Differential Roles of the D1- and D2-Like Dopamine Receptors Within the Ventral Tegmental Area in Modulating the Antinociception Induced by Forced Swim Stress in the Rat.

Several preclinical and clinical studies indicate that exposure to acute stress may decrease pain perception and increases pain tolerance. This phenomenon is called stress-induced analgesia (SIA). A variety of neurotransmitters, including dopamine, is involved in the SIA. Dopaminergic neurons in the mesolimbic circuits, originating from the ventral tegmental area (VTA), play a crucial role in various motivational, rewarding, and pain events. The present study aimed to investigate the modulatory role of VTA dopaminergic receptors in the antinociceptive responses evoked by forced swim stress (FSS) in a model of acute pain. One hundred-five adult male albino Wistar rats were subjected to stereotaxic surgery for implanting a unilateral cannula into the VTA. After one week of recovery, separate groups of animals were given different doses of SCH23390 and Sulpiride (0.25, 1, and 4 µg/0.3 µl) as D1- and D2-like receptor antagonists into the VTA, respectively. Then, the animals were exposed to FSS for a 6-min period, and the pain threshold was measured using the tail-flick test over a 60-min time set intervals. Results indicated that exposure to FSS produces a prominent antinociceptive response, diminishing by blocking both dopamine receptors in the VTA. Nonetheless, the effect of a D1-like dopamine receptor antagonist on FSS-induced analgesia was more prominent than that of a D2-like dopamine receptor antagonist. The results demonstrated that VTA dopaminergic receptors contribute to the pain process in stressful situations, and it might be provided a practical approach to designing new therapeutic agents for pain management.

Development, implementation, and evaluation of the effectiveness of an intervention program to improve the sexual competence of young adult women about to get married: a protocol study.

BACKGROUND: Having competence in initiating sexual interactions is one of the challenges of sexual health in any society. Given that the social, cultural, and religious background of some societies can prevent the acquisition of sexual competence in young women, this study will be done to design, implement, and determine the effectiveness of an intervention program to improve the sexual competence of young women on the eve of marriage. METHODS: The current research is a mixed-method study in a qualitative-quantitative sequence. In the first phase, a qualitative study will be conducted to explore the needs of sexual competence in young adult women about to get married and ways to improve it. Then, after the literature review and combining it with the results of the qualitative study, a draft of the intervention program will be developed. After reviewing the content of the program and validating it in the panel of experts, the final program will be developed. In the second phase, the effect of the program to promote the sexual competence of adult women about to get married will be determined in a quantitative study with a two-group quasi-experimental method. DISCUSSION: Providing a comprehensive and practical intervention program to promote sexual competence based on cultural, social, and religious background can help to improve the quality of sexual interactions of young women about to get married, reduce harm caused by lack of sexual competence, and ensure women's sexual health.

Preparing young people to start safe and satisfactory sexual behaviors and as a result to acquire sexual competence can play an important role in ensuring their sexual health. But in some countries, talking about sexual issues is a cultural and religious taboo. Given that Lack of sexual competence is associated with negative consequences, the present study aims to design, implement, and determine the effectiveness of a program to promote sexual competence in young adult women who are about to get married. In the first phase, to identify the needs of acquiring sexual competence and to explore the strategies for improving sexual competence, a qualitative study will be conducted with a content analysis approach. Individual interviews will be conducted with women aged 18 to 25 about to get married, the teachers of pre-marriage classes, midwives, gynecologists, reproductive health specialists, psychiatrists, and psychologists who work in the field of sexual health. Based on the findings of this phase and after reviewing the literature, an intervention program to improve sexual competence in young adult women will be designed and prepared. After the experts approve the intervention program, in the second phase, a quantitative study will be conducted to determine the effect of the intervention program on improving the sexual competence of young adult women about to get married.

Compensatory Role of Insulin in the Extinction but Not Reinstatement of Morphine-Induced Conditioned Place Preference in the Streptozotocin-Induced Diabetic Rats.

Insulin receptors are distributed in the whole brain, including different parts of the reward circuit that modulate dopamine as the primary neurotransmitter implicated in addiction. The goal of the current study was to illuminate the role of insulin in the extinction period and reinstatement of morphine-induced conditioned place preference (CPP) in the naïve and diabetic rats. One hundred and twelve male rats were randomly divided into two naïve and diabetic groups. Diabetes was induced by one dose administration of streptozotocin (STZ; 60 mg/kg; IP) ten days before the conditioning procedure. To evaluate the insulin's role in the duration of extinction period of morphine-CPP, naïve and diabetic rats received insulin (10 U/kg; IP) before each morphine injection (5 mg/kg; sc) during the 3-day conditioning phase. All rats that passed the conditioning phase and then underwent the extinction period. Morphine priming-induced reinstatement was determined in both naïve and diabetic rats by injection of different ineffective doses of morphine (0.5 and 1 mg/kg; sc) in extinguished rats. In the following experiments, three groups of diabetic rats received insulin during the conditioning, expression, or reinstatement phase to illustrate insulin's effect on the morphine-induced reinstatement and the duration of the extinction period (insulin was only treated during the acquisition phase). The results showed that the extinction period and reinstatement of morphine were potentiated in the STZ-induced diabetic rats. The obtained findings also revealed that insulin replacement shortened the extinction period of morphine-induced CPP in STZ-diabetic rats. However, insulin replacements in conditioning, expression, and reinstatement phases did not affect morphine priming-induced reinstatement in diabetic animals.

The modulatory role of dopamine receptors within the hippocampal cornu ammonis area 1 in stress-induced analgesia in an animal model of persistent inflammatory pain.

The intrinsic pain inhibitory mechanisms can be activated by fear, anxiety, and stress. Stressful experiences produce analgesia, referred to as stress-induced analgesia (SIA). Major components of the limbic system, including the ventral tegmental area, nucleus accumbens, amygdala, and hippocampus, are involved in the SIA. In this study, we tried to understand the role of dopamine receptors in the cornu ammonis area 1 (CA1) of the hippocampus in the forced swim stress (FSS)-induced analgesia. Stereotaxic surgery was unilaterally performed on 129 adult male Wistar rats weighing 220-280 g. SCH23390 (0.25, 1, and 4 µg/0.5 µl saline) or sulpiride (0.25, 1, and 4 µg/0.5 µl DMSO), as D1- and D2-like dopamine receptor antagonists, respectively, were microinjected into the CA1 area, 5 min before exposure to FSS for a 6-min period. The vehicle groups received saline or DMSO instead of SCH23390 or sulpiride, respectively. The formalin test was done using formalin injection (50 µl; 2.5%) into the plantar surface of the rat's hind paw immediately after exposure to FSS. The results demonstrated that FSS produces analgesia during the early and late phases of the formalin test. However, intra-CA1 microinjection of SCH23390 or sulpiride attenuated the FSS-induced analgesia in both phases of the formalin test. This study provides new insight into the role of D1- and D2-like dopamine receptors in the CA1 area in the FSS-induced analgesia during persistent inflammatory pain.

Prediction of PTSD related to COVID-19 in emergency staff based on the components of self-compassion and perceived social support.

BACKGROUND: On March 11th, 2020, the World Health Organization (WHO) proclaimed Coronavirus Disease of 2019 (COVID-19) a pandemic. In addition to severe health problems, the disease has had a major psychological impact on the public. The aim of this research was to examine the association between Post-Traumatic Stress Disorder (PTSD) related to COVID-19 in emergency staff and self-compassion and perceived social support. METHODS: Data were collected from 222 emergency staff working in two referral educational and health centers for COVID-19 affiliated to Tabriz University of Medical Sciences. The participants were recruited six months following the first case of hospitalization for COVID-19 in these two hospitals in Tabriz, Iran. Four questionnaires were used to measure the variables, including a researcher-made demographic checklist, PTSD Checklist for DSM-5 (PCL-5), the Multidimensional Perceived Social Support Scale (MSPSS) and the Self-Compassion Scale. RESULTS: The findings showed that age (r = 0.17, P = 0.034), self-judgment (r = 0. 36, P < 0.001), isolation (r = 0.44, P < 0.001) and over-identification (r = 0.15, P = 0.031) were associated with PTSD score, and there was also a statistically significant inverse relationship between the score of the self-kindness (r = - 0.19, P = 0.006) subscale and the overall score of PTSD in the emergency staff. CONCLUSION: During the COVID-19 pandemic, emergency staff have persistently faced potentially traumatic situations as first-line healthcare workers, suggesting the direness of this group's mental health. By identifying the predisposing factors of the psychological pathology under study, this research can be applied in clinical practice and provide useful information for designing special interventions and protocols for emergency staff.

Environmental Surface Circulation of SARS-CoV-2 RNA in Asadabad Hospital Wards.

BACKGROUND: Since early 2020, Coronavirus 2019 (COVID-19) has posed a public health risk due to serious acute respiratory syndrome. The aim of our study was to determine surface circulation of SARS-CoV-2 RNA in Asadabad Hospital wards. METHODS: Fifty swab samples were obtained from the hospital wards. The real-time test was carried out using primer/probe sets that were complementary to targets on the SARS CoV genome. RESULTS: The injection room had the highest contamination rate, while the other hospital wards were free of CO¬VID-19 contamination. CONCLUSIONS: Overall, we found that COVID-19 contaminated narrowly the surfaces in hospital wards. These findings can be used to improve safety procedures.

The moderating role of gender in the association between quality of social relationships and sleep.

To determine whether the association between perceived social support or strain in close relationships and sleep outcomes varies by gender. Participants were selected from the Biomarker projects of either the MIDUS II or MIDUS Refresher study if they were in a married-or married-like relationship and shared a bed with their partner (N = 989). A subsample also participated in a seven-day sleep study (n = 282). Perceived social support and strain from partner, family, and friends were examined by self-report questionnaires. We used the Pittsburgh Sleep Quality Index, sleep daily diary, and actigraphy to measure both subjective and objective sleep. Social support and strain were both associated with sleep outcomes. Specifically, higher social support was associated with fewer daily reports of light sleep and feeling more rested in the morning, while higher social strain was associated with higher clinical sleep disturbance. For women, but not men, social support was significantly associated with lower daily sleep disturbance while perceived social strain was significantly associated with higher daily sleep disturbance, lighter sleep, feeling less rested in the morning, lower sleep efficiency, and longer sleep onset latency. Mainly among women, social support and strain are associated with an important transdiagnostic health outcome-sleep-which may have implications for a wide range of health disparities. Interpersonal stressors may increase health risks differently for women compared to men and one mechanism that may link social relationships to long-term health outcomes is sleep.

Involvement of Hippocampal D1-Like Dopamine Receptors in the Inhibitory Effect of Cannabidiol on Acquisition and Expression of Methamphetamine-Induced Conditioned Place Preference.

Cannabidiol (CBD) is a non-psychotomimetic compound with strong potential to decrease the psychostimulant's rewarding effect with unclear receptors. Furthermore, as a part of the reward circuit, the hippocampus plays a crucial role in regulating the reward properties of drugs as determined by conditioned place preference (CPP). In the current research, CPP was used to evaluate the role of intra-CA1 microinjection of D1-like dopamine receptor antagonists in CBD's inhibitory effect on the acquisition and expression phases of methamphetamine (METH). Animals were treated by METH (1 mg/kg; sc) in a five-day schedule to induce CPP. To find out the impact of D1-like dopamine receptor antagonist, SCH23390, in the CA1 on the inhibitory influence of CBD on the acquisition of METH, the rats received intra-CA1 administration of SCH23390 (0.25, 1, and 4 µg/0.5 µl) following ICV treatment of CBD (10 µg/5 µl) over conditioning phase of METH. Furthermore, animals were given SCH23390 in the CA1 ensuing ICV microinjection of CBD (50 µg/5 µl) in the expression phase of METH to rule out the influence of SCH23390 on the suppressive effect of CBD on the expression of METH CPP. Intra-CA1 microinjection of SCH23390 abolished CBD's suppressive impact on both METH-induced CPP phases without any side effect on the locomotion. The current research disclosed that CBD inhibited the rewarding characteristic of METH via D1-like dopamine receptors in the CA1 region of the hippocampus.

Apigenin ameliorates oxidative stress and mitochondrial damage induced by multiwall carbon nanotubes in rat kidney mitochondria.

The toxicity of carbon nanotubes (CNTs) toward the mitochondria of the kidney is not fully recognized and still needs further research. Apigenin (APG) is known as a flavonoid compound and natural antioxidant. The purpose of this study was to assess the ameliorative role of APG against multiwall CNT (MWCNT)-induced kidney toxicity in rats. The animals were administrated with APG (10 mg/kg) for 2 weeks and then were exposed to MWCNTs (5 mg/m3 ) in pure and impure forms (10 and 100 nm) for 5 h/day and 5 days/week. Then, mitochondria were isolated from the kidney tissue and mitochondrial toxicity parameters were measured. Decreases in succinate dehydrogenase activity have been reported in all groups exposed to MWCNTs. Results indicated that MWCNTs in both forms and sizes were able to increase the generation of reactive oxygen species, decline mitochondrial membrane potential, induce mitochondrial swelling, and release cytochrome c in isolated kidney mitochondria. The pretreatment of APG decreased all the abovementioned mitochondrial damage and oxidative stress parameters induced by both pure and impure MWCNTs. Our results showed that MWCNTs have the ability to enter the body, subsequently, cross cellular barriers, and reach the kidney as a sensitive organ, which can result in mitochondrial damage in kidney cells including renal tubular cells. In addition, APG can be an effective nutritional antioxidant regimen against MWCNT-induced kidney damage.

The orexin receptors in the ventral tegmental area are involved in the development of sensitization to expression of morphine-induced preference in rats.

Recent studies have shown that orexin neurons in the lateral hypothalamus send a compelling project to the ventral tegmental area (VTA). Besides, orexin-1 (OX1) and orexin-2 (OX2) in the VTA are necessary for the development of morphine-induced place preference. Also, sensitivity to morphine can reinforce the rewarding effects of morphine. The current study aims to determine the role of VTAs orexin receptors in morphine sensitization in rats. In 84 adult male albino Wistar rats, two separate cannulae bilaterally implanted into the VTA. They received intra-VTA infusions of SB334867 (0.1, 1 and 10 nM) and TCS OX2 29 (1, 7 and 20 nM) as OX1 and OX2 receptor antagonists, respectively, 10 min before subcutaneous administration of morphine (5 mg/kg) during 3-day sensitization period. After a 5-day drug-free period, the conditioned place preference (CPP) paradigm induced by subthreshold doses of morphine (0.5 mg/kg), and CPP scores were measured by EthoVision software. The results revealed that the blockade of both OX1 and OX2 receptors within the VTA reduced the expression of morphine-induced CPP in the sensitized rats. It is plausible that VTAs orexin receptors are involved in the development/acquisition of sensitization to morphine-induced CPP in the rats.

The Effect of Voluntary Exercise and Prenatal Exposure to Sodium Valproate on Learning, Memory, and Anxiety of Rats' Offspring.

BACKGROUND: Antiepileptic drugs, such as sodium valproate (SV), are teratogenic as their usage by the pregnant mother has been associated with an increased risk of major congenital abnormalities in the fetus. In this study, the effects of voluntary exercise and prenatal exposure to SV on learning, memory, and anxiety in rats' offspring are investigated. METHODS: In the present study, 70 female albino Wistar rats (200-240g) were used. The rats were categorized in seven groups: 1 and 2, pregnant rats with exposure to SV (10 mg/kg/day i.p) 3 and 4, pregnant rats with exposure to SV (20 mg/kg/day i.p) 5 and 6, pregnant rats with exposure to normal saline (0.4 ml/day i.p) and 7, pregnant rats with exposure to lamotrigine (20 mg/kg/day i.p). The even and odd groups were sedentary and voluntary exercise groups, respectively. Learning and memory were tested in male offspring using shuttle-box; anxiety was tested by elevated plus-maze (each group n=12). Statistical analyses were performed using the one-way ANOVA (the Tukey test) and/or two-way ANOVA on rank. RESULTS: The results showed that voluntary exercise in male rats caused improvement of latency and duration time in the dark box compared to sedentary groups (P=0.004). Moreover, the group administrated with 10 mg/kg SV showed better learning capability than the group administrated with 20 mg/kg SV. Voluntary exercise could also improve anxiety (P=0.001). CONCLUSION: This study indicated that exercise could increase learning capacity and improve memories in rats' offspring whose mothers were exposed to SV. Voluntary exercise could improve anxiety too, and the effect was dose-dependent.

Nickel oxide nanoparticles exert selective toxicity on skin mitochondria and lysosomes isolated from the mouse model of melanoma.

Nickel oxide nanoparticles (NiO-NPs) are progressively used for an immense number of new applications in modern industries sectors. Nevertheless, the toxic impact of NiO-NPs has not been clearly elucidated on human melanoma cell lines at the cellular and molecular level. Hence, this study was designed to examine the in vitro cytotoxicity potentials of NiO-NPs on malignant cutaneous melanoma (MCM) mitochondria. Results revealed that NiO-NPs significantly increased reactive oxygen species level, lipid peroxidation, and mitochondrial membrane potential and decreased succinate dehydrogenase activity, glutathione level, and ATP content on skin mitochondria isolated from the mouse model of melanoma compared with the non-cancerous mouse skin mitochondria. Our results revealed that NiO-NPs induced lysosomal membrane labialization on mentioned mitochondria. The current study showed that NiO-NPs could significantly induce selective cytotoxicity on MCM mitochondria. Therefore, this compound may be considered as a promising candidate for further in vivo and clinical studies to reach a new anti-MCM drug.

Involvement of IL-1ß and IL-6 in antiarrhythmic properties of atorvastatin in ouabain-induced arrhythmia in rats.

PURPOSE: Evidence show that statins possess wide beneficial cardioprotective and anti-inflammatory effects; therefore, in the present experiment, we investigated the antiarrhythmic properties of atorvastatin in ouabain-induced arrhythmia in isolated rat atria and the role of several inflammatory cytokines in this effect. MATERIALS AND METHODS: Male rats were pretreated with either of atorvastatin (10 mg/kg) or vehicle, orally once daily for 6 weeks. After induction of anesthesia, we isolated the atria and after incubation with ouabain, time of onset of arrhythmia and asystole as well as atrial beating rate and contractile force were recorded. We also measured the atrial levels of IL-1ß, IL-6, and TNF-α after the injection of ouabain to animals. RESULTS: Pretreatment with atorvastatin significantly delayed the onset of arrhythmia and asystole compared with vehicle-treated group (p < .01, p < .001, respectively). Incubation of ouabain boosted both atrial beating rate and contractile force in vehicle-treated group (p < .05), while these responses in atorvastatin-treated group were not significant (p > .05). Injection of ouabain elevated the atrial levels of IL-1ß, IL-6, and TNF-α, while pretreatment of animals with atorvastatin could reverse the ouabain-induced increase in atrial IL-1ß and IL-6 (p < .01 and p < .05, respectively). CONCLUSIONS: It is concluded that observed antiarrhythmic effects of atorvastatin might be attributed to modulation of some inflammatory cytokines, at least IL-1ß and IL-6.

Safety Assessment of Mentha mozaffarianii Essential Oil: Acute and Repeated Toxicity Studies.

BACKGROUND: Mentha mozaffarianii, an endemic species from the Labiatae family, is used in Iranian traditional medicine. This study evaluated the acute and repeated oral toxicity of the Mentha mozaffarianii essential oil (MMEO) in rats and mice. METHODS: To assess the toxicity profile of the MMEO, we administered the essential oil to 48 rats and mice of both sexes by gavage in acute and repeated models. In acute toxicity, the animals were administered the MMEO (2000 mg/kg) and were monitored for 14 days. In the repeated toxicity, the MMEO was administered (100 mg/kg) daily for 4 weeks. On the 28th day, all the animals were scarified and blood and tissue samples were prepared. All the clinical, biochemical, and histopathological changes were assessed and compared with those in the controls. Statistical significance was determined by one- and two-way analyses of variance, followed by the Tukey test using GraphPad Prism 6. RESULTS: In the acute test, there was no mortality; therefore, the oral LD50 value determined in the mice and rats of both sexes was greater than 2000 mg/kg. In the repeated test, the animals received the MMEO and there was no mortality. In the biochemical analysis, there were significant increases in blood glucose, cholesterol, ALT, AST, ALP, and TSH in the female rats and also in BUN in the male rats. The histopathological studies revealed evidence of microscopic lesions in the liver, kidney, stomach, and small intestine tissues of the MMEO group. CONCLUSION: The results indicated that the acute toxicity of the MMEO in the mice and rats was of a low order and it revealed slight tissue damage to several organs when given subchronically at a dose of 100 mg/kg.

Effects of Subcutaneous Injection MnO2 Micro- and Nanoparticles on Blood Glucose Level and Lipid Profile in Rat.

BACKGROUND: The use of nanotechnology has led to rapid growth in various areas. Thus, health and safety issues of nanoparticles (NPs) should be promptly addressed. Manganese oxide (MnO2) nanoparticles (NPs) are typically used for biomedical and industrial applications. However, characterizing the potential human health effects of MnO2 NPs is required before fully exploiting these materials. The aim of this study was to investigate the toxicity of MnO2 micro- and nanoparticles on blood glucose level and lipid profile in male Wistar rats. METHODS: A total of 105 rats were divided into one control and two experimental groups. Each experimental group received a single subcutaneous injection of MnO2 micro- and nanoparticles (100 µg/kg), respectively, every two weeks for 14 weeks. Their blood glucose, cholesterol, triglycerides, LDL, and HDL levels were then measured. The data presented as mean±SEM and compared with the repeated measures using the Prism statistical software (version 6.0). RESULTS: Biochemical assessment in plasma samples showed that MnO2 micro- and nanoparticles injection significantly (P<0.01) increased the plasma glucose and cholesterol levels in all and few weeks, respectively. MnO2 nanoparticles significantly (P<0.01) decreased the HDL level in weeks 6, 12, and 14, but MnO2 microparticles decreased the HDL level only in week 12. In both MnO2 micro- and nanoparticles groups, LDL alterations were near to the control group, except for week 10. However, the same treatment had no effect on triglycerides concentrations compared to the control group. CONCLUSION: Our results show that exposure to nanosized particles at subchronic doses caused adverse changes in animal biochemical profiles, especially in glucose level. It seems that the high oxidative power of these particles is the main reason for these disturbances.

Functional and structural changes of human erythrocyte catalase induced by cimetidine: proposed model of binding.

In erythrocyte, catalase plays an important role to protect cells from hydrogen peroxide toxicity. Hydrogen peroxide is a byproduct compound which is produced during metabolic pathway of cells. Cimetidine, a histamine H2 receptor antagonist, is used for gastrointestinal tract diseases and prevents the extra release of gastric acid. In this study, the effect of cimetidine on the activity of human erythrocyte catalase was investigated. Erythrocytes were broken by hypotonic solution. The supernatant was used for catalase assay and kinetics study. Lineweaver-Burk plot was performed to determine the type of inhibition. The kinetics data revealed that cimetidine inhibited the catalase activity by mixed inhibition. The IC50 (1.54 µM) and Ki (0.45 µM) values of cimetidine determined that the drug was bound to the enzyme with high affinity. Circular dichroism and fluorescence measurement showed that the binding of cimetidine to the enzyme affected the content of secondary structure of the enzyme as well as its conformational changes. Docking studies were carried out to detect the site in which the drug was bound to the enzyme. Molecular modeling and energy calculation of the binding showed that the cyanoguanidine group of the drug connected to Asp59 via two hydrogen bonds, while the imidazole group of the drug interacted with Phe64 in the enzyme by a hydrophobic interaction. In conclusion, cimetidine could bind to human erythrocyte catalase, and its interaction caused functional and conformational changes in the enzyme.

The effects of coenzyme Q10 on seizures in mice: the involvement of nitric oxide.

Coenzyme Q10 is a potent antioxidant in both mitochondria and lipid membranes. It has also been recognized to have an effect on gene expression. This study was designed to investigate whether acute or subchronic treatment with coenzyme Q10 altered the seizures induced by pentylenetetrazole or electroshock in mice. We also evaluated the involvement of nitric oxide in the effects of coenzyme Q10 in pentylenetetrazole-induced seizure models. Acute oral treatment with different doses of coenzyme Q10 did not affect the seizure in intraperitoneal pentylenetetrazole, intravenous pentylenetetrazole, and electroshock models in mice. Subchronic oral administration of coenzyme Q10 (100 mg/kg or more) increased time latencies to the onset of myoclonic jerks and clonic seizures induced by intraperitoneal pentylenetetrazole and at the doses of 25 mg/kg or more increased the seizure threshold induced by intravenous infusion of pentylenetetrazole. Subchronic doses of coenzyme Q10 (50 mg/kg or more) also decreased the incidence of tonic seizures in the electroshock-induced seizure model. Moreover, acute treatment with the precursor of nitric oxide synthesis, L-arginine (60 mg/kg), led to a significant potentiation of the antiseizure effects of subchronic administration of coenzyme Q10 (400 mg/kg in intraperitoneal and 6.25 mg/kg in intravenous pentylenetetrazole tests). Acute treatment with l-NAME (5 mg/kg), a nonspecific nitric oxide synthase inhibitor, significantly attenuated the antiseizure effects of subchronic doses of coenzyme Q10 in both seizure models induced by pentylenetetrazole. On the other hand, acute administration of aminoguanidine (100 mg/kg), a specific inducible nitric oxide synthase inhibitor, did not affect the seizures in mice treated with subchronic doses of coenzyme Q10 in both intraperitoneal and intravenous pentylenetetrazole tests. In conclusion, only subchronic and not acute administration of coenzyme Q10 attenuated seizures induced by pentylenetetrazole or electroshock. We also demonstrated, for the first time, the interaction between nitric oxide and coenzyme Q10 in antiseizure activity probably through the induction of constitutive nitric oxide synthase.

Synthesis, analgesic and anti-inflammatory activities of new methyl-imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles.

BACKGROUND: Long-term clinical employment of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with significant side effects including gastrointestinal (GI) lesions and kidney toxicity. In this paper we designed and synthesized new imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles by molecular hybridization of previously described anti-inflammatory compounds in the hope of obtaining new safer analgesic and anti-inflammatory agents. METHODS: The target structures were synthesized by preparation of 5-methyl-1H-imidazole-4-carboxylic acid ethyl ester 5. The reaction of hydrazine hydrate with this ester afforded the 5-methyl-1H-imidazole-4-carboxylic acid hydrazide 6 which was converted to target compounds 7-15 according to the known procedures. In silico toxicity risk assessment and drug likeness predictions were done, in order to consider the privileges of the synthesized structures as drug candidates. RESULTS AND DISCUSSION: The analgesic and anti-inflammatory profile of the synthesized compounds were evaluated by writhing and carrageenan induced rat paw edema tests respectively. Compounds 8, 9 and 11-13 and 15 were active analgesic agents and compounds 8, 9 and 11-13 showed significant anti-inflammatory response in comparison with control. Compounds 11 and 13 were screened for their ulcerogenic activities and none of them showed significant ulcerogenic activity. The active Compounds 11 and 12 showed the highest drug likeness and drug score. CONCLUSIONS: The analgesic and anti-inflammatory activities of title compounds were comparable to that of standard drug indomethacin with a safer profile of activity. The results revealed that both of oxadiazole and triazole scaffolds can be determined as pharmacophores. The in silico predictions and pharmacological evaluations showed that compounds 11 and 12 can be chosen as lead for further investigations.

Harvest time optimization for medicinal and aromatic plant secondary metabolites.

Plant secondary metabolites (SMs) play a crucial role in shielding plants from pathogens and environmental stressors. These natural products find widespread applications across various industries, including pharmaceutical, food, cosmetic, and healthcare. However, the quantity and quality of these compounds in plants can be influenced by factors such as genetics, morphology, plant age, and the seasonal and daily variations. The timing of harvest holds particular significance for medicinal and aromatic plants (MAPs) as their active compounds peak at a specific moment during the plant growth cycle. Determining the optimal harvest time is essential to ensure the plants meet their intended cultivation goal. In this review, we analyzed how developmental and external factors impact the qualitative and quantitative effectiveness of SMs in MAPs. We examined recent studies on the effects of environmental and developmental factors on SMs of MAPs, compiling relevant data for analysis. The results of this review demonstrate how these factors influence the quantity and quality of plant SMs, underscoring the importance of determining the optimal harvest time (known as the balsamic time) to maximize the utilization of these compounds. Our findings offer crucial insights into the factors affecting SMs, serving as a tool for quality control in MAPs production. Moreover, this review can be a valuable resource for researchers, farmers, and industrial users aiming to optimize plant growth and harvest timing for maximum yield. Overall, our review provides valuable information for devising effective strategies to produce high-quality MAPs products.

Blockade of the orexin-2 receptors within the ventral tegmental area facilitates the extinction and prevents the reinstatement of methamphetamine-seeking behavior.

Repeated use of methamphetamine (METH) causes severe effects on the central nervous system, associated with an increased relapse rate. The orexinergic system is highly implicated in the reward circuitry and may be a promising target for treating psychostimulant dependency. The present study aimed to investigate the involvement of the orexin system, mainly the orexin-2 receptors (OX2R) in the ventral tegmental area (VTA) in the extinction and reinstatement of METH-seeking behavior using a conditioned place preference (CPP) paradigm. To this end, animals received METH (1 mg/kg; sc) for a 5-day conditioning period. Then, in the first set of experiments, different groups of rats were given intra-VTA TCS OX2 29 (1, 3, 10, or 30 nmol/0.3 µl DMSO) as an OX2R antagonist over a 10-day extinction period. In another experiment, after the extinction period, a different set of animals received a single dose of TCS OX2 29 (1, 3, 10, or 30 nmol) before the priming dose of METH (0.25 mg/kg; sc) on the reinstatement day. The results revealed that TCS OX2 29 (10 and 30 nmol) remarkably facilitated the extinction of rewarding properties of METH (P < 0.001 for both doses). Furthermore, TCS OX2 29 (3, 10, or 30 nmol) significantly suppressed the METH-induced reinstatement (3 nmol; P < 0.05, 10 nmol; P < 0.01, and 30 nmol; P < 0.001). In conclusion, the current study revealed that the orexinergic system, specifically the VTA OX2R, is involved in METH-seeking behaviors and that manipulation of this system can be considered a potential therapeutics in treating METH dependency.