Zingerone Inhibits the Neutrophil Extracellular Trap Formation and Protects against Sepsis via Nrf2-Mediated ROS Inhibition.

Neutrophils release chromatin and antimicrobial proteins to trap and kill microbes, which is termed as neutrophil extracellular trap (NET) formation. NETs play a pivotal role in host defense against infection. However, emerging evidence indicated that NETs also contribute to an exaggerated inflammatory response and organic injuries in sepsis. Zingerone, a natural compound extracted from Zingiber officinale, exerts antioxidant, anti-inflammatory, and antioncogenic properties. In this study, we found that treatment with zingerone reduced organ injury and improved the outcome in a cecal ligation puncture- (CLP-) induced polymicrobial sepsis model. Administration of zingerone also alleviates reactive oxygen species (ROS) accumulation and systematic inflammation in septic mice and inhibits neutrophil extracellular traps (NETs) formation in vivo and in vitro. Furthermore, inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) with its specific antagonist significantly counteracted the suppressive effects of zingerone on ROS and NETs and retarded the protective role of zingerone against sepsis-associated organ injury. In addition, exposure to zingerone does not affect phagocytic activity of neutrophils in vitro and bacterial dissemination in vivo. Above all, our results indicate that zingerone treatment obviously attenuates NET formation and inflammatory response via Nrf2-mediated ROS inhibition, thus providing a novel therapeutic strategy against sepsis-induced injury.

Neonatal zingerone protects against the development of high-fructose diet-induced metabolic syndrome in adult Sprague-Dawley rats.

During the early postnatal period, dietary manipulations can alter the developmental trajectory of the growing offspring, causing beneficial or adverse health outcomes later in adult life. We investigated the potential preventive effects of neonatal zingerone intake on the development of fructose-induced metabolic derangements in rats.Four-day old male and female Sprague-Dawley rat pups (n = 79) were randomly grouped and administered: 10 ml/kg body weight (bwt) of distilled water (W), 10 ml/kg bwt 20% fructose solution (FS), 10 ml/kg bwt fructose solution + 40 mg/kg bwt of zingerone in distilled water (ZF) or 40 mg/kg bwt of zingerone in distilled water (ZW) pre-weaning. After weaning, W and ZW continued on unlimited tap water, while FS and ZF continued on unlimited fructose solution for 10 weeks. Body mass and food and fluid intake were evaluated, plasma was collected for metabolic assays and visceral fat was quantified.Food intake was decreased, fructose and overall caloric intake were increased due to fructose feeding in both sexes (P < 0.05). When compared with the controls, the high-fructose diet significantly raised the terminal body masses of females (P < 0.0001), concentrations of triglycerides, total cholesterol, LDL-c, TG:HDL-c ratio and visceral fat mass relative to bwt in both sexes (P < 0.05). Zingerone prevented (P < 0.05) the fructose-induced increase in body mass (females) and hypercholesterolemia (both sexes). Levels of HDL-c, glycaemic parameters and adiponectin were not affected by the interventions (P > 0.05). Sex-related differences were observed in food, fluid and caloric intake, terminal mass, cholesterol subtypes and visceral fat percentage (P < 0.05).Zingerone could be used strategically in the neonatal phase as a prophylatic management of high-fructose diet-induced metabolic syndrome.

6-Paradol and its glucoside improve memory disorder in mice.

In this study, the effects of 6-paradol (6P) and 6-paradol-ß-glucoside (6PG) on neuritogenesis were investigated using PC12 cells. Treatment with 200 µM 6P or 6PG and nerve growth factor (NGF) (5 ng mL-1) increased the number of elongated dendritic cells 8.7 and 5.4 times, respectively, compared to that with NGF (5 ng mL-1) treatment alone. 6P and 6PG did not stimulate the phosphorylation of extracellular regulated protein kinases (ERK)1/2 and cAMP response element-binding protein (CREB) in the tropomyosin receptor kinase A (TrkA) pathway as their activities were suppressed by the pathway inhibitor, k252a. 6P enhanced Ca2+ influx into the cells, whereas 6PG had no effect on Ca2+ influx, although it stimulated PC12 cell differentiation. High-performance liquid chromatography (HPLC) analysis of 6PG in PC12 culture medium suggested that 6PG was deglycosylated to generate 6P, which exhibited the effect. Furthermore, the bioactivities of 6P and 6PG were investigated in mice, and the results revealed that they ameliorated short-term memory loss in animals during behavioral testing.

Male-lure type, lure dosage, and fly age at feeding all influence male mating success in Jarvis' fruit fly.

Males of certain Dacini fruit flies are strongly attracted to, and feed upon, plant secondary compounds such as methyl eugenol, raspberry ketone and zingerone. The consumed lure is generally found to induce physiological and behavioural changes that enhance the mating performance of lure-fed males. Male Bactrocera jarvisi respond strongly to zingerone from a young age, but only weakly respond to raspberry ketone. We hypothesized that this selective lure-response would be reflected in the physiological importance of the lure to the fly. We found that zingerone feeding by young males resulted in significantly greater mating success in competitive mating trials with lure-deprived flies, but the mating advantage was lost in older males. Lure dosage had a significant effect on the duration of the mating advantage, for example when fed 20 µg of zingerone, the advantage lasted only 1 day post-feeding, but when fed of 50 µg zingerone the advantage lasted 7 days. Raspberry ketone feeding did not confer any mating advantage to males except at one dosage (50 µg) for 1 day after feeding. When given a choice, B. jarvisi females preferred to mate with zingerone-fed versus to raspberry ketone-fed males. This study revealed lure, dosage and age of fly at time of lure administration are all important factors for maximising lure-enhanced fruit fly mating performance. These findings contribute to a better theoretical understanding of the evolution of fruit fly-lure interactions and may help improve fruit fly pest management via the Sterile Insect Technique through semiochemical-mediated enhancement of sterile male mating performance.

Dihydro-stilbene gigantol relieves CCl4-induced hepatic oxidative stress and inflammation in mice via inhibiting C5b-9 formation in the liver.

In general, anti-inflammatory treatment is considered for multiple liver diseases despite the etiology. But current drugs for alleviating liver inflammation have defects, making it necessary to develop more potent and safer drugs for liver injury. In this study, we screened a series of (dihydro-)stilbene or (dihydro-)phenanthrene derivatives extracted from Pholidota chinensis for their potential biological activities. Among 31 compounds, the dihydro-stilbene gigantol exerted most potent protective effects on human hepatocytes against lithocholic acid toxicity, and exhibited solid antioxidative and anti-inflammatory effect in vitro. In mice with CCl4-induced acute liver injury, pre-administration of gigantol (10, 20, 40 mg· kg-1· d-1, po, for 7 days) dose-dependently decreased serum transaminase levels and improved pathological changes in liver tissues. The elevated lipid peroxidation and inflammatory responses in the livers were also significantly alleviated by gigantol. The pharmacokinetic studies showed that gigantol was highly concentrated in the mouse livers, which consisted with its efficacy in preventing liver injury. Using a label-free quantitative proteomic analysis we revealed that gigantol mainly regulated the immune system process in liver tissues of CCl4-treated mice, and the complement and coagulation cascades was the predominant pathway; gigantol markedly inhibited the expression of complement component C9, which was a key component for the formation of terminal complement complex (TCC) C5b-9. These results were validated by immunohistochemistry (IHC) or real time-PCR. Confocal microscopy analysis showed that gigantol significantly inhibited the vascular deposition of TCC in the liver. In conclusion, we demonstrate for the first time that oral administration of gigantol potently relieves liver oxidative stress and inflammation, possibly via a novel mechanism of inhibiting the C5b-9 formation in the liver.

Combination of zingerone and dihydroartemisinin presented synergistic antimalarial activity against Plasmodium berghei infection in BALB/c mice as in vivo model.

Malaria is a global health problem leading to the death of 435,000 cases in tropical and sub-tropical zones. Spread and emergence of increasing resistance to the antimalarial drugs are the major challenges in the control of malaria. Therefore, searching for alternative antimalarial drugs is urgently needed, and combination treatment preferred as an approach to address this. This study aimed to evaluate in vivo antimalarial activity of zingerone (ZN), and its combination with dihydroartemisinin (DHA) against Plasmodium berghei infected mice. ZN was prepared and tested for acute oral toxicity according to the OECD guideline. In vivo antimalarial activity of different doses of ZN and combination with DHA were determined using the 4-day suppression test. The results showed that ZN was found to be safe and no mortality within the observation period, and the lethal dose might be greater than the limited dose of 1000 mg/kg. For in vivo antimalarial test, ZN exhibited significant (p < .05) parasitemia inhibition of 30.65% and 45.75% at the doses of 50 mg/kg and 100 mg/kg, respectively. Moreover, effective dose 50 (ED50) of ZN was 29.76 mg/kg. The combination treatment of ZN and DHA at the doses of ED50 values at the fixed ratio 1:1 was found to present significant (p < .001) antimalarial activity as compared to ZN and DHA treated alone with markedly prolonged mean survival time. Additionally, the combination index (0.83384) revealed the synergistic antimalarial effect. It can be concluded that ZN exerted potent antimalarial activity with no toxicity, and combination treatment with DHA produced the synergistic antimalarial effect.

Modulatory effect of zingerone against cisplatin or γ-irradiation induced hepatotoxicity by molecular targeting regulation.

Zingerone (ZO) is an ingredient of ginger (Zingiber officinale) which has different pharmacological properties. The objective of this research was to evaluate the protective effect of ZO against Cisplatin (Cis) or γ-Irradiation (IR)-induced hepatotoxicity in rats. ZO was given orally for consecutive 14 days prior to the treatment with Cis or exposure to IR at 15th day. Animals were sacrificed at the 23rd day. Cis or IR induced a marked increase in MAPK signal transduction as evidenced by increased p38 MAPK, JNK and ErK1/2. CYP2E1 and NADPH oxidase were significantly up-regulated. Inflammatory markers (TLR4, iNOS, COX-2 and MPO) and liver enzymes (AST, ALT and ALP) activities were also increased. Administration of ZO significantly ameliorated the above mentioned parameters.

Gastroprotective Effect of Zingerone on Ethanol-Induced Gastric Ulcers in Rats.

Background and objectives: Zingerone is an ingredient of ginger (Zingiber officinale) with different pharmacological activities. Several studies have investigated the effect of zingerone on various gastrointestinal diseases, including irritable bowel syndrome and diarrhea. This study is aimed to evaluate the effect of zingerone on ethanol-induced gastric ulcers in rats. Materials and Methods: Gastric ulcers were induced by ethanol (96%, 5 mL/kg, po) in male wistar rats and zingerone (50, 100, and 200 mg/kg) was administrated orally. Normal saline and ranitidine were used as negative and positive control, respectively. In this study, the number and length of ulcers, and malondialdehyde (MDA) and nitric oxide (NO) levels in stomach tissues were determined. Results: The findings showed that the mean number and length of gastric ulcers were significantly lower in zingerone-received groups than ethanol group (P < 0.05). The level of malondialdehyde was decreased in the stomach of zingerone groups (P < 0.05) compared to the ethanol group. In addition, zingerone treatment prevented the decrease of nitric oxide level by ethanol in the stomach tissue. Conclusions: The present study showed that zingerone has a protective effect on the ethanol-induced gastric ulcer, which may be due to its free radical scavenging activity.

Selectivity of Dietary Phenolics for Inhibition of Human Monoamine Oxidases A and B.

Monoamine oxidases (MAOs) regulate local levels of neurotransmitters such as dopamine, norepinephrine, and serotonin and thus have been targeted by drugs for the treatment of certain CNS disorders. However, recent studies have shown that these enzymes are upregulated with age in nervous and cardiac tissues and may be involved in degeneration of these tissues, since their metabolic mechanism releases hydrogen peroxide leading to oxidative stress. Thus, targeting these enzymes may be a potential anti-aging strategy. The purpose of this study was to compare the MAO inhibition and selectivity of selected dietary phenolic compounds, using a previously validated assay that would avoid interference from the compounds. Kynuramine metabolism by human recombinant MAO-A and MAO-B leads to formation of 4-hydroxyquinoline, with Vmax values of 10.2±0.2 and 7.35±0.69 nmol/mg/min, respectively, and Km values of 23.1±0.8 µM and 18.0±2.3 µM, respectively. For oral dosing and interactions with the gastrointestinal tract, curcumin, guaiacol, isoeugenol, pterostilbene, resveratrol, and zingerone were tested at their highest expected luminal concentrations from an oral dose. Each of these significantly inhibited both enzymes except for zingerone, which only inhibited MAO-A. The IC50 values were determined, and selectivity indices (MAO-A/MAO-B IC50 ratios) were calculated. Resveratrol and isoeugenol were selective for MAO-A, with IC50 values of 0.313±0.008 and 3.72±0.20 µM and selectivity indices of 50.5 and 27.4, respectively. Pterostilbene was selective for MAO-B, with IC50 of 0.138±0.013 µM and selectivity index of 0.0103. The inhibition of resveratrol (MAO-A) and pterostilbene (MAO-B) was consistent with competitive time-independent mechanisms. Resveratrol 4'-glucoside was the only compound which inhibited MAO-A, but itself, resveratrol 3-glucoside, and pterostilbene 4'-glucoside failed to inhibit MAO-B. Additional studies are needed to establish the effects of these compounds on MAO-A and/or MAO-B in humans.

Guaiacol/ß-cyclodextrin for rapid healing of dry socket: antibacterial activity, cytotoxicity, and bone repair-an animal study.

PURPOSE: Dry socket (DS) is one the most common and symptomatic post-extraction complications; however, no consensus on its treatment has been reached. This study aimed to develop a novel dressing material for DS containing the phenolic agent guaiacol and evaluate its biological properties. METHODS: An inclusion complex of guaiacol and ß-cyclodextrin (Gu/ßcd) was prepared by freeze-drying. Its antibacterial activity over six oral bacteria was analyzed using the microdilution method, and its cytotoxicity in osteoblasts was assessed with the MTT assay. The alveolar healing process induced by Gu/ßcd was evaluated histologically after the treatment of DS in rats. RESULTS: ßcd complexation potentiated Gu's antibacterial effect and reduced its cytotoxicity in osteoblasts. Bone trabeculae were formed in the alveolar apices of rats treated with Gu/ßcd by day 7. On day 14, woven bone occupied the apical and middle thirds of the sockets; on day 21, the entire alveolus was filled by newly formed bone, which was in a more advanced stage of repair than the positive control (Alvogyl™). CONCLUSION: The improvement in Gu's biological properties in vitro and the rapid alveolar repair in comparison with Alvogyl™ in vivo demonstrated the benefits of the Gu/ßcd complex as a future alternative for the treatment of DS.

Identification of vanilloid compounds in grains of paradise and their effects on sympathetic nerve activity.

BACKGROUND: Grains of paradise (GP) is the seed of Aframomum melegueta, which is widely distributed throughout West Africa and has been used as a spice and a folk remedy for a long time. Anti-obesity effect of GP intake was demonstrated in a previous report. Aim of the present study was to isolate some compounds in GP and clarify the anti-obesity mechanism. RESULTS: Ten vanilloid compounds were isolated. Among them, 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol and 1-(4'-hydroxy-3'-methoxyphenyl)-3-octen-5-one were determined as novel compounds and 6-gingerol, 6-paradol and 6-shogaol were identified as the major constituents in GP extract. Moreover, the extract and 6-gingerol, which is one of the principal components of GP extract, were orally administered to rats to investigate the effect on sympathetic nerve activity (SNA) in brown adipose tissue (BAT). The injection of GP extract and 6-gingerol decreased BAT-SNA, whereas capsaicin, which is a major component of chili pepper, activates the sympathetic nervous system. CONCLUSION: This study suggested that GP extract and 6-gingerol were largely unrelated to the anti-obesity effect by the activation of interscapular BAT-SNA and had a different anti-obesity mechanism to capsaicin. © 2018 Society of Chemical Industry.

Protective effects of zingerone on lipopolysaccharide-induced hepatic failure through the modulation of inflammatory pathways.

The aim of this study was to investigate the effects of zingerone (ZGR) on lipopolysaccharide (LPS)-induced liver failure in mice, and to elucidate underlying mechanisms. ZGR is a phenolic alkanone isolated from ginger, and has potential health benefits. Mice were treated intravenously with ZGR at 12 h after LPS treatment. LPS significantly increased mortality, serum levels of alanine transaminase, aspartate transaminase, and inflammatory cytokines, and toll-like receptor 4 (TLR4) protein expression; these effects of LPS were inhibited by ZGR. It also attenuated the LPS-induced activation of myeloid differentiation primary response gene 88 and TLR-associated activator of interferon-dependent signaling pathways of the TLR system. Our results suggest that ZGR protects against LPS-induced liver damage by inhibiting the TLR-mediated inflammatory pathway, indicating its potential to treat liver diseases.

Hepatoprotective potential of zingerone against nonalcoholic fatty liver disease in rats fed with fructose-enriched diet.

Overconsumption of fructose increases the risk of nonalcoholic fatty liver disease (NAFLD), obesity and metabolic syndrome. NAFLD is currently one of the most common etiologies of chronic liver disease worldwide. The aim of the present study is to evaluate the hepatoprotective potential of zingerone against fructose-enriched diet-induced rat model of nonalcoholic fatty liver disease. Male albino Wistar rats were used and randomly divided into four groups: group 1, control rats fed with standard pellet; group 2, rats were fed normal pellet with intragastric intubation of zingerone (100 mg/kg/day); group 3, rats were fed fructose enriched diet alone; group 4, rats were fed fructose enriched diet with intragastric intubation of zingerone (100 mg/kg/day). Body weight, abdominal circumference, blood glucose, lipid profile and hepatic function indicators were increased and HDL reduced in group 3 rats. Liver pathology of group 3 showed marked changes which includes micro- and macrovesicular steatosis, marked inflammatory cell infiltration, sinusoidal fibrosis and with a significant increase in the area percentage of the collagen. Administration of zingerone reversed the fructose enriched diet induced changes especially body weight, abdominal circumference, blood glucose, lipid profile, hepatic function indicators and restored pathological alteration of liver. Taken together these data provide new insights into the preventive approach of zingerone against the development of the NAFLD.

Ginger and Zingerone Ameliorate Lipopolysaccharide-Induced Acute Systemic Inflammation in Mice, Assessed by Nuclear Factor-κB Bioluminescent Imaging.

Ginger is a commonly used spice in cooking. In this study, we comprehensively evaluated the anti-inflammatory activities of ginger and its component zingerone in lipopolysaccharide (LPS)-induced acute systemic inflammation in mice via nuclear factor-κB (NF-κB) bioluminescent imaging. Ginger and zingerone significantly suppressed LPS-induced NF-κB activities in cells in a dose-dependent manner, and the maximal inhibition (84.5% ± 3.5% and 96.2% ± 0.6%) was observed at 100 µg/mL ginger and zingerone, respectively. Moreover, dietary ginger and zingerone significantly reduced LPS-induced proinflammatory cytokine production in sera by 62.9% ± 18.2% and 81.3% ± 6.2%, respectively, and NF-κB bioluminescent signals in whole body by 26.9% ± 14.3% and 38.5% ± 6.2%, respectively. In addition, ginger and zingerone suppressed LPS-induced NF-κB-driven luminescent intensities in most organs, and the maximal inhibition by ginger and zingerone was observed in small intestine. Immunohistochemical staining further showed that ginger and zingerone decreased interleukin-1ß (IL-1ß)-, CD11b-, and p65-positive areas in jejunum. In conclusion, our findings suggested that ginger and zingerone were likely to be broad-spectrum anti-inflammatory agents in most organs that suppressed the activation of NF-κB, the production of IL-1ß, and the infiltration of inflammatory cells in mice.

Haemostatic risk factors in dyslipidemic rabbits: role of 10-dehydrogingerdione as a new hypolipemic agent.

Micro and macrovascular complications occurring during hyperlipidemia are mostly attributed to haemostatic impairment and vascular endothelial dysfunction. Cholesteryl ester transfer protein (CETP) inhibitors have been emerged recently as promising hypocholesterolemic agents to confer protection against lipid-mediated atherosclerosis. Therefore, 10-dehydrogingerdione (DHGD), a novel CETP inhibitor isolated from ginger rhizomes, was selected as a natural product in the present study to illustrate its effect on haemostatic impairment associated with hyperlipidemia as compared to a currently used hypocholesterolemic agent, atorvastatin (ATOR). Rabbits were fed a high cholesterol diet (HCD) and divided into three groups. One group served as control group while the other groups received DHGD or ATOR. Dyslipidemic rabbits showed a significant increase in serum endothelin-1, ischemia modified albumin, plasminogen activator inhibitor-1, prothrombin fragments (1+2) and plasma fibrinogen along with a decrease of nitric oxide level in serum. Daily administration of ATOR or DHGD significantly decreased the aforementioned coagulation and ischemia biomarkers and increased serum nitric oxide. DHGD (natural) results seem to be more remarkable as compared to ATOR (synthetic).

Sulfonation pathway inhibitors block reactivation of latent HIV-1.

Long-lived pools of latently infected cells are a significant barrier to the development of a cure for HIV-1 infection. A better understanding of the mechanisms of reactivation from latency is needed to facilitate the development of novel therapies that address this problem. Here we show that chemical inhibitors of the sulfonation pathway prevent virus reactivation, both in latently infected J-Lat and U1 cell lines and in a primary human CD4+ T cell model of latency. In each of these models, sulfonation inhibitors decreased transcription initiation from the HIV-1 promoter. These inhibitors block transcription initiation at a step that lies downstream of nucleosome remodeling and affects RNA polymerase II recruitment to the viral promoter. These results suggest that the sulfonation pathway acts by a novel mechanism to regulate efficient virus transcription initiation during reactivation from latency, and further that augmentation of this pathway could be therapeutically useful.

Zingerone suppresses liver inflammation induced by antibiotic mediated endotoxemia through down regulating hepatic mRNA expression of inflammatory markers in Pseudomonas aeruginosa peritonitis mouse model.

Antibiotic-induced endotoxin release is associated with high mortality rate even when appropriate antibiotics are used for the treatment of severe infections in intensive care units. Since liver is involved in systemic clearance and detoxification of endotoxin hence it becomes a primary target organ for endotoxin mediated inflammation. Currently available anti-inflammatory drugs give rise to serious side effects. Hence, there is an urgent need for safe and effective anti-inflammatory therapy. It is likely that anti-inflammatory phytochemicals and neutraceutical agents may have the potential to reduce the endotoxin mediated inflammation and complications associated with endotoxin release. Keeping this in mind, the present study was planned to evaluate the hepatoprotective potential of zingerone (active compound of zingiber officinale) against liver inflammation induced by antibiotic mediated endotoxemia. The selected antibiotics capable of releasing high content of endotoxin were employed for their in vivo efficacy in P.aeruginosa peritonitis model. Released endotoxin induced inflammation and zingerone as co-anti-inflammatory therapy significantly reduced inflammatory response. Improved liver histology and reduced inflammatory markers MDA, RNI, MPO, tissue damage markers (AST, ALT, ALP) and inflammatory cytokines (MIP-2, IL-6 and TNF-α) were indicative of therapeutic potential of zingerone. The mechanism of action of zingerone may be related to significant inhibition of the mRNA expression of inflammatory markers (TLR4, RelA, NF-kB2, TNF- α, iNOS, COX-2) indicating that zingerone interferes with cell signalling pathway and suppresses hyper expression of cell signaling molecules of inflammatory pathway. Zingerone therapy significantly protected liver from endotoxin induced inflammatory damage by down regulating biochemical as well as molecular markers of inflammation. In conclusion, this study provides evidence that zingerone is a potent anti-inflammatory phytomedicine against hepatic inflammation induced by antibiotic mediated endotoxemia. These results thus suggest that zingerone treatment can be used as a co-therapy with antibiotics to reduced endotoxin induced inflammation during treatment of severe P.aeruginosa infections.

Relationship between the acyl chain length of paradol analogues and their antiobesity activity following oral ingestion.

6-Paradol is known to activate thermogenesis in brown adipose tissue (BAT), and paradol analogues with different acyl chain lengths possess different pungency thresholds. In this study, the influence of the acyl chain length on the antiobesity activity of the paradol analogues was investigated. The antiobesity activity of 6-paradol in mice fed a high-fat diet for 8 weeks was greater than that of dihydrocapsiate. A comparison of the antiobesity activities of zingerone and 6-paradol showed that the length of the acyl chain in the paradol analogue was important for strong activity. Furthermore, the antiobesity activities of 6-, 8-, and 12-paradol appeared to decrease in an acyl chain length-dependent manner. The mechanism of the antiobesity activity of 6-paradol was enhanced by increasing levels of energy metabolism in the BAT, as well as an increase in the expression of uncoupling proteins 1 via the activation of sympathetic nerve activity.

Delayed administration of zingerone mitigates the behavioral and histological alteration via repression of oxidative stress and intrinsic programmed cell death in focal transient ischemic rats.

The neuronal mitochondria succumb to ischemia-reperfusion injury and release huge amount of reactive oxygen species and ultimately lead the neurons to intrinsic pathway of programmed cell death (iPCD). The present study was undertaken to elucidate the ischemia-reperfusion-induced oxidative stress and molecular events in iPCD 24 h post ischemia-reperfusion injury and plausible mitigation by zingerone, a potent antioxidant of ginger rhizome. The right middle cerebral artery was occluded for 2 h followed by reperfusion for 22 hours. A maximum infarct volume (43.29%) and mitochondrial injury (56.99%) was observed in middle cerebral artery occlusion (MCAO) group. However, zingerone administration (50 and 100 mg/kg b.wt. orally twice) at 5 h and 12 h from initiation of MCAO showed a significant reduction in infarct volume and mitochondrial injury (p<0.001). Zingerone treatment significantly improved behavioral outputs (p<0.05) and histological architecture (p<0.001) by reducing lipid peroxidation (p<0.01), augmenting the reduced glutathione content (p<0.01) and restoring Na(+)-K(+) ATPase and superoxide dismutase activities (p<0.01) in MCAO brain. Zingerone successfully reduced the caspase-3 and -9 activities in MCAO group (p<0.05) and succeeded in lowering the expressions of pro-apoptotic proteins - Apaf-1 and Bax (p<0.001). The present study suggests that zingerone is a potent antioxidant that salvaged the ischemic penumbral zone neurons by inhibiting iPCD and oxidative stress.