Toxicogenetic profile of the monoterpene alpha-terpineol on normal and tumor eukaryotic cells.

Alpha-terpineol is a monoterpene alcohol found in essential oils from medicinal plants with some well-known pharmacological activities and widely used in cosmetics. However, the toxicological effects and additional pharmacological activities need to be clarified. Thus, the study evaluated the toxic, cytotoxic, genotoxic, hemolytic, and oxidative potential of alpha-terpineol in non-clinical bioassays. Different concentrations of alpha-terpineol were used in bioassays, including MTT (50, 100, 200, and 400 µg/mL), Artemia salina (6.25-400 µg/mL), Allium cepa (10, 50, and 100 µg/mL), comet assay (100, 200, and 500 µg/mL), cytokinesis-block micronucleus (100, 250, and 500 µg/mL), confocal microscopy for apoptosis quantification (100 and 500 µg/mL), hemolysis and Saccharomyces cerevisiae central disk test (10, 35, and 75 µg/mL). For the MTT test, alpha-terpineol was more cytotoxic on melanoma murine B16-F10 cells rather than macrophages. For A. salina test, alpha-terpineol showed LC50 of 68.29 and 76.36 µg/mL for 24 h and 48 h of exposure time, respectively. Meanwhile, alpha-terpineol was also cytotoxic to meristematic cells, which revealed inhibition of cellular division and mutagenic action by formation of bridges and delayed anaphases. The compound increased damage index and frequency of damage corroborated by the presence of micronuclei, bridges and nuclear buds at 500 µg/mL, but it caused neither hemolysis, oxidative damage on the S. cerevisiae nor cell death in normal fibroblasts. The findings indicate alpha-terpineol has cytotoxic potential by cytogenetic and molecular mechanisms associated with apoptosis and probable target effects against melanoma cells.

Activities and Molecular Mechanisms of Diterpenes, Diterpenoids, and Their Derivatives in Rheumatoid Arthritis.

Diterpenes and their derivatives have many biological activities, including anti-inflammatory and immunomodulatory effects. To date, several diterpenes, diterpenoids, and their laboratory-derived products have been demonstrated for antiarthritic activities. This study summarizes the literature about diterpenes and their derivatives acting against rheumatoid arthritis (RA) depending on the database reports until 31 August 2021. For this, we have conducted an extensive search in databases such as PubMed, Science Direct, Google Scholar, and Clinicaltrials.gov using specific relevant keywords. The search yielded 2708 published records, among which 48 have been included in this study. The findings offer several potential diterpenes and their derivatives as anti-RA in various test models. Among the diterpenes and their derivatives, andrographolide, triptolide, and tanshinone IIA have been found to exhibit anti-RA activity through diverse pathways. In addition, some important derivatives of triptolide and tanshinone IIA have also been shown to have anti-RA effects. Overall, findings suggest that these substances could reduce arthritis score, downregulate oxidative, proinflammatory, and inflammatory biomarkers, modulate various arthritis pathways, and improve joint destruction and clinical arthritic conditions, signs, symptoms, and physical functions in humans and numerous experimental animals, mainly through cytokine and chemokine as well as several physiological protein interaction pathways. Taken all together, diterpenes, diterpenoids, and their derivatives may be promising tools for RA management.

Cytogenotoxic evaluation of the acetonitrile extract, citrinin and dicitrinin-A from Penicillium citrinum.

Endophytic fungi are promising sources of bioactive substances; however, their secondary metabolites are toxic to plants, animals, and humans. This study aimed toevaluate the toxic, cytotoxic, mutagenic and oxidant/antioxidant activities of acetonitrile extract (AEPc), citrinin (CIT) and dicitrinin-A (DIC-A) of Penicillium citrinum. For this, the test substances at 0.5; 1.0; 1.5 and 2 µg/mLwere exposed for 24 and 48 h in Artemia salina, and 48 h in Allium cepa test systems. The oxidant/antioxidant test was evaluated in pre-, co- and post-treatment with the stressor hydrogen peroxide (H2O2) in Saccharomyces cerevisiae. The results suggest that the AEPc, CIT and DIC-A at 0.5; 1.0; 1.5 and 2 µg/mL showed toxicity in A. saline, with LC50 (24 h) of 2.03 µg/mL, 1.71 µg/mL and 2.29 µg/mL, and LC50 (48 h) of 0.51 µg/mL, 0.54 µg/mL and 0.54 µg/mL, respectively.In A. cepa, the test substances also exerted cytotoxic and mutagenic effects. The AEPc, CIT and DIC-A at lower concentrations modulated the damage induced by H2O2 in the proficient and mutant strains of S. cerevisiae for cytoplasmic and mitochondrial superoxide dismutase. Moreover, the AEPc at 2 µg/mL and CIT at the two highest concentrations did not affect the H2O2-induced DNA damage in the test strains. In conclusion, AEPc, CIT and DIC-A of P. citrinum may exert their toxic, cytotoxic and mutagenic effects in the test systems possibly through oxidative stress induction pathway.

Antioxidative defense against omeprazole-induced toxicogenetical effects in Swiss mice.

BACKGROUND: Omeprazole (OME), a most frequently used proton pump inhibitor in gastric acidosis, is evident to show many adverse effects, including genetic instability. This study evaluated toxicogenic effects of OME in Mus musculus. METHODS: For this study, 40 male Swiss mice were divided into 8 groups (n = 5) and treated with OME at doses of 10, 20, and 40 mg/kg and/or treated with the antioxidants retinol palmitate (100 IU/kg) and ascorbic acid (2.0 µM/kg). Cyclophosphamide 50 mg/kg, (cytotoxic agent) and the vehicle were served as positive and negative control group, respectively. After 14 days of treatment, the stomach cells along with the bone marrow and peripheral blood lymphocytes were collected and submitted to the comet assay (alkaline version) and micronucleus test. Additionally, hematological and biochemical parameters of the animals were also determined inspect of vehicle group. RESULTS: The results suggest that OME at all doses induced genotoxicity and mutagenicity in the treated cells. However, in association with the antioxidants, these effects were modulated and/or inhibited along with a DNA repair capacity. CONCLUSIONS: Taken together, antioxidants (such as retinol palmitate and ascorbic acid) may be one of the best options to counteract OME-induced cytogenetic instability.

Citrinin against breast cancer: A cytogenotoxicological study.

Breast cancer is one of the most lethal types of cancer and a leading cause of mortality among Women worldwide. Citrinin (CIT), a polyketide extracted from the fungus Penicillium citrinum, exhibits a wide range of biological activities such as antibacterial, antifungal, and cytotoxic effects. The aim of the current study was to evaluate the antitumoral effects of CIT against 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinoma in Swiss mice For this, CIT, DMBA and the standard cyclophosphamide (CPA) induced behavioral changes in experimental animals, and these changes were screened by using the rota rod and open field tests. Additionally, hematological, biochemical, immuno-histochemical, and histopathological analyses were carried out. Results suggest that CIT did not alter behavioral, hematological, and biochemical parameters in mice. DMBA induced invasive mammary carcinoma and showed genotoxic effects in the breasts, bone marrow, lymphocytes, and hepatic cells. It also caused mutagenic effects in the formation of micronuclei, bridges, shoots, and binucleate cells in bone marrow and liver. CIT and CPA genotoxic effects were observed after 3 weeks of therapy, where CIT exhibited a repair capacity and induced significant apoptotic damage in mouse lymphocytes. In conclusion, CIT showed antitumoral effects in Swiss mice, possibly through induction of apoptosis.

Retinol palmitate against toxicogenic damages of antineoplastic drugs on normal and tumor cells.

The lack of tissue selectivity of anticancer drugs generates intense collateral and adverse effects of cancer patients, making the incorporation of vitamins or micronutrients into the diet of individuals to reduce side or adverse effects of antineoplastics. The study aimed to evaluate the effects of retinol palmitate (RP) on the toxicogenic damages induced by cyclophosphamide (CPA), doxorubicin (DOX) and its association with the AC protocol (CPA + DOX), in Sarcoma 180 (S-180) tumor cell line, using the micronuclei test with a block of cytokinesis (CBMN); and in non-tumor cells derived from Mus musculus using the comet assay. The results suggest that CPA, DOX and AC protocol induced significant toxicogenic damages (P < 0.05) on the S-180 cells by induction of micronuclei, cytoplasmic bridges, nuclear buds, apoptosis, and cell necrosis, proving their antitumor effects, and significant damage (P < 0.001) to the genetic material of peripheral blood cells of healthy mice, proving the genotoxic potential of these drugs. However, RP modulated the toxicogenic effects of antineoplastic tested both in the CBMN test (P < 0.05), at the concentrations of 1, 10 and 100 IU/mL; as in the comet assay (P < 0.001) at the concentration of 100 IU/kg for the index and frequency of genotoxic damage. The accumulated results suggest that RP reduced the action of antineoplastics in non-tumor cells as well as the cytotoxic, mutagenic, and cell death in neoplastic cells.

Anti-Inflammatory, Antinociceptive, and Antioxidant Properties of Anacardic Acid in Experimental Models.

Anacardic acid (AA), a compound extracted from cashew nut liquid, exhibits numerous pharmacological activities. The aim of the current investigation was to assess the anti-inflammatory, antinociceptive, and antioxidant activities of AA in mouse models. For this, Swiss albino mice were pretreated with AA (10, 25, 50 mg/kg, intraperitoneally, ip) 30 min prior to the administration of carrageenan, as well as 25 mg/kg of prostaglandin E2, dextran, histamine, and compound 48/80. The antinociceptive activity was evaluated by formalin, abdominal, and hot plate tests, using antagonist of opioid receptors (naloxene, 3 mg/kg, ip) to identify antinociceptive mechanisms. Results from this study revealed that AA at 25 mg/kg inhibits carrageenan-induced edema. In addition, AA at 25 mg/kg reduced edema and leukocyte and neutrophilic migration to the intraperitoneal cavity, diminished myeloperoxidase activity and malondialdehyde concentration, and increased the levels of reduced glutathione. In nociceptive tests, it also decreased licking, abdominal writhing, and latency to thermal stimulation, possibly via interaction with opioid receptors. Taken together, these results indicate that AA exhibits anti-inflammatory and antinociceptive actions and also reduces oxidative stress in acute experimental models, suggesting AA as a promising compound in the pharmaceutical arena.

Palmatine antioxidant and anti-acetylcholinesterase activities: A pre-clinical assessment.

There is evidence that palmatine (PA), an alkaloid isolated from the Guatteria friesiana plant, has some important biological activities, including anti-inflammatory and antidepressant effects. In this study, the antioxidant and anti-acetylcholinesterase (AChE) effects of PA were assessed. The antioxidant capacity was evaluated in vitro and in vivo through 7 distinct assays, and the anti-AChE activity was determined in vitro. The standards, trolox and ascorbic acid were used for the in vitro antioxidant test, while hydrogen peroxide was selected as a stressor for the Saccharomyces cerevisiae test. Additionally, PA was also combined with trolox and ascorbic acid to determine the likelihood of synergistic effects occurrence to what concerns to antioxidant potential. PA exhibited a potent and concentration-dependent antioxidant potential, although a stronger antioxidant activity was stated using the PA + trolox combination. PA was also found to inhibit AChE activity when compared to the negative control. Thus, PA may be viewed as a promissory phytotherapeutic agent to manage oxidative stress-mediated neurological diseases, especially the Alzheimer's and Parkinson's diseases.

Antitumor effects of citrinin in an animal model of Sarcoma 180 via cytogenetic mechanisms.

Citrinin (CIT) is a cytotoxic, hepatotoxic, nephrotoxic and cardiotoxic metabolite obtained from Penicillium citrinum, that has been increasingly searched as an anticancer drug candidate. In this study, we assessed the antitumor effects of citrinin, using cytogenetic biomarkers for genotoxicity in Sarcoma 180 (S-180) ascitic fluid cells of mice. Citrinin, extracted from P. citrinum acetonitrile extract, was characterized by LC-MS. Cytotoxic assessment was done through using comet (alkaline version) and micronucleus assays. In S-180 cells, CI50 of CIT was 3.77 µg/mL, while at 12.5 and 100 µg/mL, CIT was as cytotoxic as doxorubicin (2 µg/mL). At 0.5, 1.0 and 2.0 µg/mL, it induced genotoxicity and mutagenicity in S-180 cells, especially at 2 µg/mL, triggering oxidative damage similar to hydrogen peroxide (10 mM). The antitumor effects were evidenced by a marked increase in S-180 cells apoptosis and necrosis due to clastogenic and/or aneugenic cytogenetic effects (micronucleus formation), as well as by induction of nucleoplasm bridges and nuclear buds, culminating in S-180 apoptosis and necrosis. CIT has potential as drug candidate for antitumor purposesbyinvolving cytogenetic mechanisms.

Pharmacological Effects and Toxicogenetic Impacts of Omeprazole: Genomic Instability and Cancer.

Omeprazole (OME) is commonly used to treat gastrointestinal disorders. However, long-term use of OME can increase the risk of gastric cancer. We aimed to characterize the pharmacological effects of OME and to correlate its adverse effects and toxicogenetic risks to the genomic instability mechanisms and cancer-based on database reports. Thus, a search (till Aug 2019) was made in the PubMed, Scopus, and ScienceDirect with relevant keywords. Based on the study objective, we included 80 clinical reports, forty-six in vitro, and 76 in vivo studies. While controversial, the findings suggest that long-term use of OME (5 to 40 mg/kg) can induce genomic instability. On the other hand, OME-mediated protective effects are well reported and related to proton pump blockade and anti-inflammatory activity through an increase in gastric flow, anti-inflammatory markers (COX-2 and interleukins) and antiapoptotic markers (caspases and BCL-2), glycoprotein expression, and neutrophil infiltration reduction. The reported adverse and toxic effects, especially in clinical studies, were atrophic gastritis, cobalamin deficiencies, homeostasis disorders, polyp development, hepatotoxicity, cytotoxicity, and genotoxicity. This study highlights that OME may induce genomic instability and increase the risk of certain types of cancer. Therefore, adequate precautions should be taken, especially in its long-term therapeutic strategies and self-medication practices.

Ascorbic acid and retinol palmitate modulatory effect on omeprazole-induced oxidative damage, and the cytogenetic changes in S. cerevisiae and S180 cells.

Omeprazole (OM), a prototype proton pump inhibitor, oxidizes thiol groups and induces DNA damage. The aim of this study was to evaluate the oxidative effects of omeprazole and its interactions with ascorbic acid (AA, 50 µM) and retinol palmitate (RP) in proficient and deficient Saccharomyces cerevisiae strains, as well as levels of cytogenetic damage in Sarcoma 180 (S180) cells. Omeprazole was tested at concentrations of 10, 20 and 40 µg/mL, whereas H2O2 (10 mM), cyclophosphamide (20 mg/mL), and saline (0.9% NaCl solution) were employed as stressor, positive control, and negative control, respectively. Results revealed that omeprazole concentration-dependently induces oxidative effects in S. cerevisiae strains. However, omeprazole co-treated with ascorbic acid (50 µM) and retinol palmitate (100 IU) significantly modulated the oxidative damage inflected on the S. cerevisiae strains. Furthermore, omeprazole did not produce micronucleus formation and chromosomal bridges in S180 cells, but induced shoots. Significant increase in karyolysis and karyorrhexis were also observed with the omeprazole treated groups, which was modulated by co-treatment with ascorbic acid and retinol palmitate. Taken all together, it is suggested that ascorbic acid and retinol palmitate can substantially modulate the oxidative damage caused by omeprazole on the S. cerevisiae strains, however, much precaution is recommended with omeprazole and antioxidant co-treatment.

Antioxidant, anti-inflammatory and cytotoxic/antitumoral bioactives from the phylum Basidiomycota and their possible mechanisms of action.

Biologically active compounds from species of the phylum Basidiomycota have been shown a wide range of pharmacological activities and provide a vast reservoir of potential innovational drugs. The aim of this review is to discuss some mechanisms of action involved in antioxidant, anti-inflammatory and cytotoxic/antitumoral activities attributed to the bioactive compounds from species of the phylum Basidiomycota. We show that isolated compounds from extracts, secondary metabolites and polysaccharides that presented antioxidant properties have mechanisms of action involved in the elimination/capture of free radicals and reduction of lipid peroxidation. Also, some bioactives with anti-inflammatory activity were reported to enhance innate and cell-mediated immune responses. Finally, compounds that presented cytotoxic/antitumoral activity induces increased free radical production, collapse of the mitochondrial membrane potential and increased expression of proteins responsible for cell cycle arrest and apoptosis. Investigating the mechanisms of action of biologically active compounds will facilitate further efforts to accelerate the discovery of novel therapeutic strategies.

Phytol as an anticarcinogenic and antitumoral agent: An in vivo study in swiss mice with DMBA-Induced breast cancer.

Phytol (PHY) (3,7,11,15-tetramethylhexadec-2-en-1-ol) exhibits various pharmacological properties including toxicity and cytotoxicity, and exerts antitumor activity. Owing to the urgent need of new pharmaceutical formulations for breast cancer therapy, this study aimed at the evaluation of antitumor activity of PHY in 7,12-dimethylbenzanthracene-cancer-induced animal model. Comet assay was employed to evaluate the cytogenetics, DNA repair, and antigenotoxic activities of PHY in neoplastic (breast) and non-neoplastic rodent cells (bone marrow, lymphocytes, and liver). Additionally, hematological, biochemical, histopathological, and immunohistochemical analyses were carried out in experimental animals. Thirty nonpregnant female mice (n = 5) underwent 7 weeks treatment with 6 mg/kg pro-carcinogen, PHY (4 mg/kg), and cyclophosphamide (25 mg/kg). Induction of cancer was confirmed by histopathology and immunohistochemistry for Ki-67. Results suggest that PHY exhibits low toxicity in comparison with other groups in hematological, biochemical, histopathological, and organ size parameters. Additionally, PHY showed modulatory effects on the pro-carcinogen, and induced genotoxicity and apoptosis in breast cancer cells. Furthermore, it showed a DNA damage repair capacity in mouse lymphocytes. These data indicate that PHY may have the potential as an anticancer candidate in pharmaceutical consumption. © 2018 IUBMB Life, 71(1):200-212, 2019.

A systematic review on the neuroprotective perspectives of beta-caryophyllene.

Beta (ß)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect. This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords "beta (ß)-caryophyllene" and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action. A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer's disease. Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.

Mutagenic, antioxidant and wound healing properties of Aloe vera.

ETHNOPHARMACOLOGICAL RELEVANCE: Aloe vera is a widely used medicinal plant for its various biological activities. This study evaluate possible mutagenic and healing effects of the aqueous extract of A. vera (AEAV) in mice and its oxidant/antioxidant potential in different proficient and deficient Saccharomyces cerevisiae strains. MATERIAL AND METHODS: The AEAV was topically treated on the wounded skin surface of male albino mice at doses of 10 and 50 mg/kg for seven successive days. The control group was similarly treated with 0.9% NaCl solution. For oxidative/anti-oxidative evaluation, both proficient and deficient strains of S. cerevisiae [cytoplasmic and mitochondrial superoxide dismutase mutant (SOD: Sod1Δ and Sod2Δ), cytoplasmic catalase mutant (CAT: Cat1Δ)], two double defective mutants of Sod1 and Sod2 and Sod1 and Cat1 genes along with a wild-type strains were used. RESULTS: The healing property of AEAV was observed at the dose of 50 mg/kg but at the same dose it showed mutagenic and cytotoxic effects in peripheral blood. AEAV did not produce the oxidizing effect, except in the mutated CAT strain at highest concentration (50 mg/kg). CONCLUSION: The high concentration of AEAV showed mutagenicity and cytotoxicity. Beside, the healing capacity is believed to be due to its anti-oxidative defense mechanism.

Mycotoxin-assisted mitochondrial dysfunction and cytotoxicity: Unexploited tools against proliferative disorders.

Mitochondria are the powerhouse of cells, which upon dysfunctions may lead to several diseases. Mycotoxins are the toxic secondary metabolites from fungi which are capable of causing diseases and death in humans and animals. They have a versatile mechanism of action in biological systems and can be used as lead compounds to treat some diseases including cancer. The present work encompasses analysis on the effects of mycotoxins on mitochondrial dysfunction. Electronic databases such as PubMed, ScienceDirect, Scopus, Web of Science, and Google Scholar were thoroughly searched for up-to-date published information associated with those mycotoxins and their effect on mitochondrial dysfunction. Findings suggest that mycotoxins such as citrinin, aflatoxin, and T-2 toxin exert multi-edged sword-like effects in test systems causing mitochondrial dysfunction. Mycotoxins can induce oxidative stress even at low concentration/dose that may be one of the major causes of mitochondrial dysfunction. On the other hand, activation of apoptotic caspases and other proteins by mycotoxins may lead to apoptotic cell death. Thus, mycotoxins-mediated mitochondrial dysfunction may be related to several chronic diseases which also makes these mycotoxins considerable as lead compounds for inducing toxic effects in cells. Their cytotoxic effects on cancer cells suggest their possible application as chemotherapeutic tools. © 2018 IUBMB Life, 70(11):1084-1092, 2018.

Protective and therapeutic potential of ginger (Zingiber officinale) extract and [6]-gingerol in cancer: A comprehensive review.

Natural dietary agents have attracted considerable attention due to their role in promoting health and reducing the risk of diseases including cancer. Ginger, one of the most ancient known spices, contains bioactive compounds with several health benefits. [6]-Gingerol constitutes the most pharmacologically active among such compounds. The aim of the present work was to review the literature pertaining to the use of ginger extract and [6]-gingerol against tumorigenic and oxidative and inflammatory processes associated with cancer, along with the underlying mechanisms of action involved in signaling pathways. This will shed some light on the protective or therapeutic role of ginger derivatives in oxidative and inflammatory regulations during metabolic disturbance and on the antiproliferative and anticancer properties. Data collected from experimental (in vitro or in vivo) and clinical studies discussed in this review indicate that ginger extract and [6]-gingerol exert their action through important mediators and pathways of cell signaling, including Bax/Bcl2, p38/MAPK, Nrf2, p65/NF-κB, TNF-α, ERK1/2, SAPK/JNK, ROS/NF-κB/COX-2, caspases-3, -9, and p53. This suggests that ginger derivatives, in the form of an extract or isolated compounds, exhibit relevant antiproliferative, antitumor, invasive, and anti-inflammatory activities.

Toxicogenetic study of omeprazole and the modulatory effects of retinol palmitate and ascorbic acid on Allium cepa.

Omeprazole (OME) is a proton pump inhibitor used for the treatment of various gastric and intestinal disease; however, studies on its effects on the genetic materials are still restricted. The present study aimed to evaluate possible toxicogenic effects of OME in Allium cepa meristems with the application of cytogenetic biomarkers for DNA damage, mutagenic, toxic and cytotoxic effects. Additionally, retinol palmitate (RP) and ascorbic acid (AA) were also co-treated with OME to evaluate possible modulatory effects of OME-induced cytogenetic damages. OME was tested at 10, 20 and 40 µg/mL, while RP and AA at 55 µg/mL and 352.2 µg/mL, respectively. Copper sulphate (0.6 µg/mL) and dechlorinated water were used as positive control and negative control, respectively. The results suggest that OME induced genotoxicity and mutagenicity in A. cepa at all tested concentrations. It was noted that cotreatment of OME with the antioxidant vitamins RP and/or AA significantly (p < 0.05) inhibited and/or modulated all toxicogenic damages induced by OME. These observations demonstrate their antigenotoxic, antimutagenic, antitoxic and anticitotoxic effects in A. cepa. This study indicates that application of antioxidants may be useful tools to overcome OME-induced toxic effects.

Effects of isopentyl ferulate on oxidative stress biomarkers and a possible GABAergic anxiolytic-like trait in Swiss mice.

This study aimed to evaluate the anxiolytic-like effect and the possible neuronal mechanism of action of isopentyl ferulate (IF). For this purpose, we used the marble burying test in Swiss albino mice. The biomarkers involved in oxidative stress were measured in the hippocampus homogenate of the test animals. In addition, the toxicity and antioxidant capacities were tested in Artemia salina and rat erythrocytes, respectively. The results suggest that, an acute administration of the IF at doses of 25, 50, 75 and 150 mg/kg (intraperitoneal, i.p.) significantly (p < 0.05) reduced the marble burying behavior of the animals as compared to the vehicle group, which demonstrates a calming effect of this chemical. It was observed that, the pre-treatment with flumazenil (2.5 mg/kg, i.p.), an antagonist of the gamma-amino butyrinc acid (GABAA) receptor, significantly reversed the marble burying behavioral activity in the animals treated with the IF 150 mg/kg dose. Moreover, the reduction in nitrite content and lipid peroxidation levels, while an increased in the reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) activities were also observed their hippocampus. Although, IF (2.36-14.16 mM) did not show toxicity in A. salina but exhibited a prominent antioxidant capacity in hydrogen peroxide-induced oxidative damage in rat erythrocytes. In conclusion, IF exhibited an anxiety-like effect in mice along with a potent antioxidant capacity, and we suppose it may have neuroprotective effects possibly via GABAergic transmission pathway.