiene structure between the benzene ring and the amide moiety tended to enhance the activity. Moreover, a principal constituent, piperine, exhibited strong in vivo hepatoprotective effect at a dose of 5 mg/kg, p.o. and its mode of action was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.

Topics: Alkaloids; Amides; Animals; Benzodioxoles; Cells, Cultured; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Dose-Response Relationship, Drug; Galactosamine; Hepatocytes; Lipopolysaccharides; Mice; Piper; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

Psoriasis is a common chronic inflammatory skin disease that is easy to relapse and difficult to cure. Piperine is the main alkaloid extracted from black pepper, and its role in psoriasis has not been previously reported. We identified that piperine ameliorated M5-induced psoriatic skin lesions. Furthermore, piperine alleviated psoriasis pathological features including epidermal hyperplasia and inflammatory cell infiltration, decreased the expression of psoriasis-characteristic cytokines, chemokines and proteins in IMQ-induced psoriasiform dermatitis. Moreover, we determined that piperine inhibited the phosphorylation of STAT3 in M5- and IMQ-induced psoriasis-like skin lesions. Our data demonstrated that piperine ameliorated psoriatic skin inflammation by inhibiting the phosphorylation of STAT3. Therefore, piperine may be one potential compound candidate for psoriasis therapy, providing new strategies for clinical intervention.

Topics: Alkaloids; Animals; Cytokines; Dermatitis; Disease Models, Animal; Humans; Imiquimod; Inflammation; Mice; Mice, Inbred BALB C; Phosphorylation; Psoriasis; Skin; STAT3 Transcription Factor

In the present study, the objective was to encapsulate piperine in nanoform by solvent evaporation method and to investigate the antidepressant-like activity of nanopiperine in lipopolysaccharide (LPS) induced depression in mice. LPS-induced depression in mice was reversed by repeated treatment of nanopiperine at dosages of 5 and 10 mg/kg body weight for 14 days. After 24 h of LPS injection, the animals were exposed to a (TST) tail suspension test and (FST) forced swim test. A sequence of behaviours was measured on days 0, 7, and 14. On day 14, the animals were euthanized, and the blood was collected; biochemical analysis was performed for the measurement of inflammatory and oxidative stress markers. Within the same period, nanopiperine improved hippocampal progenitor cell proliferation and increased brain-derived neurotrophic factor (BDNF) levels in the hippocampus of mice subjected to LPS-induced stress. In addition, the neurotransmitter estimation by the HPLC method showed that nanopiperine increased the levels of neurotransmitters. In summary, the nanopiperine showed potent neuroprotective and antidepressant activity, and stability relating to the elevated level of hippocampal BDNF level and as compared to pure piperine, the nanopiperine showed better oral bioavailability and stability.

Topics: Animals; Antidepressive Agents; Biological Availability; Brain-Derived Neurotrophic Factor; Depression; Disease Models, Animal; Hippocampus; Lipopolysaccharides; Mice

Piperine (PIP), the main active ingredient in pepper, belongs to the cinnamamide alkaloid. PIP has been found to have functions, including anti-oxidation, immune regulation, anti-tumour and promotion of drug metabolism. The present study was mainly designed to reveal the anti-tumour effect of PIP against gastric cancer and the relevant mechanism. In brief, the undifferentiated human gastric cancer cell HGC-27 was used, which was treated with different concentrations of PIP. As a result, PIP could inhibit proliferation and induce apoptosis of HGC-27 cells in a dose-dependent manner. The mechanism of PIP was associated with ROS increase and mitochondrial damage, simultaneously, the expression of key proteins of apoptosis was affected, including Bcl-2, Bax, Cyt-c, Caspase-9 and Caspase-3. Pre-treatment of ROS scavenger NAC HGC-27 cells could significantly reduce PIP-induced apoptosis and inhibit the activation of apoptotic signals. Consistently, PIP could induce ROS to increase and activate apoptotic signals in the animal model. Therefore, the present study showed that PIP can induce the generation of ROS, thereby promoting the activation of mitochondrial apoptotic pathway and exerting anti-tumour effects.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Biomarkers; Caspase 3; Caspase 9; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Immunophenotyping; Membrane Potential, Mitochondrial; Mice; Mitochondria; Piperidines; Polyunsaturated Alkamides; Reactive Oxygen Species; Signal Transduction; Stomach Neoplasms; Xenograft Model Antitumor Assays

The modulatory effects of piperine on drug metabolizing enzymes play an important role in the control of pharmacokinetic and the bioavailability properties of the administered drugs. The present study investigated the effect of piperine and piperine-donepezil co-administration on cognitive functions and synaptic plasticity at hippocampal perforant pathway (PP) to dentate gyrus (DG) synapses in an experimental model of Alzheimer's disease (AD).. Intracerebroventricularly (ICV) streptozotocin (STZ) injected rats were treated once daily with piperine, donepezil and piperine combined with donepezil for 4 weeks. Cognitive performance was evaluated using passive avoidance and Morris water maze performance tasks. Analysis of evoked field potentials was done to explore possible effects on input/output response, paired-pulse facilitation and long-term synaptic plasticity (LTP) at PP to DG synapses of hippocampus.. Rats subjected to ICV injection of STZ exhibited cognitive deficit associated with a hippocampal oxidative stress, effects that were reversed by chronic treatment with piperine or donepezil and or piperine combined with donepezil. Chronic treatment with piperine or donepezil restored the disruptive effects of STZ on LTP without altering basal synaptic transmission.. We found that optimal hippocampal function is dependent on tissue redox homeostasis. Piperine might reduce the synaptotoxic effects of STZ on hippocampal synaptic neurotransmission and correspondently is a good potential for neuroprotection against oxidative damage from ICV injection of STZ. These results suggest that piperine or donepezil significantly ameliorate cognitive deficit and LTP induction by attenuating oxidative status.

Topics: Alkaloids; Alzheimer Disease; Animals; Avoidance Learning; Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Disease Models, Animal; Donepezil; Drug Therapy, Combination; Hippocampus; Male; Neuronal Plasticity; Nootropic Agents; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Streptozocin; Treatment Outcome

Topics: Alkaloids; Animals; Apoptosis; Behavior, Animal; Benzodioxoles; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Kelch-Like ECH-Associated Protein 1; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; NF-E2-Related Factor 2; Parkinson Disease; PC12 Cells; Piperidines; Polyunsaturated Alkamides; Rats; Structure-Activity Relationship

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Systemic lupus erythematosus (SLE) is a chronic multi-system inflammatory disease associated with autoantibody formation. Clinical management of lupus is associated with multiple adverse events. Resveratrol is a phytoalexin with several pharmacological properties. This study aimed to evaluate the combinatorial effect of resveratrol (25 mg/kg and 50 mg/kg) and its bio-enhancer piperine (1/10th dose of resveratrol) on pristane-induced SLE murine model. Mice were injected with 0.5 ml of pristane and after 2 months they were orally dosed with resveratrol combinations for 4 months. Determined by indirect immunofluorescence, resveratrol was unable to abrogate autoantibody formation. The increased IFN-α, IL-6 and TNF-α was mitigated by low dose of resveratrol and piperine (RP-1). None of the doses regulated the increase in nitric oxide. Lipogranulomas associated with injected pristane were not observed after RP-1 and high dose of resveratrol (Res-2) treatment. Lupus mice witnessed IgG and IgM immune complexes by direct immunofluorescence assay and associated histopathological observations in kidneys, liver, lung, spleen and skin. None of the treatment regimens were able to regulate the manifestations observed in spleen and skin. RP-1 and Res-2 proved beneficial in kidney, liver and lungs and were able to ameliorate lupus associated manifestations. Renal manifestations (proteinuria and decreased creatinine in urine) were successfully mitigated by RP-1 and Res-2 and high dose combination of resveratrol and piperine. Oxidative stress (reactive oxygen species by flowcytometry and catalase, superoxide dismutase, glutathione peroxidase, reduced glutathione and lipid peroxidation by biochemical analysis) was evident by pristane injection. These were regulated by different doses of resveratrol alone and in combination with piperine. Hence, resveratrol when used in combination with piperine successfully reduces some measures of morbidity with little or no effect on mortality associated with lupus.

Topics: Alkaloids; Animals; Autoantibodies; Benzodioxoles; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Lupus Erythematosus, Systemic; Mice; Mice, Inbred BALB C; Piperidines; Polyunsaturated Alkamides; Resveratrol; Terpenes; Treatment Outcome

Mast cells play an important role in inflammatory and allergic diseases. MAS-related G protein-coupled receptor X2 (MRGPRX2) is a novel G protein-coupled receptor in mast cells that mediates drug-induced anaphylactoid reactions. Piperine has been reported to have anti-inflammatory and anti-allergic pharmacological activities. However, whether the pharmacological effects are regulated by MRGPRX2 has not yet been reported. The purpose of this study was to assess the anti-anaphylactoid effect of Piperine and to explore its potential mechanism. The anti-anaphylactoid effect of Piperine was assessed by an in vivo mouse hindpaw extravasation model. Mast cell intracellular calcium mobilization was measured by a calcium imaging assay. An enzyme immunoassay was used to evaluate the release of pro-inflammatory factors from stimulated mast cells. Activated mast cell related signals were assessed by western blot. A cell membrane chromatography assay was used to determine the binding characteristics of Piperine and MRGPRX2. The results showed that Piperine suppressed mast cell intracellular Ca

Topics: Alkaloids; Anaphylaxis; Animals; Benzodioxoles; Disease Models, Animal; Humans; Male; Mast Cells; Mice; Piperidines; Polyunsaturated Alkamides; Receptors, G-Protein-Coupled

Kelch-like ECH-associated protein (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) protein-protein interaction has become an important drug target for the treatment of Alzheimer's disease. In this study, we found a novel piperine derivative (HJ22) synthesized by our group with great ability to bind to Keap-1 and activate Keap1-Nrf2-ARE signaling pathway in vitro, driving us to investigate the beneficial effects of HJ22 on ibotenic acid (IBO)-induced neurological disorders in rats and underlying mechanisms. Interestingly, HJ22 significantly ameliorated IBO-induced cognitive impairment in Morris water maze, Y-maze and passive avoidance tests. Moreover, HJ22 significantly attenuated cholinergic dysfunction and neuronal morphological changes via inhibiting apoptotic cell death induced by IBO. Notably, HJ22 inhibited the interaction between Keap1 and Nrf2, and subsequently up-regulated nuclear Nrf2 expression, thereby inhibiting oxidative stress and Thioredoxin-interacting protein (TXNIP)-mediated Nod-like receptor protein 3 (NLRP3) inflammasome activation. These findings demonstrated that HJ22 exhibited potent therapeutic effects against IBO-induced cognitive impairment by alleviating cholinergic damage, oxidative stress, apoptosis and neuroinflammation, which might be partly attributed to its inhibitory activity on Keap1-Nrf2 protein-protein interaction.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Cells, Cultured; Cognitive Dysfunction; Disease Models, Animal; Humans; Ibotenic Acid; Inflammasomes; Inflammation; Kelch-Like ECH-Associated Protein 1; Neurons; NF-E2-Related Factor 2; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Protein Binding; Protein Interaction Domains and Motifs; Rats; Rats, Sprague-Dawley

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.

Topics: Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Disease Models, Animal; Hippocampus; Long-Term Potentiation; Male; Memory; Memory Disorders; Neuronal Plasticity; Neuroprotective Agents; Neurotoxicity Syndromes; Piperidines; Polyunsaturated Alkamides; Rats, Wistar; Streptozocin; Time Factors

Systemic lupus erythematosus is a multisystem autoimmune disease. Apart from usual treatments, approximately 50% of lupus patients use complementary medicine. Resveratrol is a phytoalexin with various pharmacological properties. We hypothesised that prophylactic treatment with resveratrol may abrogate manifestations in pristane-induced murine model of lupus-like disease and piperine; a bio-enhancer of resveratrol may enhance these properties. The prophylactic effect of resveratrol (25 mg/kg body weight: P-Res) alone and in combination with piperine (2.5 mg/kg body weight: P-RP) were assessed. P-Res and P-RP were equally efficient in mitigating oxidative stress (enzyme activity of catalase, superoxide dismutase, glutathione peroxidase and level of reduced glutathione, lipid peroxidation, and reactive oxygen species). Inflammation is associated with an increase in inflammatory cytokines. IL-6 was decreased by 71.60% with P-Res, and TNF-α was reduced by 59.70% with P-Res and 62.66% with P-RP (p < 0.05). Prevention of renal pathologies was evident by reduction in creatinine level by P-RP (p < 0.05) and abrogation of proteinuria (P-Res and P-RP). P-RP was efficient in restoring histopathology of liver and lungs and decreased immune complexes in lungs. P-Res proved more beneficial by extenuating lipogranulomas, histopathological manifestations in kidney, liver, and lungs, and eliminating immune complexes in liver and lungs. None of the treatments could regulate auto-antibody formation. Resveratrol decreases the susceptibility of developing pathogenesis in murine model of lupus-like disease. The results also conclude that addressing the bioavailability of resveratrol using it in combination with piperine does not prove more efficacious in preventing lupus-associated pathologies than resveratrol alone.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Cytokines; Disease Models, Animal; Female; Inflammation; Kidney; Lipid Peroxidation; Liver; Lung; Lupus Erythematosus, Systemic; Mice; Mice, Inbred BALB C; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Resveratrol; Terpenes

Mastitis, inflammation in the breast, affects breastfeedingwomenin the postpartumperiod. In the present study, we investigated the protective effects of piperine against mastitis using a mouse mastitis model. LPS-induced mastitis was established by injecting LPS into the canals of the mammary gland. Piperine was given intraperitoneally 1 h before and 12 h after LPS treatment. The results showed that the LPS-induced mammary histopathological changes and MPO activity were attenuated by piperine. LPS-induced inflammatory cytokines TNF-α andIL-1β were also inhibited by piperine. Furthermore, LPS-induced NF-κB activation was suppressed by the treatment with piperine. In addition, we found piperine dose-dependently increased the expression of PPARγ. All of these results suggested that piperine had protective effects against LPS-induced mastitis and that the mechanism may be mediated through the activation of PPARγ.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Benzodioxoles; Disease Models, Animal; Female; Humans; Immunohistochemistry; Interleukin-1beta; Lipopolysaccharides; Mammary Glands, Human; Mastitis; Mice; Mice, Inbred BALB C; NF-kappa B; Peroxidase; Piperidines; Polyunsaturated Alkamides; PPAR gamma; Tumor Necrosis Factor-alpha; Up-Regulation

Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation and fibrosis. Currently, there are no drugs for the treatment of pancreatic fibrosis associated with CP. Piperine, a natural alkaloid found in black pepper, has been reported to show anti‑inflammatory, anti‑oxidative, and antitumor activities. Although piperine exhibits numerous properties in regards to the regulation of diverse diseases, the effects of piperine on CP have not been established. To investigate the effects of piperine on CP in vivo, we induced CP in mice through the repetitive administration of cerulein (50 µg/kg) six times at 1‑h intervals, 5 times per week, for a total of 3 weeks. In the pre‑treatment groups, piperine (1, 5, or 10 mg/kg) or corn oil were administrated orally at 1 h before the first cerulein injection, once a day, 5 times a week, for a total of 3 weeks. In the post‑treatment groups, piperine (10 mg/kg) or corn oil was administered orally at 1 or 2 week after the first cerulein injection. Pancreases were collected for histological analysis. In addition, pancreatic stellate cells (PSCs) were isolated to examine the anti‑fibrogenic effects and regulatory mechanisms of piperine. Piperine treatment significantly inhibited histological damage in the pancreas, increased the pancreatic acinar cell survival, reduced collagen deposition and reduced pro‑inflammatory cytokines and chemokines. In addition, piperine treatment reduced the expression of fibrotic mediators, such as α‑smooth muscle actin (α‑SMA), collagen, and fibronectin 1 in the pancreas and PSCs. Moreover, piperine treatment reduced the production of transforming growth factor (TGF)‑β in the pancreas and PSCs. Furthermore, piperine treatment inhibited TGF‑β‑induced pSMAD2/3 activation but not pSMAD1/5 in the PSCs. These findings suggest that piperine treatment ameliorates pancreatic fibrosis by inhibiting TGF‑β/SMAD2/3 signaling during CP.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Benzodioxoles; Disease Models, Animal; Female; Fibrosis; Mice; Mice, Inbred C57BL; Pancreas; Pancreatitis, Chronic; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Piperine, the major alkaloid constituent of black pepper, has been reported to possess a wide range of pharmacological effects on the central nervous system, including antidepressant, anticonvulsant and anti-ischemic activities. In the present study, we aimed to investigate the therapeutic potential and neuroprotective mechanisms of piperine in an experimental mouse model of sporadic Alzheimer's disease (sAD) induced by intracerebroventricular (ICV) infusion of streptozotocin (STZ). STZ was infused bilaterally at a dose of 1.5 mg/kg/day on day 1 and day 3. From day 8, piperine (2.5-10 mg/kg body weight) was administered intraperitoneally once daily for 15 consecutive days. The locomotor activity and cognitive performance of mice were evaluated using open field test and Morris water maze test, respectively. On day 23, all animals were sacrificed, and the hippocampus was used for biochemical, neurochemical and neuroinflammatory determinations. Our data revealed that the ICV-STZ-infused sAD mouse showed an increased oxidative-nitrosative stress, an altered neurotransmission and an elevated neuroinflammation in hippocampus, as well as significant cognitive deficits. All these alterations can be ameliorated by piperine in a dose-dependent manner. In summary, our findings predict a therapeutic potential of piperine against cognitive deficits in sAD mouse. This effect might be due to its abilities to ameliorate oxidative-nitrosative stress, restore neurotransmission and reduce neuroinflammation.

Topics: Alkaloids; Alzheimer Disease; Animals; Benzodioxoles; Cognition Disorders; Disease Models, Animal; Hippocampus; Inflammation; Infusions, Intraventricular; Male; Maze Learning; Memory Disorders; Mice; Neuroprotective Agents; Nitrogen; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Streptozocin

Carbamazepine (CBZ) with piperine, the active ingredient in black pepper, which is omnipresent in food and may be potentially used for epilepsy control owing to its anticonvulsant effects, can be coadministered to epileptic patients. Since piperine has previously demonstrated its inhibition of the CYP3A-mediated metabolism of CBZ to carbamazepine-10,11-epoxide (CBZE), the present study aimed to investigate the impact of piperine on CBZ pharmacokinetics (PKs) in rats and pharmacodynamics in zebrafish and mouse acute seizure models. Plasma and brain PKs were studied in rats after a single-dose or 2-week combined oral administration of piperine (3.5/35 mg/kg, q.d.) and CBZ (40 mg/kg, t.i.d.) by blood sampling and brain microdialysis. Although no PK change was noticed after a single coadministration, significantly decreased plasma and brain concentrations of CBZ and CBZE with inhibited rat liver Cyp3a2 were demonstrated after long-term combined administration. Our developed compartmental model for the PK characterization of CBZ and CBZE in the blood and brain further estimated that coadministration with high-dose piperine could lead to decreases of 26%, 35%, and 38% in bioavailability, metabolism, and brain uptake of CBZ, respectively. Regardless of the PK changes, a limited impact on the antiepileptic effect of CBZ was found after the coadministration of CBZ and piperine in the tested seizure models. In conclusion, single-dose cotreatment of CBZ and piperine did not result in any significant PK or pharmacodynamic interactions, whereas their long-term cotreatment could lead to inhibited liver metabolism and the markedly reduced systemic and brain exposure of CBZ and CBZE.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Brain; Carbamazepine; Cytochrome P-450 Enzyme Inhibitors; Disease Models, Animal; Drug Interactions; Epilepsy; Liver; Male; Mice; Mice, Inbred C57BL; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Tissue Distribution; Zebrafish

Recent evidence suggests that encapsulation of hydrophobic drugs in biodegradable polymers opens a new horizon in nanomedicine filed. Piperine, a main alkaloid form of black pepper possesses potent anticonvulsant activity. However, the low water solubility of piperine has limited its clinical application. In this study, piperine was loaded on chitosan-sodium tripolyphosphate nanoparticles (CS-STPP NPs) and the effect of piperine NPs on seizures behavior and astrocytes activation was assessed in pentylentetrazol (PTZ)-induced kindling model. Animals have received the daily injection of free piperine or piperine NPs at doses of 5 or 10mg/kg, 10days before PTZ injections and their intraperitoneally (i.p) administration continued until the last PTZ injection. The neuroprotective effects of piperine NPs were evaluated using nissl staining and immunostaining against NeuN. Astrocytes activation was examined by GFAP immunostaining. Behavioral data showed that piperine NPs have inhibited the development of seizure parameters compared to the free piperine groups. In addition, the levels of cell loss and astrocytes activation were reduced in piperine NPs groups. In conclusion, these data suggest that piperine NPs enhance the neuroprotection and ameliorate the astrocytes activation in chemical kindling model of epilepsy. This may provide an effective therapeutic strategy for the treatment of epilepsy disorder.

Topics: Alkaloids; Animals; Astrocytes; Benzodioxoles; Chitosan; Disease Models, Animal; Epilepsy; Humans; Hydrophobic and Hydrophilic Interactions; Kindling, Neurologic; Mice; Nanoparticles; Neurons; Organophosphorus Compounds; Pentylenetetrazole; Piperidines; Polyunsaturated Alkamides; Stearic Acids

Parkinson's disease (PD) is a multifactorial neurological disorder caused by selective dopaminergic neuronal loss. Quercetin (QC) in combination with piperine (bioenhancer) acts as potential antioxidant, anti-inflammatory and neuroprotective against 6-OHDA rat model of PD. Rats were injected 6-OHDA (8μg/2μl, saline) unilaterally, intranigrally once into right SNpc. Pre-treatment with QC (25 and 50mg/kg, p.o.) alone and combination of QC (25mg/kg, p.o.) with piperine (2.5mg/kg, p.o.) were given for 14days starting from 8th day of 6-OHDA infusion. Post lesions were confirmed by rotational behavior with amphetamine (2.5mg/kg, i.p.) and motor coordination was assessed by narrow beam walk, open field and rotarod apparatus on the weekly basis. On 22nd day, animals were sacrificed and striatum homogenates were used for biochemical (LPO, GSH, Nitrite), neuroinflammatory (TNF-α, IL-1 β and IL-6) and neurotransmitter (dopamine, norepinephrine, serotonin, GABA, glutamate) analysis. Rats pre-treated with QC alone and in combination with piperine have significantly attenuated the 6-OHDA induced rotational behavior and motor deficits. Further, these drugs have significantly improved antioxidant potential, decreased striatal proinflammatory cytokines level as well as restored neurotransmitters level. The neuroprotective enhancement of QC along with piperine is attributed through antioxidant, anti-inflammatory and preventing neurotransmitter alteration mechanisms.

Topics: Alkaloids; Animals; Benzodioxoles; Brain Chemistry; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glutathione; Hand Strength; Locomotion; Male; Neurodegenerative Diseases; Neuroprotective Agents; Neurotransmitter Agents; Nitrites; Oxidopamine; Piperidines; Polyunsaturated Alkamides; Psychomotor Performance; Quercetin; Rats; Rats, Wistar; Sympatholytics; Thiobarbituric Acid Reactive Substances; Time Factors

Stress occurs in everyday life and persistence of it causes memory loss. Bioflavonoids like quercetin are reported to have poor bioavailability and limited therapeutic potential against stress induced neurological disorders. Therefore, the present study is an attempt to elucidate the therapeutic potency of combination of quercetin with piperine; a bioavailability enhancer against chronic unpredictable stress (CUS)-induced behavioral and biochemical alterations. Laca mice were subjected to a series of stressful events for a period of 28 days. Quercetin (20, 40 and 80 mg/kg, p.o.), piperine (20 mg/kg, p.o.) and their combinations were administered daily 30 min before CUS procedure. Piracetam (100 mg/kg, i.p.) served as a standard control. CUS caused impaired spatial navigation in Morris water maze test and poor retention in elevated plus maze task. Further, there was significant increase in brain oxidative stress markers and neuro-inflammation (TNF-α). This was coupled with marked rise in acetylcholinesterase and serum corticosterone levels. Co-administration of piperine with quercetin significantly elevated their potential to restore these behavioral, biochemical and molecular changes associated with mouse model of CUS. These results suggest that piperine enhances the neuroprotective effects of quercetin against CUS-induced oxidative stress, neuro-inflammation and memory deficits.

Topics: Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Biological Availability; Chronic Disease; Cognitive Dysfunction; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Male; Mice, Inbred Strains; Neurogenic Inflammation; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Quercetin; Stress, Psychological

Allogeneic hematopoetic stem cell transplantation (allo-HSCT) is a standard treatment for leukemia and other hematologic malignancies. The major complication of allo-HSCT is graft-versus-host-disease (GVHD), a progressive inflammatory illness characterized by donor immune cells attacking the organs of the recipient. Current GVHD prevention and treatment strategies use immune suppressive drugs and/or anti-T cell reagents these can lead to increased risk of infections and tumor relapse. Recent research demonstrated that epigallocatechin gallate (EGCG), a component found in green tea leaves at a level of 25-35% at dry weight, may be useful in the inhibition of GVHD due to its immune modulatory, anti-oxidative and anti-angiogenic capacities. In murine allo-HSCT recipients treated with EGCG, we found significantly reduced GVHD scores, reduced target organ GVHD and improved survival. EGCG treated allo-HSCT recipients had significantly higher numbers of regulatory T cells in GVHD target organs and in the blood. Furthermore, EGCG treatment resulted in diminished oxidative stress indicated by significant changes of glutathione blood levels as well as glutathione peroxidase in the colon. In summary, our study provides novel evidence demonstrating that EGCG ameliorates lethal GVHD and reduces GVHD-related target organ damage. Possible mechanisms are increased regulatory T cell numbers and reduced oxidative stress.

Topics: Alkaloids; Allografts; Animals; Antioxidants; Benzodioxoles; Catechin; Disease Models, Animal; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neovascularization, Pathologic; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Quercetin; T-Lymphocytes, Regulatory; Tea

Piperine exhibits anti-inflammatory activity, and has a long history of medicinal use. The objective of this study was to investigate the protective effects of piperine on inflammation, alveolar bone and collagen fibers in experimental periodontitis. We evaluated the related expression of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, matrix metalloproteinase (MMP)-8 and MMP-13 to enhance insight into these effects.. Thirty-two Wistar rats were divided into four groups of eight animals each: control group, periodontitis group, periodontitis plus 50 mg/kg piperine group and periodontitis plus 100 mg/kg piperine group. Histopathologic changes were detected by hematoxylin and eosin staining. Alveolar bone loss and trabecula microstructures were evaluated by micro-computed tomography. Changes in collagen fibers were assessed by picrosirius red staining. Western blot analysis was conducted to determine the levels of IL-1β, TNF-α, MMP-8 and MMP-13.. Piperine clearly inhibited alveolar bone loss and reformed trabecula microstructures in a dose-dependent manner. Histological staining showed that piperine significantly reduced the infiltration of inflammation in soft tissues. Both doses of piperine limited the fractions of degraded areas in collagen fibers. Piperine (100 mg/kg) significantly downregulated the expressions of IL-1β, MMP-8 and MMP-13 in periodontitis, but not that of TNF-α.. Piperine displays significantly protective effects on inflammation, alveolar bone loss, bone microstructures and collagen fiber degradation in experimental periodontitis. The effects may be ascribed to its inhibitory activity on the expressions of IL-1β, MMP-8 and MMP-13.

Topics: Alkaloids; Alveolar Bone Loss; Animals; Benzodioxoles; Blotting, Western; Collagen; Cytochrome P-450 Enzyme Inhibitors; Disease Models, Animal; Histocytochemistry; Inflammation; Interleukin-1beta; Male; Matrix Metalloproteinase 13; Matrix Metalloproteinase 8; Periodontitis; Piperidines; Polyunsaturated Alkamides; Proteolysis; Rats, Wistar; Treatment Outcome; Tumor Necrosis Factor-alpha; X-Ray Microtomography

Allergic rhinitis (AR) is a global health problem that affects a large number of population. Piperine (PIP) has been reported to exhibit anti-inflammatory, anti-histaminic, and immunomodulatory activities; however, its antiallergic profile has not been studied.. The objective of the study was to investigate the antiallergic potential of PIP in ova-albumin (OVA)-induced AR, mast cell degranulation (MSD), and OVA-induced paw edema.. Mice were sensitized with OVA alternately on 1, 3, 5, 7, 9, 11, and 13th day. They were treated with either vehicle, PIP (10, 20, and 40 mg/kg, p.o.), or montelukast (10 mg/kg, p.o.) from the 14th to 20th day. On the 21st day, intranasal (OVA: 5% µl) challenge was done. Animals were evaluated for physiological parameters, biochemical parameters, spleen weight, expression of interleukins (IL-6 and IL-1β), and immunoglobin-E (IgE). Histopathology of nasal mucosa, lungs, and spleen was carried out. MSD and paw edema studies were made to understand the mechanism of action.. PIP (10, 20, and 40 mg/kg, p.o.) showed a significant dose-dependent protection with respect to nasal rubbing, redness of nose, and sneezing (p < 0.001) following nasal challenge. PIP dose dependently reduced histamine, NO concentration (p < 0.001), as well as reduced expression of IL-6, IL-1β, and IgE (p < 0.001) as compared with the control group. Histopathology showed inhibition of infiltration of eosinophils and hyperplasia. It dose dependently reduced MSD and paw edema (p < 0.001).. PIP acts by mast cell-stabilizing activity, exhibits immunomodulatory and anti-inflammatory activity, thereby providing an effective treatment for AR.

Topics: Acetates; Alkaloids; Animals; Anti-Allergic Agents; Benzodioxoles; Biomarkers; Cell Degranulation; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Eosinophils; Histamine; Immunoglobulin E; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Mast Cells; Nitric Oxide; Ovalbumin; Piperidines; Polyunsaturated Alkamides; Quinolines; Rhinitis, Allergic; Spleen; Sulfides; Time Factors

Alzheimer's disease (AD) is one of the most patient devastating central nervous system diseases with no curative therapy. An effective oral therapy with brain-targeting potential is required that is hampered by blood-brain barrier. Piperine (PIP) is a natural alkaloid with memory enhancing potentials. Oral PIP delivery suffers from its hydrophobicity and first-pass metabolism. In this study, novel Tween-modified monoolein cubosomes (T-cubs) were elaborated as bioactive nanocarriers for brain-targeted oral delivery of PIP. Seven liquid crystalline nanoparticles (cubosomes) were prepared testing different bioactive surfactants (Tween 80, poloxamer, and Cremophor). Full in vitro characterization was carried out based on particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro release. Morphological examination and structure elucidation were performed using transmission and polarizing microscopes. Sporadic dementia of Alzheimer's type was induced in 42 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-α for inflammation. Liver and kidney toxicity studies were conducted as well. Among others, T-cubs exhibited optimum particle size (167.00±10.49 nm), polydispersity index (0.18±0.01), and zeta potential (-34.60±0.47 mv) with high entrapment efficiency (86.67%±0.62%). Cubs could significantly sustain PIP in vitro release. In vivo studies revealed T-cubs potential to significantly enhance PIP cognitive effect and even restore cognitive function to the normal level. Superiority of T-cubs over others suggested brain-targeting effect of Tween. Toxicological studies contended safety of cubs on kidney, liver, and even brain. T-cubs exhibited potential anti-inflammatory and anti-apoptotic activity of loaded PIP, indicating potential to stop AD progression that was first suggested in this article. Novel oral nanoparticles elaborated possess promising in vitro and in vivo characteristics with high safety for effective chronic treatment of AD.

Topics: Administration, Oral; Alkaloids; Alzheimer Disease; Animals; Benzodioxoles; Blood-Brain Barrier; Brain; Caspase 3; Disease Models, Animal; Drug Delivery Systems; Glycerides; Humans; Inflammation; Kidney; Liquid Crystals; Liver; Male; Nanomedicine; Nanoparticles; Oxidative Stress; Particle Size; Piperidines; Poloxamer; Polyethylene Glycols; Polysorbates; Polyunsaturated Alkamides; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Pepper, a daily-used seasoning for promoting appetite, is widely used in folk medicine for treating gastrointestinal diseases. Piperine is the major alkaloid in pepper and possesses a wide range of pharmacological activities. However, the mechanism for linking metabolic and medicinal activities of piperine remains unknown. Here we report that piperine robustly boosts mTORC1 activity by recruiting more system L1 amino acid transporter (SLC7A5/SLC3A2) to the cell membrane, thus promoting amino acid metabolism. Piperine-induced increase of mTORC1 activity in resident peritoneal macrophages (pMΦs) is correlated with enhanced production of IL-6 and TNF-α upon LPS stimulation. Such an enhancement of cytokine production could be abrogated by inhibitors of the mTOR signaling pathway, indicating mTOR's action in this process. Moreover, piperine treatment protected resident pMΦs from bacterium-induced apoptosis and disappearance, and increased their bacterial phagocytic ability. Consequently, piperine administration conferred mice resistance against bacterial infection and even sepsis. Our data highlight that piperine has the capacity to metabolically reprogram peritoneal resident macrophages to fortify their innate functions against bacterial infection.

Topics: Alkaloids; Amino Acids; Animals; Anti-Bacterial Agents; Apoptosis; Benzodioxoles; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Female; Fusion Regulatory Protein 1, Heavy Chain; HeLa Cells; Humans; Immunity, Innate; Inflammation Mediators; Interleukin-6; Large Neutral Amino Acid-Transporter 1; Lipopolysaccharides; Macrophage Activation; Macrophages, Peritoneal; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Multiprotein Complexes; Phagocytosis; Piperidines; Polyunsaturated Alkamides; RAW 264.7 Cells; RNA Interference; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; Transfection; Tumor Necrosis Factor-alpha

Parkinson's disease (PD) is second only to Alzheimer's disease as the most common and debilitating age-associated neurodegenerative disorder. Currently, no therapy has been shown to unequivocally retard or arrest the progression of the disease. The aim of the present study was to investigate the protective effect of piperine on the 1-methyl-4-phenyl-1,2,3,6‑tetrahydropyridine (MPTP)-induced Parkinson's mouse model. For MPTP treatment, the animals received repeated intraperitoneal injections (i.p.) of MPTP (30 mg/kg) solution for 7 days. Piperine (10 mg/kg) was administered orally for 15 days including 8 days of pretreatment. Motor behavior analysis was conducted with the rotarod test. The Morris water maze (MWM) was used to assess the cognitive learning ability of the mice. A histological examination was subsequently conducted. The results ddemonstrate that piperine treatment attenuated MPTP-induced deficits in motor coordination and cognitive functioning. Piperine also prevented MPTP-induced decreases in the number of tyrosine hydroxylase-positive cells in the substantia nigra. Additionally, piperine reduced the number of activated microglia, expression of cytokine IL-1β, and oxidative stress following MPTP treatment. An anti-apoptotic property of piperine was identified by maintaining the balance of Bcl-2/Bax. In conclusion, the results show that piperine exerts a protective effect on dopaminergic neurons via antioxidant, anti-apoptotic, and anti-inflammatory mechanisms in an MPTP-induced mouse model of PD. Thus, piperine is a potential therapeutic treatment for PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Alkaloids; Animals; Anti-Inflammatory Agents; Apoptosis; Benzodioxoles; Disease Models, Animal; Dopaminergic Neurons; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Motor Activity; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Piperidines; Polyunsaturated Alkamides; Rotarod Performance Test; Substantia Nigra; Tyrosine 3-Monooxygenase

Previous studies in our laboratory have demonstrated that piperine produced antidepressant-like action in various mouse models of behavioral despair. This study aimed to investigate the role of brain-derived neurotrophic factor (BDNF) signalling in the antidepressant-like effect of piperine in mice exposed to chronic unpredictable mild stress (CUMS). The results showed that CUMS caused depression-like behavior in mice, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. It was also found that BDNF protein expression in the hippocampus and frontal cortex were significantly decreased in CUMS-treated mice. Chronic treatment of piperine at the dose of 10mg/kg significantly ameliorated behavioural deficits of CUMS-treated mice in the sucrose preference test and forced swim test. Piperine treatment also significantly decreased immobility time in the forced swim test in naive mice. In parallel, chronic piperine treatment significantly increased BDNF protein expression in the hippocampus and frontal cortex of both naive and CUMS-treated mice. In addition, inhibition of BDNF signalling by injection of K252a, an inhibitor of the BDNF receptor TrkB, significantly blocked the antidepressant-like effect of piperine in the sucrose preference test and forced swim test of CUMS-treated mice. Taken together, this study suggests that BDNF signalling is an essential mediator for the antidepressant-like effect of piperine.

Topics: Alkaloids; Animals; Antidepressive Agents; Benzodioxoles; Brain-Derived Neurotrophic Factor; Carbazoles; Chronic Disease; Disease Models, Animal; Enzyme Inhibitors; Food Preferences; Indole Alkaloids; Male; Mice; Mice, Inbred ICR; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Stress, Psychological; Sucrose; Sweetening Agents; Time Factors

Triple-negative breast cancer (TNBC) is most the aggressive type of breast cancer and is poorly responsive to endocrine therapeutics; however, one of the most attractive treatments is tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based therapies. To identify compounds that enhance the efficacy of TRAIL-based therapies, we screened 55 compounds from natural products in combination with TRAIL in TNBC cells.. Human TNBC cells, MDA-MB-468 and MDA-MB-231, and murine TNBC cells, 4T1, were used. Cell viability, apoptotic cells, and cell cycle were quantified by the WST-1 assay, annexin-V/7-amino-actinomycinD (7-AAD) staining and Propidium iodide (PI) staining, respectively. In vivo effects of piperine were evaluated in the orthotopic-inoculated 4T1-luc mouse model.. After screening, we identified piperine as the most potent adjuvant at enhancing the efficacy of TRAIL-based therapies in TNBC cells in vitro and in vivo, which might be mediated through inhibition of survivin and p65 phosphorylation.. Piperine may enhance TRAIL-based therapeutics for TNBC.

Topics: Alkaloids; Animals; Antineoplastic Agents; Apoptosis; Benzodioxoles; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Drug Synergism; Female; Humans; Inhibitor of Apoptosis Proteins; Mice; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Survivin; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor RelA; Triple Negative Breast Neoplasms; Tumor Burden

Post natal exposure to VPA (valproic acid) in mice induces behavioral deficits, abnormal sensitivity to sensory stimuli and self-injurious behavior, observed in autism. Piperine has been reported to have protective effect on brain. The present study aimed at evaluating effect of piperine on VPA induced neurobehavioral and biochemical alterations in BALB/c mice. Young BALB/c mice 13 days old were procured from five different litters and segregated into five groups (n=6; 3 male, 3 female) i.e., Group I served as control group, received physiological saline on PND (Post natal day) 14 & Tween 80 p.o. from PND13-40. Group II served as normal treated group and received piperine (20mg/kg p.o.) from PND 13-40 and saline s.c. on PND 14. Group III served as valproate treated group received VPA (400mg/kg s.c.) on PND 14 and Tween 80 p.o. from PND 13-40. Group IV & V served as disease treated group received VPA (400mg/kg s.c.) on PND 14 & piperine (5 & 20mg/kg p.o.) from PND 13-40 respectively. BALB/c mice pups were subjected to behavioral testing to assess motor skill development, nociceptive response, locomotion, anxiety, and cognition on various postnatal days up to PND 40. At the end of behavioral evaluation, mice were sacrificed; brain was isolated for biochemical estimations (serotonin, glutathione, MDA and nitric oxide) and histopathological examination. Our study revealed that treatment with piperine significantly improved behavioral alterations, lowered oxidative stress markers, and restored histoarchitecture of cerebellum. This ameliorating effect of piperine is attributed to its anti-oxidant activity, cognition enhancing and neuroprotective activity.

Topics: Alkaloids; Animals; Anxiety; Autistic Disorder; Benzodioxoles; Biomarkers; Brain; Cognition; Disease Models, Animal; Locomotion; Mice; Mice, Inbred BALB C; Motor Skills; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Time Factors; Treatment Outcome; Valproic Acid

An investigation was made to explore the possibility of anxiolytic activity of piperine in unstressed and stressed mice along with the underlying role of nitriergic and GABAergic modulation for the noted activity of piperine.. Piperine (5, 10 and 20mg/kg, ip) was administered to unstressed mice. In another groups of animals, piperine was administered 30 min before subjecting them to immobilization stress for 6h. Antianxiety activity was evaluated by employing elevated plus maze, light-dark box and social interaction test. Diazepam was employed as standard anxiolytic drug.. Piperine produced significant antianxiety-like activity in unstressed and stressed mice. The anxiolytic-like activity of piperine was comparable to diazepam. In unstressed mice, piperine significantly increased brain GABA levels, but could not produce any change in plasma nitrite levels. Meanwhile, in stressed mice, piperine did not produce any significant change in GABA levels, but significantly decreased nitrite levels. Pre-treatment with aminoguanidine (50mg/kg, ip), an inducible nitric oxide synthase (NOS) inhibitor, significantly potentiated the anxiolytic-like activity of piperine, as compared to piperine and aminoguanidine alone in stressed mice. On the other hand, pretreatment with 7-nitroindazole (20mg/kg, ip), a neuronal NOS inhibitor significantly potentiated the antianxiety-like activity of piperine, as compared to piperine and 7-nitroindazole alone in unstressed mice.. These data suggest that the piperine produced significant anxiolytic activity in unstressed mice possibly through increase in GABA levels and inhibition of neuronal NOS. On the other hand, antianxiety activity in stressed mice might be through inhibition of inducible NOS.

Topics: Alkaloids; Animals; Anti-Anxiety Agents; Anxiety; Benzodioxoles; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Guanidines; Indazoles; Male; Maze Learning; Mice; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitrites; Piperidines; Polyunsaturated Alkamides; Stress, Psychological

The present study was aimed to characterize the anticonvulsant effects of piperine in combination with well established antiepileptic drug (AED) phenytoin, in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of phenytoin with piperine at the fixed-ratio of 1:1 from the MES test with respect to long-term memory and skeletal muscular strength were evaluated along with free plasma concentration of piperine and phenytoin. Parameters of oxidative stress (glutathione, malondialdehyde), brain serotonin and serum calcium levels were also determined to probe the mechanism involved in the interaction. Test of parallelism revealed that 2 drugs were associated with non-parallel dose response effects, hence only one fixed ratio combination (1:1) was evaluated which displayed additive interaction between the 2 drugs with a slight tendency towards superadditivity. Free plasma concentrations of piperine and phenytoin revealed no significant changes in their concentrations when the drugs were combined at the fixed-ratio of 1:1. In combination, neither long-term memory nor skeletal muscular strength was impaired. Analysis of biochemical parameters showed that the piperine alone or in combination with phenytoin successfully reversed the parameters of oxidative stress and increased brain serotonin levels as compared to MES group. However, no significant alteration in the serum calcium levels was observed by any treatment. In conclusion, the combination displayed additive interaction and slight tendency towards synergistic potential with protection towards side effects associated with AED therapy and is worthy of consideration for further investigations.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Calcium; Disease Models, Animal; Drug Therapy, Combination; Electroshock; Lipid Peroxidation; Male; Memory, Long-Term; Mice; Muscle Strength; Phenytoin; Piperidines; Polyunsaturated Alkamides; Seizures

Bilateral destruction of the olfactory bulbs is known to cause behavioral changes analogous to symptoms of depression. Curcumin, a traditional Indian spice is currently being investigated in different psychiatric problems including depression. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study is an attempt to elucidate the neuroprotective mechanism of curcumin and its co-administration with piperine against olfactory bulbectomy induced depression in rats.. Rats undergone olfactory bulbs ablations were analyzed after post-surgical rehabilitation period of 2 weeks. Animals were then treated with different doses of curcumin (100, 200 and 400 mg/kg; p.o.), piperine (20 mg/kg; p.o.) and their combination daily for another 2 weeks. Imipramine (10 mg/kg; i.p.) served as a standard control. Various behavioral tests like forced swim test (FST), open field behaviour and sucrose preference test (SPT) were performed, followed by estimation of biochemical, mitochondrial, molecular and histopathological parameters in rat brain.. Ablation of olfactory bulbs caused depression-like symptoms as evidenced by increased immobility time in FST, hyperactivity in open field arena, and anhedonic like response in SPT along with alterations in mitochondrial enzyme complexes, increased serum corticosterone levels and oxidative damage. These deficits were integrated with increased inflammatory cytokines (TNF-α) and apoptotic factor (caspase-3) levels along with a marked reduction in neurogenesis factor (BDNF) in the brain of olfactory bulbectomized (OBX) rats. Curcumin treatment significantly and dose-dependently restored all these behavioral, biochemical, mitochondrial, molecular and histopathological alterations associated with OBX induced depression. Further, co-administration of piperine with curcumin significantly potentiated their neuroprotective effects as compared to their effects alone.. The present study highlights that curcumin along with piperine exhibits neuroprotection against olfactory bulbectomy induced depression possibly by modulating oxidative-nitrosative stress induced neuroinflammation and apoptosis.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Brain; Brain-Derived Neurotrophic Factor; Caspase 3; Corticosterone; Curcumin; Depression; Disease Models, Animal; Drug Therapy, Combination; Electron Transport Chain Complex Proteins; Food Preferences; Immobilization; Inflammation; Lipid Peroxidation; Male; Mitochondria; Olfactory Bulb; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Signal Transduction; Sucrose; Tumor Necrosis Factor-alpha

Piperine is a spice principle, and its protective role against oxidative damage and lipid peroxidation has been reported. In this study, we aimed to investigate the effects of piperine in the prevention of ischemia-reperfusion injury to the small intestine.. Rats were allocated to three groups of 8 rats each. Rats in the sham group underwent laparotomy and observation only. Animals in the control and study groups underwent 45 minutes ischemia followed by 60 minutes reperfusion. In the study group, 10 mg/kg piperine was administered intraperitoneally just before the reperfusion procedure. Blood samples were obtained for measurement of lactate levels, and resection of the terminal ileum was performed to evaluate the histopathologic specimens and tissue malondialdehyde, superoxide dismutase, and glutathione activities. All results were expressed as mean±SD. Comparisons between groups were made by using the one way analysis of variance (ANOVA).. Lactate and malondialdehyde levels were significantly higher in the control group than the study and sham groups (p<0.001). In the study group, superoxide dismutase, and glutathione activities were significantly higher than in the control group (p<0.001). The sham group had the highest activities. Histopathologic examination showed disruption of villous pattern and lamina propria in the control group.. Intraperitoneal administration of 10 mg/kg piperine just before the reperfusion may reduce ischemia-reperfusion injury to the small intestine.

Topics: Alkaloids; Animals; Benzodioxoles; Disease Models, Animal; Glutathione; Ileum; Injections, Intraperitoneal; Ischemic Preconditioning; Lipid Peroxidation; Male; Malondialdehyde; Piperidines; Polyunsaturated Alkamides; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase; Torsion Abnormality

In the present study, we examined the molecular mechanism by which Piperine (bioactive compound of Piper nigrum) inhibits neuronal cell apoptosis. We further investigated the anti-inflammatory effect of Piperine on 6-OHDA induced Parkinson's disease. Consistent with its antioxidant properties, Piperine (10 mg/kg bwt) reduced 6-OHDA-induced lipid peroxidation and stimulated glutathione levels in striatum of rats. Furthermore, Piperine treatment diminished cytochrome-c release from mitochondria and reduced caspase-3 and caspase-9 activation induced by 6-OHDA. Treatment with Piperine markedly inhibited poly(ADP-ribose) polymerase activation, pro-apoptotic Bax levels and elevation of Bcl-2 levels. Piperine reduces contralateral rotations induced by apomorphine. Further narrow beam test and rotarod also showed improvement in motor coordination and balance behavior in rats treated with Piperine. In addition Piperine depletes inflammatory markers, TNF-α and IL-1β in 6-OHDA-induced Parkinson's rats. We propose that, in addition to its antioxidant properties Piperine exerts a protective effect via anti-apoptotic and anti-inflammatory mechanism on 6-OHDA induced Parkinson's disease.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Apomorphine; Apoptosis; Behavior, Animal; Benzodioxoles; Disease Models, Animal; Male; Oxidative Stress; Oxidopamine; Parkinson Disease; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Piperine, an alkaloid present in the Piper genus, was shown to have an anticonvulsant activity, evaluated by the pilocarpine-induced model, in mice. Pilocarpine (350mg/kg, i.p.) was administered 30min after piperine (2.5, 5, 10 and 20mg/kg, i.p.) which significantly increased latencies to 1st convulsion and to death, and percentage of survivals. These parameters were also increased in the pilocarpine groups pretreated with atropine plus piperine (10 and 2.5mg/kg, respectively), as related to the pilocarpine group. However, they were not altered in the pilocarpine groups pretreated with memantine (a NMDA-type glutamate receptors blocker, 2mg/kg, p.o.) or nimodipine (a calcium channel blocker, 10mg/kg, p.o.), both associated with piperine (1 or 2.5mg/kg), as compared to the piperine plus pilocarpine group. Moreover, the pilocarpine group pretreated with diazepam (which binds to the GABAA receptor, 0.2 and 0.5mg/kg, i.p.) plus piperine (1 and 2.5mg/kg) significantly increased latency to the 1st convulsion, as related to the pilocarpine group, suggesting that the GABAergic system is involved with the piperine action. Furthermore, the piperine effect was blocked by flumazenil (2mg/kg, i.p.), a benzodiazepine antagonist. Untreated P350 animals showed decreased striatal DA and increased DOPAC and HVA levels that were not affected in the piperine plus pilocarpine groups. Piperine increased striatal levels of GABA, glycine and taurine, and reversed pilocarpine-induced increases in nitrite contents in sera and brain. Hippocampi from the untreated pilocarpine group showed an increased number of TNF-α immunostained cells in all areas, as opposed to the pilocarpine group pretreated with piperine. Taken together, piperine anticonvulsant effects are the result of its anti-inflammatory and antioxidant actions, as well as TNF-α reduction. In addition, piperine effects on inhibitory amino acids and on the GABAergic system may certainly contribute to the drug anticonvulsant activity.

Topics: Alkaloids; Amino Acids; Animals; Anticonvulsants; Antioxidants; Atropine; Benzodioxoles; Biogenic Monoamines; Brain; Diazepam; Disease Models, Animal; Epilepsy; Flumazenil; gamma-Aminobutyric Acid; Humans; Male; Memantine; Mice; Nimodipine; Nitrites; Pilocarpine; Piperidines; Polyunsaturated Alkamides; Seizures; Tumor Necrosis Factor-alpha

Argulus are common aquatic ectoparasites that create one of the major threats to aquaculture due to absence of suitable therapy. Piperine, a bioactive component of Piper longum, has medicinal properties and acts as anti-inflammatory, antibacterial, and antifungal, considering eco-friendliness and cost-effectiveness. The present study aimed to evaluate antiparasitic effect of piperine against an ectoparasite Argulus spp. on Carassius auratus. Artificial Argulus infection was carried out by cohabitation method, and the fishes were selected for in vivo study when intensity of Argulus infestation was observed to be 15-20 Argulus per fish. In vitro and in vivo studies were performed at different concentration 1.0 (T (1)), 3.0 (T (2)), 5.0 (T (3)), 7.0 (T (4)), and 9.0 mg l(-1) (T (5)) of piperine solution to treat Argulus for 3 and 72 h, respectively. The acute toxicity test for piperine EC 97 % against goldfish was performed for 96 h. The 96 h median lethal concentration (LC(50)) for piperine was found to be 52.64 mg l(-1). In vitro effect of piperine solution led to 100 % mortality of Argulus at 9.0 mg l(-1) in 3 h whereas, under in vivo test, the 100 % antiparasitic efficacy of piperine solution was found at 9.0 mg l(-1) in 48 h. The EC(50) for 48 h was 9.0 mg l(-1), and thus, therapeutic index is 5.8. The results revealed that piperine at a concentration of 9.0 mg l(-1) can be used as a potential natural agent for controlling Argulus parasite.

Topics: Alkaloids; Animals; Antiparasitic Agents; Arguloida; Benzodioxoles; Disease Models, Animal; Ectoparasitic Infestations; Goldfish; Piper; Piperidines; Polyunsaturated Alkamides; Survival Analysis; Treatment Outcome

In the present study, the anti-inflammatory effect of piperine was investigated on monosodium urate crystal-induced inflammation in mice, an experimental model for gouty arthritis, and compared it with that of the nonsteroidal anti-inflammatory drug, indomethacin. The levels of lysosomal enzymes, lipid peroxidation, tumor necrosis factor-α, and paw volume were increased significantly, and the activities of antioxidant status were in turn decreased in monosodium urate crystal-induced mice, whereas these changes were reverted to near normal levels upon piperine (30 mg/kg b.wt, i.p.) treatment. In vitro, piperine (50/100 ug/ml) suppressed the level of β-glucuronidase and lactate dehydrogenase in monosodium urate crystal-incubated polymorphonuclear leucocytes in concentration-dependent manner when compared to control cells. Thus, the present study clearly indicated that piperine inhibit the monosodium urate crystal-induced inflammation and can be regarded as therapeutic drug for the treatment of acute gouty arthritis.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Arthritis, Gouty; Benzodioxoles; Disease Models, Animal; Female; Humans; In Vitro Techniques; Indomethacin; Lipid Peroxidation; Lysosomes; Male; Mice; Neutrophils; Piperidines; Polyunsaturated Alkamides; Tumor Necrosis Factor-alpha; Uric Acid

Long-term treatment with haloperidol is associated with a number of extrapyramidal side effects, particularly the irregular movements of chorionic type. This limitation presents a marked therapeutic challenge. The present study investigates the molecular etiology of haloperidol neurotoxicity and the role of curcumin, a well-known anti-oxidant, in ameliorating these adverse effects. The redox status of haloperidol-treated brains along with NO, TNF-α, NF-kappaB p65 subunit, caspase-3, and monoamine neurotransmitters were measured in the striatum of rat brain. Chronic treatment with haloperidol (5 mg/kg, i.p., 21 days) produced orofacial dyskinetic movements which were coupled with marked increase in oxidative stress parameters, TNF-α, caspase-3 activity in cytoplasmic lysate and active p65 sub unit of NF-kappaB in nuclear lysates of the striatum. Neurochemically, chronic administration of haloperidol resulted in a significant decrease in the levels of norepinephrine, dopamine, and serotonin. The prototype atypical anti-psychotic, clozapine (10 mg/kg, i.p., 21 days) produced mild oxidative stress but did not alter any other parameters. Interestingly, co-administration of curcumin (25 and 50 mg/kg, i.p., 21 days) dose-dependently prevented all the behavioral, cellular, and neurochemical changes associated with the chronic administration of haloperidol. Curcumin per se (50 mg/kg) did not show any side effects. Co-administration of piperine significantly enhanced the effect of curcumin (25 mg/kg) but not of curcumin (50 mg/kg). Collectively, the data indicated the potential of curcumin as an adjunct to haloperidol treatment and provided initial clues to the underlying molecular mechanisms in haloperidol neurotoxicity. This study also provides a rationale for the combination of piperine and curcumin.

Topics: Alkaloids; Analysis of Variance; Animals; Apoptosis; Behavior, Animal; Benzodioxoles; Caspase 3; Colorimetry; Curcumin; Cytokines; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Haloperidol; Inflammation; Male; Neuroprotective Agents; Neurotoxicity Syndromes; Neurotransmitter Agents; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Statistics as Topic; Thiobarbituric Acid Reactive Substances

Piperine, a trans-trans-isomer of 1-piperoyl-piperidine, was tested in combination with mupirocin for antimicrobial activity against Staphylococcus aureus strains including meticillin-resistant S. aureus. The combination markedly reduced the MIC of mupirocin and also lowered the mutation frequency. Enhanced accumulation and efflux of ethidium bromide from wild-type and mutant (Mup(r)-1) strains in the presence of piperine indicated that inhibition of efflux could be a possible mechanism of potentiation of mupirocin activity by piperine. The combination of piperine with mupirocin in a dermal infection model of mice showed better in vivo efficacy when compared with the commercially available formulation of 2 % mupirocin.

Topics: Alkaloids; Animals; Anti-Bacterial Agents; Bacterial Proteins; Benzodioxoles; Disease Models, Animal; Drug Synergism; Enzyme Inhibitors; Ethidium; Female; Membrane Transport Proteins; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Mupirocin; Piperidines; Polyunsaturated Alkamides; Rodent Diseases; Staphylococcal Infections; Treatment Outcome

Spices are traditionally known to have digestive stimulant action and to cure digestive disorders. In this study, the protective effect of dietary spices with respect to activities of antioxidant enzymes in gastric and intestinal mucosa was examined. Groups of Wistar rats were fed for 8 weeks with diets containing black pepper (0.5%), piperine (0.02%), red pepper (3.0%), capsaicin (0.01%), and ginger (0.05%). All these spices significantly enhanced the activities of antioxidant enzymes--superoxide dismutase, catalase, glutathione reductase, and glutathione-S-transferase--in both gastric and intestinal mucosa, suggesting a gastrointestinal protective role for these spices. In a separate study, these dietary spices were found to alleviate the diminished activities of antioxidant enzymes in gastric and intestinal mucosa under conditions of ethanol-induced oxidative stress. The gastroprotective effect of the spices was also reflected in their positive effect on mucosal glycoproteins, thereby lowering mucosal injury. The amelioration of the ethanol-induced decrease in the activities of antioxidant enzymes in gastric and intestinal mucosa by dietary spices suggests their beneficial gastrointestinal protective role. This is the first report on the gastrointestinal protective potential of dietary spices.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Capsaicin; Capsicum; Catalase; Cytoprotection; Diet; Disease Models, Animal; Ethanol; Gastric Mucosa; Gastrointestinal Agents; Gastrointestinal Diseases; Glutathione Reductase; Glutathione Transferase; Glycoproteins; Intestinal Mucosa; Male; Mucus; Oxidative Stress; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Spices; Superoxide Dismutase; Zingiber officinale

Pentylenetetrazol (PTZ)-induced oxidative stress results in disturbance of the antioxidant enzyme status accompanied by neuronal injury and the development of epilepsy in rats. The present study evaluated the antioxidant effects of curcumin against PTZ-induced convulsions. Over a period of 30 days, i.p. injections of subconvulsive doses of PTZ on alternate days resulted in the development of a well-known kindling model of epilepsy. Spectrophotometric analysis revealed a markedly elevated activity of the antioxidant enzymes malondialdehyde (MDA), catalase and glutathione S-transferase (GST) in the cerebrum and cerebellum of epileptic rats due to PTZ-induced oxidative stress. Oral supplementation of curcumin at a dose of 2 g/kg for 30 days resulted in a transient decrease in MDA, catalase and GST levels in the rat cerebrum and cerebellum. Piperine (20 mg/kg orally) was administered along with curcumin to enhance the bioavailability of the latter up to 20-fold more. Combined treatment with curcumin and carbamazepine (3.6 mg/kg orally) also gave similar results, indicating that the potent antioxidant curcumin can be used as an adjuvant in antiepileptic therapy.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Biological Availability; Carbamazepine; Catalase; Curcumin; Disease Models, Animal; Drug Therapy, Combination; Epilepsy; Glutathione Transferase; Injections, Intraperitoneal; Male; Malondialdehyde; Oxidative Stress; Pentylenetetrazole; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

This study aimed to investigate the effect of piperine on airway hyperresponsiveness, pulmonary eosinophilic infiltration, various immune cell phenotypes, Th2 cytokine production, immunoglobulin E and histamine production in a murine model of asthma.. Asthma was induced in Balb/c mice by ovalbumin sensitization and inhalation. Piperine (4.5 and 2.25 mg/kg) was orally administered 5 times a week for 8 weeks. At 1 day after the last ovalbumin exposure, airway hyperresponsiveness was determined and samples of bronchoalveolar lavage fluid, lung cells and serum were collected for further analysis.. Piperine-treated groups had suppressed eosinophil infiltration, allergic airway inflammation and airway hyperresponsiveness, and these occurred by suppression of the production of interleukin-4, interleukin-5, immunoglobulin E and histamine. Moreover, polymerase chain reaction products for thymus and activation regulated chemokine from lung cell RNA preparations were decreased in the piperine-treated group compared with control groups, although transforming growth factor-beta products were increased in the piperine-treated group.. The results suggest that the therapeutic mechanism by which piperine effectively treats asthma is based on a reduction of Th2 cytokines (interleukin-4, interleukin-5), eosinophil infiltration, and by marked reduction of thymus and activation regulated chemokine, eotaxin-2 and interleukin-13 mRNA expression (especially transcription of nuclear factor-kappaB dependent genes) in lung tissue, as well as reduced interleukin-4, interleukin-5 and eotaxin levels in bronchoalveolar lavage fluid, and histamine and ovalbumin-specific immunoglobulin E production in serum.

Topics: Alkaloids; Animals; Asthma; Benzodioxoles; Bronchial Hyperreactivity; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophils; Female; Histamine; Immunoglobulin E; Mice; Mice, Inbred BALB C; Ovalbumin; Piperidines; Polyunsaturated Alkamides; RNA, Messenger; T-Lymphocytes; Th2 Cells

Piplartine {5,6-dihydro-1-[1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl]-2(1H)pyridinone} and piperine {1-5-(1,3)-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]piperidine} are alkaloid amides isolated from Piper. Both have been reported to show cytotoxic activity towards several tumor cell lines. In the present study, the in vivo antitumor activity of these compounds was evaluated in 60 female Swiss mice (N = 10 per group) transplanted with Sarcoma 180. Histopathological and morphological analyses of the tumor and the organs, including liver, spleen, and kidney, were performed in order to evaluate the toxicological aspects of the treatment with these amides. Administration of piplartine or piperine (50 or 100 mg kg(-1) day(-1) intraperitoneally for 7 days starting 1 day after inoculation) inhibited solid tumor development in mice transplanted with Sarcoma 180 cells. The inhibition rates were 28.7 and 52.3% for piplartine and 55.1 and 56.8% for piperine, after 7 days of treatment, at the lower and higher doses, respectively. The antitumor activity of piplartine was related to inhibition of the tumor proliferation rate, as observed by reduction of Ki67 staining, a nuclear antigen associated with G1, S, G2, and M cell cycle phases, in tumors from treated animals. However, piperine did not inhibit cell proliferation as observed in Ki67 immunohistochemical analysis. Histopathological analysis of liver and kidney showed that both organs were reversibly affected by piplartine and piperine treatment, but in a different way. Piperine was more toxic to the liver, leading to ballooning degeneration of hepatocytes, accompanied by microvesicular steatosis in some areas, than piplartine which, in turn, was more toxic to the kidney, leading to discrete hydropic changes of the proximal tubular and glomerular epithelium and tubular hemorrhage in treated animals.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Benzodioxoles; Cell Proliferation; Disease Models, Animal; Female; Kidney; Liver; Mice; Neoplasm Transplantation; Piper; Piperidines; Piperidones; Plant Extracts; Plant Roots; Polyunsaturated Alkamides; Sarcoma 180; Spleen

Chemoprevention has emerged as a very effective preventive measure against carcinogenesis. Many bioactive compounds present in edible as well in herbal plants have revealed their cancer chemopreventive potential. In the present study, our goal was to investigate the impact of piperine, a principle ingredient of pepper, on alterations of mitochondrial antioxidant system and lipid peroxidation in Benzo(a)pyrene (B(a)P) induced experimental lung carcinogenesis. Oral supplementation of piperine (50 mg/kg body weight) effectively suppressed lung carcinogenesis in B(a)p induced mice as revealed by the decrease in the extent of mitochondrial lipid peroxidation and concomitant increase in the activities of enzymatic antioxidants (superoxide dismutase, catalase and glutathione peroxidase) and non enzymatic antioxidant (reduced glutathione, vitamin E and vitamin C) levels when compared to lung carcinogenesis bearing animals. Our data suggests that piperine may extent its chemopreventive effect by modulating lipid peroxidation and augmenting antioxidant defense system.

Topics: Alkaloids; Animals; Antineoplastic Agents; Antioxidants; Benzo(a)pyrene; Benzodioxoles; Disease Models, Animal; Lipid Peroxidation; Lung Neoplasms; Male; Mice; Mitochondria; Phytotherapy; Piperidines; Plants, Medicinal; Polyunsaturated Alkamides

Piperine (1-peperoyl piperidine) was isolated from Piper nigrum Linn for the evaluation of anti-inflammatory activity in rats. Different acute and chronic experimental models like carrageenin-induced rat paw edema, cotton pellet granuloma, and croton oil-induced granuloma pouch, were employed. Simultaneously, biochemical estimations were made to elucidate the underlying mechanism of the action. Piperine acted significantly on early acute changes in inflammatory processes and chronic granulative changes. It also acted partially through stimulation of pituitary adrenal axis. Exudative changes in both acute and chronic models, however, were insignificant.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Disease Models, Animal; Drug Evaluation, Preclinical; Granuloma; Inflammation; Male; Piperidines; Pituitary-Adrenal System; Polyunsaturated Alkamides; Rats