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Abstract Glutamatergic neurotransmission and oxidative stress are involved in the pathophysiology of seizures. Some anticonvulsants exert their effects through modulation of these pathways. Trigonelline (TRG) has been shown to possess various pharmacological effects like neuroprotection. Therefore, this study was performed to determine TRG’s anticonvulsant effects, focusing on its potential effects on N-methyl-D-aspartate (NMDA) receptors, a type of glutamate receptor, and oxidative stress state in the prefrontal cortex (PFC) in PTZ-induced seizure in mice. Seventy-two male mice were randomly divided into nine groups. The groups included mice that received normal saline, TRG at doses of 10, 50, and 100 mg/kg, diazepam, NMDA (an agonist), ketamine (an antagonist), the effective dose of TRG with NMDA, as well as sub-effective dose of TRG with ketamine, respectively. All agents were administrated intraperitoneally 60 min before induction of seizures by PTZ. Latency to seizure, total antioxidant capacity (TAC), and malondialdehyde (MDA) levels in serum and PFC were measured. Furthermore, the gene expression of NR2A and NR2B, subunits of NMDA receptors, was measured in the PFC. TRG administration increased the latency to seizure onset and enhanced TAC while reducing MDA levels in both the PFC and serum. TRG also decreased the gene expression of NR2B in the PFC. Unexpectedly, the findings revealed that the concurrent administration of ketamine amplified, whereas NMDA mitigated, the impact of TRG on latency to seizure. Furthermore, NMDA diminished the positive effects of TRG on antioxidant capacity and oxidative stress, while ketamine amplified these beneficial effects, indicating a complex interaction between TRG and NMDA receptor modulation. In the gene expression of NMDA receptors, results showed that ketamine significantly decreased the gene expression of NR2B when co-administrated with a sub-effective dose of TRG. It was found that, at least partially, the anticonvulsant effect of TRG in PTZ-induced seizures in male mice was mediated by the attenuation of glutamatergic neurotransmission as well as the reduction of oxidative stress.

Autism spectrum disorder (ASD) is a neurodegenerative disease with increasing incidence in the world. The maternal separation (MS) stress at early life with its own neuroendocrine and neurostructural changes can provide the basis for development of ASD. Previously it has been reported neuroprotective characteristics for anethole. The PI3K/AKT/mTOR signaling pathway has pivotal role in the function of central nervous system (CNS). This study aimed to evaluate the possible effects of anethole on the autistic-like behaviors in the maternally separated (MS) mice focusing on the potential role of the PI3K/AKT/mTOR pathway. Forty male Naval Medical Research Institute (NMRI) mice were assigned to five groups (n = 8) comprising a control group (treated with normal saline) and four groups subjected to MS and treated with normal saline and or anethole at doses of 31.25, 62.5 and 125 mg/kg, respectively. All gents were administrated via intraperitoneal (i.p.) route for 14 constant days. Behavioral tests were conducted, including the three-chamber test, shuttle box and resident-intruder test. The gene expression of the PI3K, AKT and mTOR assessed in the hippocampus by qRT-PCR. Findings indicated that MS is associated with autistic-like behaviors. Anethole increased the sociability and social preference indexes in the three-chamber test, increased duration of secondary latency in the shuttle box test and decreased aggressive behaviors in the resident-intruder test. Also, anethole increased the gene expression of PI3K, AKT and mTOR in the hippocampus of MS mice. We concluded that anethole through increase in the gene expression of PI3K/ AKT/mTOR mitigated autistic-like behaviors induced by MS in mice.

Epilepsy poses a significant challenge, especially for drug-resistant cases, necessitating novel treatment avenues. This study explores the potential interplay between nitric oxide (NO) and the anticonvulsant effects of betulin, a triterpene with promising neuroprotective properties. While betulin exhibits anticonvulsant effects, the specific involvement of NO remains inadequately understood, constituting a pivotal gap in current knowledge. One hundred NMRI mice were randomly assigned to diverse treatment groups, with seizures induced by pentylenetetrazol (PTZ). Parameters such as seizure threshold, nitrite levels, total antioxidant capacity (TAC), malondialdehyde (MDA) levels, and iNOS/nNOS gene expressions were assessed. Betulin significantly increased seizure thresholds and mitigated PTZ-induced NO levels. These findings suggest a potential modulation of NO-related pathways, emphasizing betulin's anti-inflammatory and antioxidant attributes. The study sheds light on betulin's multifaceted impact on oxidative stress, NO regulation, and iNOS/nNOS gene expressions. The ability of betulin to suppress iNOS/nNOS gene expressions, leading to reduce NO production, underscores its potential as an anticonvulsant.

Introduction: Plenty evidences suggests that neuroinflammation and oxidative stress augmented the neural sensitivity specifying that neuro-immune response is involved in the pathophysiology of pain. Ferulic acid (FA), a natural antioxidant found in various fruits, has various pharmacological properties. The purpose of the current study was to assess the antinociceptive effect of FA in a mouse model of formalin test with focus on its anti-neuroinflammatory and antioxidative stress effects. Methods: The injection of FA (40 mg/kg), piroxicam (2 mg/kg), and saline (0.9% NaCl) (1 ml/kg) was done intraperitoneally and after one hour, formalin injected into the plantar surface of the hind paw of mice. Then pain behavior was documented during 60 min. Then mice were euthanized and prefrontal cortex (PFC) samples were taken. Malondialdehyde (MDA) level, antioxidant capacity and expression of inflammatory genes, counting tumor necrosis factor (TNF-) and interleukine 1 (IL-1) evaluated in the PFC. Results: exhibited that FA declined the pain behavior following injection of formalin. Besides, FA significantly diminished the MDA level and increased the antioxidant capacity in the PFC. We revealed that FA diminished the expression of TNF-α and IL-1β genes in the PFC. Conclusion: We conclude that FA exerted antinociceptive effects in the formalin test in mice, at least partially, by reducing oxidative stress and neuroimmune response in the PFC.

Abstract The occurrence of major depressive disorder is widespread and can be observed in individuals belonging to all societies. It has been suggested that changes in the NO pathway and heightened oxidative stress may play a role in developing this condition. Anethole is a diterpene aromatic compound found in the Umbelliferae, Apiaceae, and Schisandraceae families. It has potential pharmacological effects like antioxidant, anxiolytic, analgesic, anti-inflammatory, antidiabetic, gastroprotective, anticancer, estrogenic, and antimicrobial activities. This study aimed to investigate the potential antidepressant properties of Anethole in a mouse model experiencing maternal separation stress while also examining its impact on oxidative stress and nitrite levels. The research involved the participation of 40 male NMRI mice, separated into five distinct groups to conduct the study. The control group was administered 1 ml/kg of normal saline, while the MS groups were given normal saline and Anethole at 10, 50, and 100 mg/kg doses. The study comprised various behavioural tests, including the open field test (OFT), forced swimming test (FST), and splash test, to assess the effects of Anethole on the mice. In addition to the behavioural tests, measurements were taken to evaluate the total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrite levels in the hippocampus of the mice. According to the findings, maternal separation stress (MS) led to depressive-like conduct in mice, including a rise in immobility duration during the FST and a reduction in the duration of grooming behaviour in the splash test. Additionally, the results indicated that MS correlated with an increase in the levels of MDA and nitrite and a reduction in the TAC in the hippocampus. However, the administration of Anethole resulted in an increase in grooming activity time during the splash test and a decrease in immobility time during the FST. Anethole also exhibited antioxidant characteristics, as demonstrated by its ability to lower MDA and nitrite levels while increasing the TAC in the hippocampus. The results suggest that Anethole may have an antidepressant-like impact on mice separated from their mothers, likely partly due to its antioxidant properties in the hippocampus.

Abstract Background and aim Social isolation stress (SIS) is a stressor known to trigger depressive behaviors. Psychiatric disorders are associated with neurobiological changes, such as neuroinflammation and an increase in nitric oxide (NO) signaling. Despite the well‐established detrimental effects of SIS and the involvement of neuroinflammation and NO in depression, potential management strategies, especially resocialization, remain insufficiently explored. Our aim was to elucidate the effects of resocialization on depressive behaviors in socially isolated mice, with a focus on the possible involvement of neuroinflammation and nitrite in the hippocampus (HIP). Methods We utilized 24 Naval Medical Research Institute male mice, maintained under both social and isolation conditions (SC and IC). After the isolation period, the mice were divided into two groups of eight, including the SIS group and a resocialized group. The SC group was kept without exposure to isolation stress. We conducted the open‐field test, forced swimming test, and splash test to evaluate depressive behaviors. Additionally, nitrite levels, as well as the gene expression of interleukin (IL)‐1β, tumor necrosis factor (TNF), and toll‐like receptor 4 (TLR4) in the HIP, were measured. Results The study found that resocialization significantly reduces depressive behaviors in SIS mice. The results suggest that the antidepressive effects of resocialization may be partially due to the modulation of the neuroinflammatory response and nitrite levels in the HIP. This is supported by the observed decrease in hippocampal gene expression of IL‐1β, TLR4, and TNF, along with a reduction in nitrite levels following resocialization. Conclusion These insights could pave the way for new management strategies for depression, emphasizing the potential benefits of social interactions.

Experimental autism in rodents can be caused by prenatal valproic acid (VPA) exposure. Some diseases, such as attention-deficit hyperactivity disorder (ADHD), insomnia, opiate withdrawal, and generalized anxiety disorder can be treated by consuming Passiflora incarnata, due to the possession of bioactive compounds like alkaloids, phenols, and flavonoids.The present study aims to investigate the role of the hydroalcoholic extract of Passiflora incarnata in behavioral and oxidative stress aberrations induced by VPA.On the gestational day (GD), 12.5, pregnant Wistar rats received VPA (600 mg/kg subcutaneously). Male pups were treated with the extract (30,100, and 300 mg/kg) from postnatal day 35 to the end of the experiment, and underwent behavioral testing to evaluate locomotion, repetitive, and stereotyped movements, anxiety, and social and cognitive behaviors. After behavioral testing, the blood sample was taken from the left ventricle to determine serum catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), and total antioxidant capacity (TAC). Then the animals were euthanized and their brains were taken out for histological assays of the prefrontal cortex (PFC) and CA1 hippocampus with hematoxylin/eosin. The total phenol and flavonoid content and antioxidant activity of the extract were also measured. A significant improvement was observed in behavioral disturbances, particularly with 300 mg/kg of Passiflora. Moreover, the formation of oxidative stress markers significantly decreased at this dose. The extract also reduced the percentage of damaged cells in the CA1 and PFC. The results indicated that Passiflora extract could ameliorate VPA-induced behavioral aberrations possibly due to the antioxidant actions of its bioactive compounds.

Background and aims: This study aimed to determine the effects of Astragalus fasciculifolius hydroalcoholic extract on rat ileum contractions: The role of adrenergic, opioid, and nitric oxide (NO) receptors. Methods: A. fasciculifolius extract was prepared using 70% alcohol by maceration extraction. 2 cm pieces from the end of the rat ileum were placed in a tissue bath containing Tyrode’s solution. The tissue bath solution is constantly oxygenated. Potassium chloride (KCl), naloxone, Nω-nitro-L-arginine methyl ester (L-NAME), propranolol, and different concentrations of calcium chloride were used to stimulate the ileum. Ileum contractions were recorded isotonically under 1 g of initial tension. The results were calculated as the amount of shortening (in millimeters). Results: This study showed that A. fasciculifolius extract caused a significant increase in ileum contraction compared to the control group (P < 0.001). This increase in contraction was amplified in combination with opioid or NO receptor antagonists (P < 0.001). Also, this effect was not significantly different in association with beta-adrenergic receptor antagonists. Conclusion: The results of this study showed that A. fasciculifolius extract enhances the contractile function of the ileum in rats. This function is reinforced by opioid receptor antagonists and NO.

Introduction: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition. Maternal separation (MS) stress is an early-life stress factor associated with behaviors resembling Autism. Both MECP2 and oxidative stress are implicated in the pathophysiology of Autism. Umbelliprenin (UMB) is a coumarin compound with various pharmacological properties. Our study aimed to investigate the potential effects of UMB in mitigating autistic-like behaviors in a mouse model subjected to MS stress, focusing on probable alterations in MECP2 gene expression in the hippocampus.Methods: MS paradigm was performed, and mice were treated with saline or UMB. Behavioral tests consisting of the three-chamber test (evaluating social interaction), shuttle box (assessing passive avoidance memory), elevated plus-maze (measuring anxiety-like behaviors), and marble-burying test (evaluating repetitive behaviors) were conducted. Gene expression of MECP2 and measurements of total antioxidant capacity (TAC), nitrite level, and malondialdehyde (MDA) level were assessed in the hippocampus.Results: The findings demonstrated that MS-induced behaviors resembling Autism, accompanied by decreased MECP2 gene expression, elevated nitrite, MDA levels, and reduced TAC in the hippocampus. UMB mitigated these autistic-like behaviors induced by MS and attenuated the adverse effects of MS on oxidative stress and MECP2 gene expression in the hippocampus.Conclusion: In conclusion, UMB likely attenuated autistic-like behaviors caused by MS stress, probably, through the reduction of oxidative stress and an increase in MECP2 gene expression.

Background: The outbreak of Coronavirus Disease 2019 (COVID-19) has originated from Wuhan, China and rapidly spread all over the world. This disease is caused by a coronavirus termed Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) that mainly infects the human respiratory tract. Herbal agents including Atractylodes lancea, Ephedra, Curcumin, and Echinacea purpurea had immunomodulatory effects and antiviral activities on other respiratory viruses including Influenza virus. They strengthen the innate immunity through increasing the phagocytic activity and anti-inflammatory activity. These herbs could be used as a complementary therapy to prevent entry of COVID-19 and improve immune system. This review delves into the role and therapeutic compounds of various herbal agents in relation to immunity, their effectiveness in treating other viral respiratory illnesses, and their potential influence on COVID-19 disease.

Abstract Objective In this study, the therapeutic effect of quinic acid (QA), which has anti‐inflammatory activity, was investigated on acetic acid‐induced colitis in male Wistar rats. Methods Ulcerative colitis (UC) was induced in rats by acetic acid intrarectally, and the protective effects of QA in 10, 30, 60, and 100 mg/kg doses were investigated. Rats were treated for 5 days and their colon tissues were dissected out at the end. Macroscopic and histopathological examinations were performed in colon tissues. Also, the expression of inflammatory and apoptotic genes, including TLR4, IL‐1β, INOS, IL‐6, TNF‐α, NF‐κB, Caspase‐3, Caspase‐8, Bax, and Bcl‐2, was measured. Biochemistry indices, such as malondialdehyde (MDA) and nitrite oxide (NO) content, in addition to, total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase (CAT), and enzymes activities were also assessed. Results Colitis increased the levels of MDA and NO, and enhanced the inflammatory and apoptotic gene expressions, while reducing the SOD and CAT enzymes activity, and TAC levels in the colitis rats. Also, results showed that colitis was associated with the infiltration of inflammatory cells, epithelium damage, and edema in colon tissue. QA significantly ameliorated histopathological indices, oxidative stress, inflammation, and apoptosis in colitis rats. Conclusion QA ameliorated UC through the inhibition of two TLR4‐NF‐κB and NF‐κB‐INOS‐NO signaling pathways, which results in the reduction of colitis complications, including oxidative stress, inflammation, apoptosis and histopathological injuries in rats. Therefore it can be concluded, that QA exerts its therapeutic effects through antiapoptotic, antioxidant, and anti‐inflammatory properties.

Background and aims: Trichomoniasis is the most common non-viral sexually transmitted infection worldwide; although it is treated by a 5-nitroimidazole drug family such as metronidazole (MTZ) with numerous side effects, and in this regard, alternative new drugs are required. Therefore, this study examined the anti-Trichomoniasis effect of the hydroalcoholic extract of some traditional medicinal plants of Iran in vitro. Methods: In this experimental study, the hydroalcoholic extracts of medicinal plants were prepared by maceration at a stock concentration of 20 mg/mL in the saline solution and then used for in vitro anti-trichomonas experiments. Trichomonas vaginalis trophozoites were isolated from the patient and cultured in a Trypticase Yeast extract Iron-Serum-33 medium. In addition, 200 μL of the culture medium containing 5×104 trophozoites was diluted in plate wells, and 10 doses were separately added on trophozoites for each extract serially diluted between 0.12 and 16 mg/mL in triplicate. The plates were incubated for 48 hours at 37 ° C with 5% CO2 . The number of trophozoites was counted with a hemocytometer and Trypan blue staining. Finally, the half maximal inhibitory concentration (IC50) was calculated by probit analysis. Results: Among the tested plants, Eugenia caryophyllata, Camellia sinensis, and Terminalia chebula Retz showed the best anti-trichomonal activity with IC50 values of 1.21, 1.62, and 1.66 mg/mL, respectively. All tested extracts had more IC50 than MTZ (IC50 100 mg/mL), an antiprotozoal drug used as a positive control. Conclusion: According to the results of this study, E. caryophylata, C. sinensis and T. chebula Retz affected the growth of T. vaginalis. Thus, it is recommended that other studies use this plant for the treatment of trichomoniasis infection.

Background and aims: Inflammatory bowel disease is a chronic inflammatory disease whose prevalence is rising worldwide. The treatment-related challenges of this disease have expanded the research on other compounds with suitable therapeutic properties. Carvacrol monoterpene phenolic compound, with a wide range of therapeutic properties, can be an appropriate choice. This study aims to investigate the protective effect of carvacrol on acetic acid-induced colitis in mice, further emphasizing the modulating role of oxidative stress and inflammation. Methods: This experimental study was conducted on 60 mice divided into six groups. Colitis was induced by intrarectal injection of acetic acid. Five groups of mice received carvacrol at doses of 12.5, 25, 50, and 100 mg/kg and normal saline (1 ml/kg). One group was considered normal (without colitis) and received normal saline (1 ml/kg). The severity of colitis complications was assessed through histopathological examination of colon tissue samples. Furthermore, the malondialdehyde (MDA) level, total antioxidant capacity (TAC), and gene expression of inflammatory markers were investigated in the colon samples. Data analysis was done by PRISM version 8 using one-way ANOVA and Tukey’s test. Results: The results showed that the induction of colitis caused significant damage to the intestinal mucosal layers, and the administration of carvacrol reduced the severity of this damage. Interestingly, the TAC of all groups that received carvacrol was higher than that of the group that received normal saline (P < 0.05). The administration of carvacrol decreased the MDA level (P < 0.05). In addition, the gene expression of interleukin-1beta (IL-1β), Toll-like receptor 4 (TLR4), and tumor necrosis factor-alpha (TNF-α) reduced after carvacrol administration (P < 0.05). Conclusion: Carvacrol exerted a protective effect on the acetic acid-induced colitis in mice, probably via inhibiting the inflammatory cascade and modulating oxidative stress.

Background and aims: Epilepsy is a neurological disorder causing brain dysfunctions. Treatment and control of epilepsy have long been a challenge in medical sciences. Despite the variety of current anticonvulsant drugs, research continues to discover new drugs with the highest efficacy and the lowest side effects. In the present study, the anticonvulsant effects of anethole in the seizure induction with pentylenetetrazole (PTZ) were evaluated in a mice model with respect to its possible antioxidant effects. PTZ is known to cause generalized epilepsy in animal models.Methods: Accordingly, in this experimental study, 40 mice were divided into 5 groups; the first group received normal saline, the second group received 10 mg/kg diazepam, and the third to fifth groups were given anethole at 31.25, 62.5 and 125 mg/kg, respectively. Injections were conducted intraperitoneally for one week; then seizures were induced by the intravenous injection of 90 mg/kg PTZ. After determination of the duration of seizures in different groups, the mice were finally placed under deep anesthesia and their prefrontal cortex tissue was isolated to measure nitric oxide (NO), antioxidant capacity and malondialdehyde (MDA) concentrations.Results: The results showed that anethole increased the delay in the onset of seizures, decreased the amount of nitrite in the brain, enhanced antioxidant capacity, and reduced MDA content in a dose-dependent manner.Conclusion: Overall, our results indicated the anticonvulsant effects of anethole that could be mediated by inhibiting oxidative stress.

Abstract Ebola virus (EBOV) is a dangerous zoonotic infectious disease. To date, more than 25 EBOV outbreaks have been documented, the majority of which have occurred in Central Africa. The rVSVG-ZEBOV-GP vaccine (ERVEBO), a live attenuated vaccine, has been approved by the US Food and Drug Administration (FDA) to combat EBOV. Because of the several drawbacks of live attenuated vaccines, multi-epitope vaccines probably appear to be safer than live attenuated vaccines. In this work, we employed immunoinformatics tools to design a multi-epitope vaccine against EBOV. We collected sequences of VP35, VP24, VP30, VP40, GP, and NP proteins from the NCBI database. T-cell and linear B-cell epitopes from target proteins were identified and tested for antigenicity, toxicity, allergenicity, and conservancy. The selected epitopes were then linked together in the vaccine's primary structure using appropriate linkers, and the 50S ribosomal L7/L12 (Locus RL7 MYCTU) sequence was added as an adjuvant to the vaccine construct's N-terminal. The physicochemical, antigenicity, and allergenicity parameters of the vaccine were all found to be satisfactory. The 3D model of the vaccine was predicted, refined, and validated. The vaccine construct had a stable and strong interaction with toll-like receptor 4 (TLR4) based on molecular docking and molecular dynamic simulation (MD) analysis. The results of codon optimization and in silico cloning revealed that the proposed vaccine was highly expressed in Escherichia coli (E. coli). The findings of this study are promising; however, experimental validations should be carried out to confirm these findings.

Recent studies have been demonstrated that neuroinflammation plays a crucial role in the pathophysiology of depression. Therefore, anti-inflammatory medications could be regarded as a potentially effective treatments for depression. Ellagic acid (EA) is a natural polyphenol with antioxidant and anti-inflammatory properties. This study aimed to evaluate the antidepressant-like effect of EA in a mouse model of social isolation stress (SIS), considering its potential anti-neuroinflammatory properties. In this study, 48 male mice were divided into six groups (n = 8), including saline-treated control (socially conditioned (SC)) group and SIS (isolation conditioned (IC)) groups treated with saline or EA at doses of 12.5, 25, 50, and 100 mg/kg, respectively. Saline and EA were administrated intraperitoneally for 14 constant days. Immobility time in the forced swimming test (FST) and grooming activity time in the splash test were measured. The gene expression of inflammatory cytokines relevant to neuroinflammation was assessed in the hippocampus by real-time PCR. Results showed that SIS significantly increased immobility time in the FST and reduced grooming activity time in the splash test. In addition, the expression of inflammatory genes, including TNF-α, IL-1β, and TLR4 increased in IC mice's hippocampi. Findings showed that EA decreased immobility time in the FST and increased grooming activity time in the splash test. Moreover, EA attenuated neuroimmune-response in the hippocampus. In conclusion, finding determined that EA, through attenuation of neuroinflammation in the hippocampus, partially at least, exerted an antidepressant-like effect in the mouse model of SIS.

Background. Epilepsy is one of the most common neurological disorders after stroke. Due to the side effects and poor response of conventional anticonvulsant drugs, researchers have turned their attention to find new drugs. Carvacrol is a phenolic compound with neuroprotective, anti-inflammatory, antioxidant and anticonvulsant effects. The aim of the study was to investigate the anticonvulsant effects of carvacrol in PTZ-induced seizures in male mice and to investigate the role of N-Methyl-D-Aspartic Acid (NMDA) receptor. Methods. In the present experimental study, 90 mice were randomly divided into 9 groups (n=10). Drugs were injected intraperitoneally 30 minutes before PTZ injection. Then, seizure onset time, serum and brain antioxidant capacity (TAC) and malondialdehyde (MDA) and NMDA receptor gene expression in the hippocampus were examined. Results. Seizure onset time in the group received carvacrol (20 and 40 mg/kg) was significantly longer than the PTZ group (P

Abstract Background Depression is one of the most common mental illnesses worldwide. Nitric oxide (NO) is involved in the pathophysiology of depression. Auraptene (a coumarin derivative) has been shown to possess pharmacological effects on neurological diseases. Purpose The present study aimed to investigate the possible role of the NO pathway in Auraptene antidepressant effects in male mice. Methods Behavioral tests were used to assess depression-like behaviors. The mice received Auraptene at 10, 30, and 100 mg/kg, the combination of the sub-effective (ineffective) dose of Auraptene (10 mg/kg) and L-NAME, and the combination of the effective dose of Auraptene (30 mg/kg) and L-arginine. Finally, OFT, TST, FST, brain, serum MDA level, antioxidant capacity, hippocampus, and serum NO level were measured. Results The data analysis showed that Auraptene (30 mg/kg) improved depression-like behaviors. Auraptene (30 mg/kg) also significantly reduced serum NO levels (P

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Maternal separation (MS) stress is an established model of early-life stress associated with autistic-like behaviors. Altered glutamatergic and nitrergic neurotransmissions may contribute to the pathophysiology of ASD. However, the specific mechanisms underlying these alterations and their relationship to MS-induced autistic-like behaviors remain unclear. Addressing this knowledge gap, this study aims to elucidate the involvement of the nitric oxide (NO)/ N-methyl-D-aspartate (NMDA) pathway in MS-induced autistic-like behaviors in mice. This knowledge has the potential to guide future research, potentially leading to the development of targeted interventions or treatments aimed at modulating the NO/NMDA pathway to ameliorate ASD symptoms. Ninety male Naval Medical Research Institute (NMRI) mice were assigned to six groups (n = 15) comprising a control group (treated with saline) and five groups subjected to MS and treated with saline, ketamine, NMDA, L-NAME, and L-arginine. Behavioral tests were conducted, including the three-chamber test, shuttle box, elevated plus-maze, and marble burying test. Gene expression of iNOS, nNOS, and NMDA-R subunits (NR2A and NR2B), along with nitrite levels, was evaluated in the hippocampus. The findings demonstrated that MS induced autistic-like behaviors, accompanied by increased gene expression of iNOS, nNOS, NR2B, NR2A, and elevated nitrite levels in the hippocampus. Modulation of the NO/NMDA pathway with activators and inhibitors altered the effects of MS. These results suggest that the NO/NMDA pathway plays a role in mediating the negative effects of MS and potentially contributes to the development of autistic-like behaviors in maternally separated mice.

Background and Aims: Anxiety is one of the symptoms of menopause, which is due to stopping of ovarian activity. The aim of this study was to investigate the effect of Foeniculum vulgare L. extract on anxiety-like behaviors in ovariectomized mice.Methods: Eighty female mice weighing 25-30 g and aged 6-8 weeks were divided into 10 groups of eight each, controls: the group without ovariectomy given distilled water, positive controls: the ovariectomized group receiving 40 µg/kg of estradiol valerate, the groups without ovariectomy given F. vulgare extract by gavage at 200, 500, and 750 mg/kg, the ovariectomized group given distilled water, the ovariectomized groups given F. vulgare extract at 200, 500, and 750 mg/kg, and the ovariectomized group given diazepam at 1 mg/kg. Elevated plus maze (EPM) and open field were used to investigate anxiety in mice. The level of malondialdehyde (MDA) and total antioxidant capacity (TAC) of the brain and serum were also measured. Results: In ovariectomized mice, the number of entries to the closed arms of EPM was significantly increased compared with control group (P

Background and aims: Pain is a human societies problems that has always had a lot of attention to control. However, some patients became resistance to analgesic effect of common analgesics. A main goal of the researches on the field of pain is to find effective medications with less side effects. In this regards, natural derivatives of medicinal plants are under considering of researchers. It has been determined that oxidative stress involved in the pathophysiology of pain. The aim of this study is to investigate the analgesic effect of quinic acid considering its possible antioxidative effects in male mice.Methods: In this experimental study, 40 male mice were divided into 4 groups (N=10) received normal saline (1 ml/kg), dexamethasone (5 mg/ kg), quinic acid (QA) (10 mg/kg) and QA (50 mg/kg) for 7 constant days via intraperitoneal route. Then, the pain response was assessed using hot plate test. Finally, mice were euthanized and hippocampi dissected out. The levels of malondialdehyde (MDA), nitrite as well as antioxidant capacity were measure in the hippocampus.Results: The results showed that QA significantly increased the duration of delay in pain response to heat. Furthermore, QA significantly increased the antioxidant capacity as well as decreased the levels of MDA and nitrite in the hippocampus.Conclusion: we concluded that QA, partially at least, through mitigation of oxidative stress (increased the antioxidant capacity as well as decreased the levels of MDA and nitrite) exerts analgesic effect in the hot plate test in male mice.

Background and purpose: Stachys pilifera is used in traditional medicine due to its antioxidant, anti-inflammatory, and antimicrobial effects. The goal of this study was to examine the renoprotective activity of the hydroalcoholic extract of aerial parts of S. pilifera on paracetamol (PCM)-induced nephrotoxicity. Experimental approach: The Wistar female rats were randomly divided into four groups including control, PCM, S. pilifera hydroalcoholic extract (SPE), and PCM + SPE. The animals received SPE (500 mg/kg) for one week and PCM (3 g/kg) on the 6th day orally. Kidney function tests and oxidant/antioxidant markers were determined in serum and tissue homogenate, respectively. Protein and mRNA levels of TNF-α, as well as hematoxylin and eosin staining, were assessed in the kidney tissue. Findings/Results: Treatment with SPE in the PCM group significantly decreased blood urea nitrogen and creatinine against the merely PCM rats (P < 0.05). The amount of nitric oxide metabolite and superoxide dismutase activity in the group receiving SPE showed a significant increase compared to PCM rats (P < 0.05). A significant difference in TNF-α levels between the groups was not observed. Histological changes were improved in the rats treated with SPE. Conclusion and implications: Totally, our findings showed that SPE can inhibit PCM nephrotoxicity by enhancing kidney function markers, antioxidant status, and histological changes. Though, more researches are required to estimate the possible mechanism of SPE.

Much attention has been recently given to the effect of diet compounds on physical and mental health. Gallic acid is a phenolic compound with antioxidant activity. This compound is widely presented in black tea leaves, green tea, apples, grapes, strawberries, and pineapples. During the past years, it has been reported that gallic acid is effective against nervous system’s disorders including Alzheimer’s disease, Parkinson’s disease, ischemia, and reperfusion, depression and anxiety. These indicate that gallic acid can be considered as a valuable agent for nutraceutical interventions. In this study, several clinical studies suggested that gallic acid can improve human health by preventing or delaying the onset of neurological diseases. The present study indicated the neuroprotective features of gallic acid including the pre-clinical evidence for its effects in AD and PD and other diseases related to the nervous system. Significant efforts are required to confirm the neuroprotective effects of gallic acid in treating the diseases related to the nervous system.

Context Experiencing early-life adversity plays a key role in the development of mood disorders in adulthood. Experiencing adversities during early life period negatively affects brain development. Sex steroids such as progesterone affect the brain structure and functions and subsequently affects behaviour. Objective We assess the antidepressant-like effect of progesterone in a mouse model of maternal separation (MS) stress, focussing on its anti-neuroinflammatory and antioxidative effects. Materials and methods NMRI mice were treated with progesterone (10, 50, and 100 mg/kg, i.p., respectively) for 14 days. Valid behavioural tests including forced swimming test (FST), splash test and open field test (OFT) were used. Quantitative reverse transcription-PCR (qRT-PCR) was used for evaluation of genetic expression in the hippocampus. Antioxidant capacity was assessed by the FRAP method and the level of malondialdehide by TBA. Results MS provoked depressive-like behaviour in mice. Treatment of MS mice with progesterone increased the grooming activity time in the splash test and decreased the immobility time in the FST. In addition, progesterone decreased the expression of inflammatory genes related to neuroinflammation (IL-1β, TNF-α, TLR4 and NLRP3) as well as increased the antioxidant capacity and decreased the lipid peroxidation (MDA) in the hippocampus. Discussion and Conclusion Administration of progesterone significantly mitigated the negative effects of MS on behaviours relevant to depressive-like behaviour as well as attenuated neuro-immune response and oxidative stress in the hippocampus of MS mice. In this context, we conclude that progesterone, at least partially, via attenuation of oxidative stress and neuroinflammation, exerts antidepressant-like effects.

Numerous studies have implicated oxidative stress in the development of complications of diabetes. During hyperglycemia, production of oxidant agents such as reactive oxygen species and reactive nitrogen species increases. This process, along with a decrease in the activity of antioxidant enzymes, induces oxidative stress in the body. This redox imbalance causes damage to vital biomolecules such as proteins, lipids and DNA and results in the generation of harmful products for the body. Mechanisms associated with the creation of oxidative stress conditions and subsequently complications of diabetes are explained through several pathways such as flux through the polyol pathway, intracellular production of advanced glycation end products precursors, protein kinase-C activation, and increased activities of the hexosamine pathway. On the other hand, the study of polymorphism in the antioxidant enzymes genes indicates that some of the gene polymorphisms reduce the antioxidant power of the enzymes. This article aims to review various studies to demonstrate the effect of oxidative stress on the pathogenesis of diabetes and the positive role of antioxidants on diabetic complications.

Background and Aim. Epilepsy is the most common neurological disorder after stroke. Ellagic acid (EA) has been shown to possess neuroprotective effects. The N-methyl-D-aspartate receptor (NMDA-R) is involved in the pathophysiology of seizure. We aimed to evaluate the possible involvement of NMDA-R in the anticonvulsant effect of EA in pentylenetetrazole- (PTZ-) induced seizures in male mice. Methods. In this experimental study, 64 mice were divided into 8 groups and received the following: normal saline; EA at doses of 6.25, 12.5, and 25 mg/kg; NMDA agonist at a dose of 75 mg/kg; NMDA antagonist (ketamine) at a dose of 0.5 mg/kg; an effective dose of EA plus NMDA agonist; and a subeffective dose of EA plus ketamine. We induced seizure using intravenous administration of PTZ. 60 minutes before induction of seizure, drugs were administrated. Duration lasts to seizure-induced was measured. Finally, the gene expression of NMDA receptor subunits (Nr2a and Nr2b) was assessed in the prefrontal cortex. Results. Results showed that EA increased the seizure threshold and decreased the expression of Nr2a and Nr2b. We determined that ketamine potentiated and NMDA attenuated the effects of subeffective and effective doses of EA. Conclusion. EA probably via attenuation of the NMDA-R pathway possesses an anticonvulsant effect in PTZ-induced seizure in mice.

The aim of present study is to investigate pretreatment with hydroalcoholic extract of Alpinia officinarum rhizome on the severity of epilepsy and memory impairment in rat. In this experimental study, rats were randomly assigned to seven groups. Control group and negative control group were intraperitoneally injected with normal saline and PTZ, respectively, for 10 days. The intervention groups received A. officinarum extract at different doses (50, 100 and 150 mg/kg) 30 minutes before PTZ injection. A. officinarum extract treatment in rats with PTZ-induced kindling exerted significant increase in seizure latency and significant decrease in the frequency of total body seizure, frequent spinning, and jumping. Flumazenil significantly inhibited the antiepileptic effects of A. officinarum extract in the rat receiving the extract at 150 mg/kg. A. officinarum extract can inhibit PTZ-induced seizure and memory impairment, and therefore can be considered as a potent agent which warranted further research to clarify its effects.

Context: Diclofenac (DIC) is known for its anti-inflammatory and analgesic properties but liver toxicity is one of the main targets to use this drug. Previous studies have demonstrated that quercetin may decrease the toxicity of synthetic drugs. Aim: To assess the protective effect of quercetin against DIC-induced liver toxicity in rats. Methods: The rats exposed to DIC (50 mg/kg; i.p.) were treated with different doses of quercetin (20, 40 and 80 mg/kg). The levels of glutathione peroxidase (GPx), superoxide dismutase (SOD), intracellular glutathione (GSH) and catalase (CAT) in the liver tissue were assessed. Results: Results indicated a significant decline in above-mentioned factors in DIC-alone treated group compared to the control group. Also, levels of the triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), total bilirubin, alkaline phosphatase (ALP), nitrite content, alanine aminotransferase (ALT), malondialdehyde (MDA), serum tumor necrosis factor-α (TNF-α), serum interleukin-1β (IL-1β), aspartate aminotransferase (AST), and inflammatory cytokines were evaluated and results indicted remarkable elevation in these factors in DIC-alone treated group compared to the control group. Treatment with quercetin caused a significant elevation in GPx, SOD, GSH, CAT and a significant reduction in levels of TG, TC, LDL-C, VLDL-C, total bilirubin, ALP, nitrite content, ALT, MDA, serum TNF-α, serum IL-1β, AST and inflammatory cytokines in DIC-alone treated group compared to the control group (p

Social isolation stress (SIS) as a type of chronic stress could induce depressive- and anxiety-like behaviors. Our study evaluates the role of opioid system on negative behavioral impacts of SIS in male NMRI mice. We investigated effects of morphine, a nonselective opioid receptor (OR) agonist, naltrexone (NLX), an OR antagonist, naltrindole (NLT), a delta opioid receptor (DOR) antagonist, SNC80, a DOR agonist, U-69593, a kappa opioid receptor (KOR) agonist, nor-Binaltorphimine, a selective KOR antagonist and cyprodime hydrochloride a selective mu opioid receptor (MOR) antagonist on depressive- and anxiety-like behaviors. Using RT-PCR we evaluated ORs gene expression in mice brain. Our findings showed that SIS induced anxiety- and depressive-like behavior in the forced swimming test, open field test, splash test and hole-board test. Moreover, administration of SNC-80 significantly mitigated anxiety- and depressive-like behaviors. NLT decreased grooming-activity in the splash test. Excitingly, administration of agents affecting KOR failed to alter the negative effects of SIS. RT-PCR demonstrated that MOR and KOR gene expression decreased in socially isolated mice; however, SIS did not affect DORs expression. Our findings suggest that SIS at least in part, probably via altering endogenous opioids particularly MORs and KORs but not DORs mediated negative impacts on behavior; also, it could be concluded that DORs might be considered as a novel target for studying depression and anxiety.

Context: Parkinson’s disease (PD) is a neurodegenerative disorder due to gradual loss of dopaminergic nerves in the substantia nigra (SN) in the midbrain. PD leads to certain motor disorders including resting tremor, muscle stiffness and slow movement. Medicinal plants have shown positive pharmacological effects in treating different models of PD. Objective: Tendency to use natural products, especially plants, for the treatment of PD has been growing. This article reviews the basic aspects of medicinal plants and their bioactive compounds that could be used to treat PD. Methods: Reliable articles indexed in databases ISI, SID, PubMed, PubMed Central, Scopus and Web of Science were used. A total of 12 plant-derived active ingredients and 18 herbal extracts were included. Different compounds have so far been isolated from plants that affect PD especially by targeting pathways associated with the pathogenesis of the disease. Results: Although some herbal extracts such as Hibiscus asper Hook. f. (Malvaceae), Ginkgo biloba L. (Ginkgoaceae), Carthamus tinctorius L (Asteraceae) and certain active ingredients, such as berberine and curcumin, have shown positive effects in animal models of PD, potential active ingredients and mechanisms of action should be investigated in additional studies. Discussion and conclusions: Despite the wide variety of plants in the world, a limited number of them have been studied for anti-Parkinsonian activity, and therefore, there are numerous perspectives in this field for future studies on plants and their bioactive compounds.

Background and Aim. Depression is a social problem with high economic burden in the society. Finding an effective agent with high efficacy and few side effects is therefore needed. Involvement of neuroimmune response as well as nitric oxide (NO) has been determined in the pathophysiology of depression. Limonene is a terpene with various pharmacological properties. Thus, we aimed to evaluate antidepressant-like effect of limonene on a mouse model of maternal separation (MS) focusing on neuroinflammation and NO level in the hippocampus. Methods. Mice were randomly divided into experimental groups as follows: the control group received normal saline and MS groups received normal saline, limonene (10 and 20 mg/kg), L-NAME (10 mg/kg), L-arginine (L-arg) (75 mg/kg), limonene (10 mg/kg) plus L-NAME, and limonene (20 mg/kg) plus L-arg. Behavioral tests including the forced swimming test (FST), open field test (OFT), and splash test were performed. Finally, serum and hippocampal nitrite levels as well as the expression of inflammatory genes (IL-1β and TNF-α) in the hippocampus were measured. Results. We showed that MS caused depressive-like behavior. Treatment of MS mice with limonene reduced the duration of immobility time in FST and increases the grooming activity time in the splash test. Limonene also reduces serum and brain nitrite levels and reduces the expression of IL-1β and TNF-α in the hippocampus. We found that L-NAME potentiated the effects of a subeffective dose of limonene. Conclusion. We concluded that the antidepressant-like effects of limonene are probably mediated through inhibition of neuroinflammation and attenuation of nitrite levels in the hippocampus.

The adenylyl cyclase (AC) pathway is involved in the pathophysiology of depression. Finding new antidepressants with high medicinal properties and low side effects is warranted. Therefore, this study was designed to determine the antidepressant-like effect of tropisetron on a maternal separation (MS) model in mice, considering the possible role of AC. NMRI male mice were divided into eleven groups. The control group was treated with saline and MS groups were treated with saline, tropisetron (a 5-HT3 receptor antagonist) at doses of 1, 3, and 5 mg/kg; forskolin (an activator of AC) at doses of 5, 10, and 25 mg/kg; a subeffective dose of forskolin with a subeffective dose of tropisetron; and an effective dose of tropisetron plus an effective dose of NB001 (3 mg/kg) (an AC inhibitor). After treatment, animals were subjected to behavioral tests including the forced swimming test (FST), splash test, and open field test (OFT). We showed that MS caused depressive-like behaviors determined as an increase in the immobility time in the forced swimming test (FST) and decreased grooming time in the splash test. Our results showed that administration of tropisetron, as well as forskolin, mitigated the depressive-like behaviors in MS mice. We found that coadministration of a subeffective dose of tropisetron plus a subeffective dose of forskolin potentiated the antidepressant-like effect of tropisetron. However, coadministration of an effective dose of NB001 with an effective dose of tropisetron did not significantly affect the antidepressant-like effect of tropisetron. We concluded that the antidepressant-like effects of tropisetron on MS mice are partially mediated through the adenylyl cyclase pathway.

Background and aim: Anxiety disorders are one of the most common psychiatric disorders worldwide. Common anti-anxiety medications are associated with several side effects. Caffeic acid (CA) is a phenolic compound with several pharmacological effects. The aim of this study was to investigate the anxiolytic-like effect of CA in maternally separated (MS) mice focusing on the possible involvement of the NMDA receptor. Materials and methods: In this study, we used the MS paradigm (as a valid animal model of anxiety) in male mice and examined their anxiety-like behavior in postnatal day (PND) 45. The animals were divided into 12 experimental groups. Mice treated with CA alone and in combination with the NMDA receptor agonist/antagonist and then using open field (OFT) and elevated plus maze (EPM) anxiety-like behavior was assessed. Finally, the expression of NMDA receptor subtypes was assessed in the hippocampus using RT- PCR. Results: Finding showed that CA exerted anxiolytic –like effects in the OFT and EPM tests. We showed that administration of effective dose of NMDA significantly reversed the anxiolytic-like effect of effective dose of CA and co-administration of ketamine (a NMDA receptor antagonist) significantly potentiated the effect of sub-effective dose of CA. Furthermore, ketamine enhanced the CA-reducing effect on NMDA receptors in the MS mice. Conclusion: Our finding demonstrated that, probably at least, NMDA receptors are involved in the anxiety-like properties of CA in MS mice.

There is little information available about the effects of early-life parental stress on the reproductive potential of the next generation. The aim of this study is to examine the reproductive potential of male mice whose parents experienced maternal separation stress. In the present study, male first-generation offspring from parents were undergone of maternal separation (MS) were examined. Sperm characteristics, histological changes in testis, reactive oxygen species (ROS) production, expression of apoptotic and inflammatory genes and proteins were assessed. Findings showed that MS experienced by parents significantly decreased the morphology and viability of spermatozoa. Furthermore, significant changes in testicular tissue histology were observed. Increased production of ROS, decreased glutathione peroxidase (GPX) and adenosine triphosphate (ATP) concentrations, and affected the expression of genes and cytokines involved in inflammation. Finally, the mean percentage of caspase-1 and NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) positive cells was significantly higher in first-generation group. MS experienced by parents may negatively affect the reproduction of first generation offspring.

Spermatogenesis is a complicated process in which sperm is susceptible to various chemotherapy drugs such as cyclophosphamide (CP). As olive leaf extract (OLE) and its active ingredient, oleuropein, have variousantioxidant, anti-apoptotic, and anti-inflammatory properties the aim of the present study was to investigate the effects of OLE and oleuropein on male reproductive function focusing antioxidative effects and histological modifications in the testes of CP-exposed mice.In order to do this, 80 NMRI male mice were divided into eight groups including control group, group received CP, group received OLE, group received oleuropein, group received OLE following CP exposure, group received oleuropein following CP exposure, group received OLE plus oleuropein and group received OLE plus oleuropein following CP exposure. In all groups CP (single dose of 100 mg/kg (, OLE (100 mg/kg for consequence 28 days) and oleuropein (100 mg/kg for consequence 28 days) were injected intraperitoneally. Moreover, testis histology, sperm parameters and serum levels of LH, FSH, MDA and antioxidant capacity were investigated. Results showed that CP caused oxidative state and abnormal changes in sperms and testes. Besides, treatments with oleuropein and OLE led to mitigate the harmful effects of CP on the male reproductive system. In conclusion, our findings showed that olive's compounds can diminish the hazardous effects of CP on spermatogenesis in mice.

Background and Aim. Rutin is a flavonol with neuroprotective activity. The aim of the present study is to investigate the role of the glutamatergic system in the antidepressant-like effect of rutin in a mouse model of maternal separation (MS) stress focusing on histological changes in the CA3 area of the hippocampus. Methods. Mouse neonates were exposed to MS paradigm 3 hours daily from postnatal days (PND) 2 to 14. The control and MS mice were divided separately into 16 groups (n=8) (8 groups for each set) including mice that received normal saline, mice that received rutin at doses of 10, 50, and 100 mg/kg, mice that received NMDA at a dose of 150 mg/kg, mice that received ketamine (NMDA antagonist) at a dose of 0.25 mg/kg, mice that received NMDA antagonist plus a subeffective dose of rutin, and mice that received NMDA plus an effective dose of rutin. Forced swimming test (FST) was performed. Afterwards, the hippocampus was evaluated in cases of histopathological changes as well as expression of NR2A and NR2B genes. Results. Rutin significantly reduced immobility time in the FST. The expression of NR2A and NR2B subunits of NMDA receptor in MS mice was significantly higher than that in the control group. Rutin significantly decreased the expression of NR2B and NR2A subunits in the hippocampus. The CA3 diameter and percentage of dark neurons in the hippocampus of MS mice significantly decreased and increased, respectively, which partially reversed following rutin administration. Conclusion. Rutin, partially, through a neuroprotective effect on the hippocampus exerted antidepressant-like effect. We concluded that NMDA receptors, at least in part, mediated the beneficial effect of rutin.

Introduction: According to studies, statins possess analgesics and anti-inflammatory properties. In the present study, we examined the antinociceptive, anti-inflammatory and antioxidative effects of rosuvastatin in an experimental model of Chronic Constriction Injury (CCI). Methods: Our study was conducted on four groups; sham, CCI (the control group), CCI+rosuvastatin (i.p. 5 mg/kg), and CCI+rosuvastatin (i.p. 10 mg/kg). We performed heat hyperalgesia, cold and mechanical allodynia tests on the 3rd, 7th, 14th, and 21st after inducing CCI. Blood samples were collected to measure the serum levels of Tumor Necrosis Factor (TNF)-α, and Interleukin (IL)-6. Rats spinal cords were also examined to measure tissue concentration of Malondialdehyde (MDA), Superoxide Dismutase (SOD), and Glutathione Peroxidase (GPx) enzymes. Results: Our findings showed that CCI resulted in significant increase in heat hyperalgesia, cold and mechanical allodynia on the 7th, 14th and 21st day. Rosuvastatin use attenuated the CCI-induced hyperalgesia and allodynia. Rosuvastatin use also resulted in reduction of TNF-α, IL-6, and MDA levels. However, rosuvastatin therapy increased the concentration of SOD and GPx in the CCI+Ros (5 mg/kg) and the CCI+Ros (10 mg/kg) groups compared to the CCI group. Conclusion: Rosuvastatin attenuated the CCI-induced neuropathic pain and inflammation. Thus, antinociceptive effects of rosuvastatin might be channeled through inhibition of inflammatory biomarkers and antioxidant properties.

Background: Nephropathy is the main problem of diabetes and can be classified into several phases according to the presence of albuminuria. Adenosine monophosphate-activated protein kinase (AMPK) operates as a sensor of energy charge. Objectives: The aim of our study was to evaluate the reno-protective properties of AMPK signaling pathway against streptozotocin (STZ)-induced nephropathy in the rat. Materials and Methods: Forty male Wistar rats were randomly distributed into four groups. Group 1 was normal rats (N group); group 2 was diabetic rats (D group); group 3 received diabetic rats + metformin (DM group), and group 4 received giabetic rats + metformin + dorsomorphin (DMD group). Serum albumin, uric acid, total protein and creatinine for estimation of renal injury were measured. Finally, the histological study was evaluated. Results: Reduction of body weight, albumin and total protein in the diabetic rat was reversed by metformin administration. Our results showed that serum uric acid and creatinine were significantly increased in diabetic rats and decreased after treatment with metformin in diabetic rats. AMPK improved the histopathology and morphological changes in STZinduced diabetic rats. Administration of dorsomorphin (AMPK inhibitor) with metformin can reverse the beneficial effects of AMPK. Conclusions: AMPK signaling pathway ameliorates diabetic nephropathy by modifications of serum albumin, uric acid, total protein, creatinine and attenuation of kidney damage.

Human societies have been in close contact with their environments since the beginning of their formation and used the ingredients of the environment to obtain food and medicine. Awareness and application of plants to prepare food and medicine have been realized through trial and error, and gradually human became able to meet his needs from his surroundings. Information about medicinal plants has long been transmitted gradually and from generation to generation, a human knowledge has gradually become complete with the formation of civilizations and the provision of more facilities. Medicinal plants are used as a medical resource in almost all cultures. Ensuring the safety, quality and effectiveness of medicinal plants and herbal drugs very recently became a key issue in industrialized and developing countries. By standardizing and evaluating the health of active plant-derived compounds, herbal drugs can help the emergence of a new era of the healthcare system to treat human diseases in the future. Awareness of traditional knowledge and medicinal plants can play a key role in the exploitation and discovery of natural plant resources. In order to maintain this knowledge, comprehensive approach and collaboration are needed to maintain historical records on medicinal plants and use these resources in favour of human beings, before they are destroyed forever. Therefore, this review was conducted to investigate and describe the process of using medicinal plants throughout history. This review focuses on the recent various important challenges in quality evaluation of medicinal plants in the authenticity, efficacy, toxicity and consistency.