Evaluation of mutagenesis, necrosis and apoptosis induced by omeprazole in stomach cells of patients with gastritis.

BACKGROUND: Gastritis is a superficial and prevalent inflammatory lesion that is considered a public health concern once can cause gastric ulcers and gastric cancer, especially when associated with Helicobacter pylori infection. Proton pump inhibitors, such as omeprazole, are the most widely used drugs to treat this illness. The aim of the study was evaluate cytogenetic effects of omeprazole in stomach epithelial cells of patients with gastritis in presence and absence of H. pylori, through cytogenetic biomarkers and catalse and superoxide dismutase analysis. METHODS: The study included 152 patients from the Gastroenterology Outpatient Clinic of Hospital Getúlio Vargas, Teresina-Brazil, that reported continuous and prolonged omeprazole use in doses of 20, 30 and 40 mg/kg. The participants were divided into groups: (1) patients without gastritis (n = 32); (2) patients without gastritis but with OME use (n = 24); (3) patients with gastritis (n = 26); (4) patients with gastritis undergoing OME therapy (n = 26); (5) patients with gastritis and H. pylori (n = 22) and (6) patients with gastritis and H. pylori on OME therapy (n = 22). RESULTS: OME induced cytogenetic imbalance in the stomach epithelium through the formation of micronuclei (group 6 > 1, 2, 3, 4, 5; group 5 > 1, 2, 3; group 4 > 1, 2, 3); bridges (groups 4 and 6 > 1, 2, 3, 5 and group 2 > 3, 5); buds (groups 2,4,6 > , 1, 3, 5); binucleated cells (group 6 > 1, 2, 3, 4, 5; group 4 > 1, 2, 3); (groups 2 and 3 > 1); picnoses (group 6 > 1, 2, 3, 4, 5), groups 2 and 5 > 1, 3; group 4 > 1, 2, 3, 5); cariorrexis (groups 6 and 4 > 1, 2, 3, 5; groups 2, 3, 5 > 1) and karyolysis (groups 2, 4, and 6 > 1, 3, 5; groups 3 and 5 > 1). The OME cytogenetic instability was associated with H. pylori infection, indicating clastogenic/aneugenic effects, chromosomes alterations, gene expression changes, cytotoxicity and apoptosis. CONCLUSIONS: The cytogenetic changescan be attributed to several mechanisms that are still unclear, including oxidative damage, as observed by increased catalase and superoxide dismutase expresion. Positive correlations between antioxidant enzymes were found with micronuclei formation, and were negative for picnoses. Thus, the continuous and prolonged omeprazole use induces genetic instability, which can be monitored through cytogenetic analyzes, as precursor for gastric cancer.

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.

Buccal micronucleus cytome assay: Inter-laboratory scoring exercise and micronucleus and nuclear abnormalities frequencies in different populations from Brazil.

The Buccal Micronucleus Cytome Assay (BMCyt) has become an important biomonitoring tool for assessing cytogenetic damage in many studied populations. Each laboratory applies protocols that vary according to the method of collecting and preparing samples. Besides, Brazil is a country of great territorial extensions that received immigrants from various parts of the world with different genetic backgrounds. Therefore, the present study aimed to evaluate the inter-laboratory variation in scoring the same set of slides using the more comprehensive scoring criteria, to standardize the BMCyt protocol, to observe the basal alterations in populations of different Brazilian regions and to compare it with other places around the world. Our results showed that a valuable number of laboratories participated, ten laboratories from different regions of the country, for the validation of the BMCyt in human biomonitoring studies, resulting in the 804 healthy individuals. This was possible because we observed: a range of measures needs to be considered, such as the baseline frequency of DNA damage and cell death in non-exposed individuals; age when grouped showed an influence on DNA damage, although when evaluated by group we did not see an influence; association between smoking habit and all endpoints of the BMCyt (except karyolytic cells) was evident; the basal MN frequency, in the majority of groups, follows those around the world; and the BMCyt was confirmed as a good health status biomarker. We emphasize the need for constant discussions on the parameters of cell death due to greater difficulty among the analyzers.

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.

Antidepressant-like effect of anacardic acid in mice via the L-arginine-nitric oxide-serotonergic system.

Depression, a multifactorial neuronal disorder with high morbidity/mortality, is associated with psychological, psychosocial, hereditary, and environmental etiologies, where reactive species exert pathophysiological functions. Anacardic acid (AA), a natural compound obtained from cashew nut liquid, has several pharmacological activities, including antioxidant and anticonvulsant. The aim of the present study was to evaluate the antidepressant-like effect of AA and the involvement of serotonergic, noradrenergic, and L-arginine-nitric oxide (NO) in tail suspension and forced swim tests and, more so, to investigate its antioxidant effect in Saccharomyces cerevisiae and in male Swiss mice (n = 8). In order to identify the antidepressant mechanisms, AA (10, 25, or 50 mg/kg, p.o.) was given 30 min before clonidine (2-adrenergic receptor agonist), L-arginine (NO precursor), propranolol (ß-adrenergic receptor antagonist), and several other agonists or antagonists used. On the other hand, clonidine, noradrenoreceptor, noradrenaline, and L-arginine were used to identify the antidepressant mechanisms. Results suggest that AA exerts antidepressant-like activity, especially at higher doses, possibly by inhibiting serotonin and 5HT-1A reuptake receptors and by inhibiting NO synthetase and guanylyl cyclase enzymes. Additionally, AA exhibited antioxidant effect in S. cerevisiae. This antioxidant capacity may be linked to its antidepressant-like effect but does not interact with α- and ß-adrenoceptor receptors. In conclusion, AA may be used as a promising agent to treat depression, especially which arises from oxidative stress.

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.

Effect of Diets, Familial History, and Alternative Therapies on Genomic Instability of Breast Cancer Patients.

This study evaluates a correlation between family history, micronutrients intake, and alternative therapies with genetic instability, before and during breast cancer treatment. For this study, a total of 150 women were selected. Among those, 50 women were breast cancer patients on chemotherapy, while 50 breast cancer patients were on radiotherapy, and 50 were healthy females. All the participants signed the informed consent form and answered the public health questionnaire. Samples of buccal epithelial and peripheral blood cells were collected and analyzed through micronucleus and comet assays. The cells were evaluated for apoptosis and DNA damage. Results showed the association of patients' family history with an increase in toxicogenetic damage before and during cancer therapy. On the other hand, patients with late-onset cancer also presented genetic instability before and during therapy, along with those who did not take sufficient vegetables and alternative therapies. A positive correlation was observed between the genetic instability and alternative therapies, while inverse correlation was recorded with the vegetable consumption. Results clearly explain that the nutritional aspects and alternative therapies influence the genetic instability before and during cancer therapies especially in radiotherapy treated patients. Our data could be used for the monitoring therapies and management of breast cancer patients.

Persistent Increased Frequency of Genomic Instability in Women Diagnosed with Breast Cancer: Before, during, and after Treatments.

This study aimed to evaluate DNA damage in patients with breast cancer before treatment (background) and after chemotherapy (QT) and radiotherapy (RT) treatment using the Comet assay in peripheral blood and the micronucleus test in buccal cells. We also evaluated repair of DNA damage after the end of RT, as well as the response of patient's cells before treatment with an oxidizing agent (H2O2; challenge assay). Fifty women with a mammographic diagnosis negative for cancer (control group) and 100 women with a diagnosis of breast cancer (followed up during the treatment) were involved in this study. The significant DNA damage was observed by increasing in the index and frequency of damage along with the increasing of the frequency of micronuclei in peripheral blood and cells of the buccal mucosa, respectively. Despite the variability of the responses of breast cancer patients, the individuals presented lesions on the DNA, detected by the Comet assay and micronucleus Test, from the diagnosis until the end of the oncological treatment and were more susceptible to oxidative stress. We can conclude that the damages were due to clastogenic and/or aneugenic effects related to the neoplasia itself and that they increased, especially after RT.

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.

Anxiolytic effect of anacardic acids from cashew (Anacardium occidentale) nut shell in mice.

Antianxiety drugs currently in use are associated with a number of serious side effects. Present study was designed to evaluate the efficacy of anacardic acids (AAs) isolated from cashew nut (Anacardium occidentale L.) shell liquid (CNSL) to treat anxiety as well as its role in oxidative stress in mice model. Anxiolytic effect of AA was evaluated using rota-rod and a set of behavioral tests in male Swiss albino mice at the doses of 10, 25, and 50 mg/kg. Flumazenil was used to evaluate the possible involvement of GABAergic system in the mechanism of action of AA. The effect of AA on oxidative stress in mice was evaluated by determining the concentration of malondialdehyde (MDA), reduced glutathione, and catalase (CAT) activity. The detection of DNA damage of the treated animals was performed using alkaline comet test in the hippocampus and frontal cortex of the animals. The results demonstrated that AA did not produce myorelaxant and sedative effects, nor did it cause a decrease in locomotor activity. The anxiolytic effect of AA was well-evident in all tests, especially at higher dose levels (25 and 50 mg/mg). Flumazenil reversed the anxiolytic effect of AA at all doses. In addition, AA reduced oxidative stress by decreasing the concentration of MDA and increasing the levels of reduced glutathione (GSH) and CAT activity. Statistical analysis by Pearson's correlation indicated a positive correlation between anxiolytic effect of AA to its antioxidant and lipid peroxidation inhibitory activity. Furthermore, increased CAT activity and GSH concentrations in the hippocampus and frontal cortex of mice was also complementary to the reduced genotoxic damage observed in the study. In comet assay, AA did not increase in DNA damage. In conclusion, the results supported that AA possesses GABAA receptor mediated anxiolytic activity with the lack of myorelaxation and genotoxicity. © 2018 IUBMB Life, 70(5):420-431, 2018.

A comprehensive review on biological properties of citrinin.

Citrinin (CIT) is a mycotoxin which causes contamination in the food and is associated with different toxic effects. A web search on CIT has been conducted covering the timespan since 1946. The accumulated data indicate that CIT is produced by several fungal strains belonging to Penicillium, Aspergillus and Monascus genera, and is usually found together with another nephrotoxic mycotoxin, ochratoxin A. Although, it is evident that CIT exposure can exert toxic effects on the heart, liver, kidney, as well as reproductive system, the mechanism of CIT-induced toxicity remains largely elusive. It is still controversial what are the genotoxic and mutagenic effects of CIT. Until now, its toxic effect has been linked to the CIT-mediated oxidative stress and mitochondrial dysfunction in biological systems. However, the toxicity strongly depends on its concentration, route, frequency and time of exposure, as well as from the used test systems. Besides the toxic effects, CIT is also reported to possess a broad spectrum of bioactivities, including antibacterial, antifungal, and potential anticancer and neuro-protective effects in vitro. This systematic review presents the current state of CIT research with emphasis on its bioactivity profile.

Occupational and life-style factors-acquired mutagenicity in agric-workers of northeastern Brazil.

Pesticides are a complex mixture of chemicals used to protect crops from a number of pests and diseases. They have been considered as potential mutagenic agents. This study aims at evaluation of the mutagenic effect of pesticide exposure to agricultural workers through chromosomal aberrations (CA) and micronucleus (MN) assay in peripheral blood lymphocytes and oral mucosal cells, respectively. The exposed group was consisted with 97 farmers, while the control (un-exposed) group consisted of 55. The results showed a significant (p < 0.05) increase in frequency of CA and MN in the exposed group. Both CA and MN profiles were linked to a significant (p < 0.05) co-relation with the confounding factors such as smoking habits, alcohol, vegetables, tea/coffee, vitamins, and sweetener consumptions. More cytogenetic events were denoted in smoking and alcohol consumption as well as non-personal protective equipment (non-PPE) and low/no vegetables user farmers. In conclusion, a deficiency of dietary and medicaments-derived antioxidants, while consumption of alcohol and tobacco, as well as effects of radiation, heavy metal poisoning (especially from sweeteners), and non-PPE using habits, may contribute cytogenetic damage to the workers.

Physico-chemical and genotoxicity analysis of Guaribas river water in the Northeast Brazil.

River pollution in Brazil is significant. This study aimed to evaluate the physico-chemical and genotoxic profiles of the Guaribas river water, located in Northeast Brazil (State of Piauí, Brazil). The study conducted during the dry and wet seasons to understand the frequency of pollution throughout the year. Genotoxicity analysis was done with the blood of Oreochromis niloticus by using the comet assay. Water samples were collected from upstream, within and downstream the city Picos. The results suggest a significant (p < 0.05) genotoxic effect of the Guaribas river water when compared to the control group. In comparison to the control group, in the river water we found a significant increase in metals such as - Fe, Zn, Cr, Cu and Al. In conclusion, Guaribas river carries polluted water, especially a large quantity of toxic metals, which may impart the genotoxic effect.

Cytogenotoxicological defense of retinyl palmitate in the front damage of antineoplastics.

Cancer, the multifactorial pathology and to date is the most lethal causes of death in the world. Cyclophosphamide (CPA) and doxorubicin (DOX) are the individually or combindly used two anticancer drugs. The antineoplastic drugs-mediated genetic instability can be overcome by using antioxidants. The study evaluated the cytogenotoxic modulatory potentials of retinyl palmitate (RP) caused by CPA and DOX in Swiss mice. For this, adult Mus musculus of either sex were divided equally regarding to the gender. Toxicogenetic effects were induced by the intraperitoneal (i.p.) administration of the CPA (20mg/kg) and/or DOX (2mg/kg), following to test for comet assay and micronucleus test in bone marrow cells after 48h (DOX) and 7h (CPA) of the administration of RP (100 IU/kg). Both CPA and DOX significantly (p<0.05) increased with the index and frequency of damages, clastogenic and/or aneugenic effects with the augmenting of micronuclei, demonstrating the cytotoxicity interference on the ratio of normochromatic to polychromatic erythrocytes and bone marrow cells of mice, that were found to reduce in RP treatment groups. In conclusion, RP has a modulatory effect on CPA and DOX-mediated cytogenotoxic events. The findings may be a good indication to manage the antioneoplastic drug-induced stress mediated detrimental effects by using RP, especially as a side effect minimizer.

Correlations between Risk Factors for Breast Cancer and Genetic Instability in Cancer Patients-A Clinical Perspective Study.

Molecular epidemiological studies have identified several risk factors linking to the genes and external factors in the pathogenesis of breast cancer. In this sense, genetic instability caused by DNA damage and DNA repair inefficiencies are important molecular events for the diagnosis and prognosis of therapies. Therefore, the objective of this study was to analyze correlation between sociocultural, occupational, and lifestyle risk factors with levels of genetic instability in non-neoplastic cells of breast cancer patients. Total 150 individuals were included in the study that included 50 breast cancer patients submitted to chemotherapy (QT), 50 breast cancer patients submitted to radiotherapy (RT), and 50 healthy women without any cancer. Cytogenetic biomarkers for apoptosis and DNA damage were evaluated in samples of buccal epithelial and peripheral blood cells through micronuclei and comet assay tests. Elder age patients (61-80 years) had higher levels of apoptosis (catriolysis by karyolysis) and DNA damage at the diagnosis (baseline damage) with increased cell damage during QT and especially during RT. We also reported the increased frequencies of cytogenetic biomarkers in patients who were exposed to ionizing radiation as well as for alcoholism and smoking. QT and RT induced high levels of fragmentation (karyorrhexis) and nuclear dissolution (karyolysis) and DNA damage. Correlations were observed between age and karyorrhexis at diagnosis; smoking and karyolysis during RT; and radiation and karyolysis during QT. These correlations indicate that risk factors may also influence the genetic instability in non-neoplastic cells caused to the patients during cancer therapies.

Therapeutic Potential of Essential Oils Focusing on Diterpenes.

Among all plant derivates, essential oils (EOs) have gained the attention of many scientists. Diterpenes, a family of components present in some EO, are becoming a milestone in the EOs world. The goal of this review is to describe a scenario of diterpenes taking into health-consumption deportment. Previous studies revealed that diterpenes have antioxidant, antimicrobial, antiviral, antiprotozoal, cytotoxic, anticancer, antigenotoxic, antimutagenic, chemopreventive, antiinflammatory, antinociceptive, immunostimulatory, organoprotective, antidiabetic, lipid-lowering, antiallergic, antiplatelet, antithrombotic, and antitoxin activities. In conclusion, diterpenes may be an immense featuring concern in pharmaceutical consumption from a drug discovery point of view. Copyright © 2016 John Wiley & Sons, Ltd.

Diterpenes: Advances in Neurobiological Drug Research.

A significant number of studies have been performed with diterpene effect on the brain. Our study aims to make a systematic revision on them. The initial purpose of this review was to screen diterpenes with neurological activity, in particular those that have already been studied and published in different journals (databases until August 2015). The second purpose was to make an action-wise discussion as results viewed on them by taking into drug discovery and development account. Diterpenes considered in this review were selected on the basis of updated information on them and having sufficient information on their screenings. We identified several examples of diterpenes having an interest in further study. We have included the possible sources of them as observed in evidence, their known molecular neurobiological mechanisms, and the active constituents responsible for such activities with the doses and test systems. Results suggest diterpenes to have neurobiological activities like neuro-protection, anti-epileptic, anxiolytic, anti-Alzheimer's disease, anti-Parkinson's disease, anti-cerebral ischemia, anti-neuropathic pain, anti-neuro-inflammatory, and many more. In conclusion, diterpenes may be the prominent candidates in neurobiological drug research. Copyright © 2016 John Wiley & Sons, Ltd.