Effect of Hydroalcoholic Extract of Stachys lavandulifolia on Pentylenetetrazole-induced Seizures in Male Mice: The Role of GABAergic and Opioidergic Systems.

Introduction: Epilepsy is one of the most common neurological disorders. Though there are several effective drugs for treating epilepsy, most drugs are associated with side effects and drug interactions. Stachys lavandulifolia used in Iranian traditional medicine has proven anti-anxiety and sedative properties. The current study aimed to evaluate the anticonvulsant effect of hydroalcoholic extract of S. lavandulifoliaon the Pentylenetetrazole (PTZ)-induced seizure in male mice and the role of benzodiazepine and opioid receptors. Methods: This study was conducted on 100 male mice, randomly categorized into 10 groups: Normal Saline (NS), two diazepam groups (0.025 and 0.1 mg/kg), three S. lavandulifolia extract groups (50, 100, and 200 mg/kg), diazepam 0.025 mg/kg+S. lavandulifolia extract 50 mg/kg, and three groups that pretreated with NS, flumazenil, or naloxone, 5 min before injection of 200 mg/kg S. lavandulifolia extract. After 30 min, PTZ (80 mg/kg) was injected into animals, and seizure indices were evaluated. Results: The S. lavandulifoliaextract attenuated the PTZ-induced seizures in a dose-dependent manner, and pretreatment with flumazenil reversed this effect. However, pretreatment with naloxone could not reverse this effect because seizure indices in the naloxone pretreated group were lower than that in the normal saline group. The combination of an ineffective dose of diazepam and S. lavandulifoliaextract decreased PTZ-induced seizures. Conclusion: The results of our study showed the anticonvulsant properties of hydroalcoholic extract of S. lavandulifolia. These effects might be due to the impact of the components of this extract on the central benzodiazepine system. Highlights: Hydroalcoholic extract of S. lavandulifolia attenuated the PTZ-induced seizures in a dose dependent manner.Pretreatment with flumazenil (blocker of benzodiazepines receptor) reversed anti-seizure effect of S. lavandulifolia extract.Combination of an ineffective dose of diazepam and S. lavandulifolia extract decreased PTZ-induced seizures. Plain Language Summary: Epilepsy is one of the most common neurological disorders after stroke and is characterized by recurrent seizures due to abnormal excessive neural activity in the brain. Although there are many anticonvulsant drugs on the market, not all patients with epilepsy can be treated and one-third of patients suffer from recurring epilepsy despite using different antiepileptic drugs and more than 50% of them show side effects drugs during treatment. So, it is necessary to conduct further studies to develop more effective anti-epilepsy drugs with the minimum side effects. In recent years, plenty of studies have been conducted on medical plants, and S. lavandulifolia reported among the Iranian traditional medicine with antianxiety and sedative features. Some studies have mentioned the sedative and anti-inflammatory function of S. lavandulifolia, and its significant effects on anxiety have been approved comparable to diazepam. Overall, considering the anti-anxiety, analgesic, and sedative effects of the hydroalcoholic extract of S. lavandulifolia, it might possess anti-convulsive effects, too. The purpose of the current study was designed to investigate whether the effect of intra peritoneal injection of hydroalcoholic extract of S. lavandulifolia on the PTZ-induced convulsion in male mice and assessed the role of benzodiazepine and opioid receptors. Results of this study demonstrated that S. lavandulifolia extract attenuated the PTZ-induced seizures in a dose dependent manner, and pretreatment with flumazenil (blocker of benzodiazepines receptor) reversed this effect. However, pretreatment with naloxone (Non-selective blocker of opioids receptor) could not reverse this effect but the combination of an ineffective dose of diazepam and S. lavandulifolia extract decreased PTZ-induced seizures, thus anti-epileptic effect of S. lavandulifolia mediated by benzodiazepine receptors.

The role of medicinal products in the treatment of inflammatory bowel diseases (IBD) through inhibition of TLR4/NF-kappaB pathway.

Inflammatory bowel disease (IBD) is a lifelong and recurrent disease of the gastrointestinal tract that afflicts many people in the world. Growing evidence has currently indicated that dysfunction of immune system, particularly toll-like receptors 4 (TLR4) signaling pathway dysfunction plays a pivotal part in the pathogenesis of IBD. TLR4 signaling is involved both in the pathogenesis and in the efficacy of treatment of IBD. There are some medicinal products and herbal medicines, which their role in the treatment of IBD through modulation of TLR4 signaling has been implicated. The purpose of this review article is to summarize those medicinal products and herbal medicines.

Effect of vitamin D supplementation on CREB-TrkB-BDNF pathway in the hippocampus of diabetic rats.

OBJECTIVES: Cyclic AMP (adenosine monophosphate) response element-binding protein (CREB) and Brain-derived neurotrophic factor (BDNF) are reported to broadly involve in learning capacity and memory. BDNF exerts its functions via tropomyosin receptor kinase B (TrkB). BDNF transcription is regulated by stimulating CREB phosphorylation. The CREB-TrkB-BDNF pathway is reported to be affected by diabetes, which may contribute to its cognitive deficits. This study was conducted to investigate the effect of vitamin D supplementation on the hippocampal fraction of this pathway in an animal model of type-1 diabetes mellitus (T1DM). MATERIALS AND METHODS: Thirty-six adult male Sprague-Dawley rats were randomly divided into 4 groups as follows: Group 1: normal healthy rats (n=8); group 2: normal healthy rats receiving sesame oil supplementation as placebo (n=8); Group 3: diabetic rats receiving sesame oil (n=10); and Group 4: diabetic rats treated with 4300 IU/kg/week vitamin D dissolved in sesame oil (n=10). Diabetes was induced by intraperitoneal (IP) injection of streptozotocin. Blood and hippocampal samples were acquired at the end of the experiment. RNA was extracted from the hippocampus, and real-time PCR (polymerase chain reaction) was performed for BDNF and TrkB gene expression. RESULTS: Administration of vitamin D (4300 IU/kg/week) in a T1DM animal model increased CREB phosphorylation in the hippocampus, but the serum and hippocampal BDNF levels and TrkB and BDNF gene expression did not change significantly. CONCLUSION: Vitamin D increased hippocampal CREB phosphorylation in a T1DM animal model. Our findings showed that vitamin D might be protective against central nervous system complications in diabetes. However, future studies are warranted.

Novel effect of Arthrocen (avocado/soy unsaponifiables) on pentylenetetrazole-induced seizure threshold in mice: Role of GABAergic pathway.

Arthrocen, an avocado/soy unsaponifiable (ASU)-containing agent, is now used in the clinic and has potentially to decrease joint inflammation and pain associated with mild to severe osteoarthritis. Phytosterols are the major component of Arthrocen with documented anti-inflammatory properties, antioxidant, and analgesic effects. Here, we evaluated ASU anticonvulsant effect by its oral administration in pentylenetetrazole (PTZ)-induced seizure threshold and Maximal Electroshock Seizure (MES) Models. Also, the involvement of N-methyl-d-aspartate (NMDA) receptor, benzodiazepine receptor, and nitric oxide (NO) pathway were studied in anticonvulsant effect of ASU in male NMRI mice. Acute administration of Arthrocen (150, 75, 30, 10 mg/kg) by oral gavage significantly (p < 0.001) increased the clonic seizure threshold induced by intravenous administration of PTZ. Nonspecific inducible NO synthase (NOS) inhibitor L-NAME (10 mg/kg) and a specific NMDA receptor antagonist MK-801 (0.05 mg/kg) did not affect the anticonvulsant effect of Arthrocen, while pretreatment with flumazenil (0.25 mg/kg), a selective benzodiazepine receptor antagonist, reversed this effect (p < 0.01). Also, Arthrocen treated mice did not affect tonic hindlimb extension in the MES model. The data showed that Arthrocen might produce its anticonvulsant effect by enhancing GABAergic neurotransmission and/or action in the brain.

The Effect of Vitamin D Supplementation on Serum and Muscle Irisin Levels, and FNDC5 Expression in Diabetic Rats.

BACKGROUND: Diabetes mellitus and metabolic disorders are a major burden on the healthcare system. Irisin is a novel myokine reported to have beneficial effects on glucose and lipid metabolism. Vitamin D deficiency has been implicated in the development of diabetes and hold a critical role in diabetes-related complications. In the present study, we examined the efficacy of vitamin D supplementation on serum irisin levels, skeletal muscle irisin levels, and the expression of the irisin precursor, FNDC5 (fibronectin-type III domain-containing 5) in type I diabetes mellitus rats. METHODS: Thirty-six adult male Sprague-Dawley rats (150 - 250 g) were randomly divided into four groups: group I: healthy control rats with no treatment (n=8), group II: healthy control rats receiving sesame oil as a placebo (n=8), group III: diabetic rats receiving sesame oil as placebo (n=10), group IV: diabetic rats treated with 4300 IU/kg/week vitamin D (n=10). Diabetes was induced by intraperitoneal (IP) injection of streptozotocin. At the end of the vitamin D intervention blood and triceps muscle samples were collected. RNA was extracted from muscle and real-time PCR was performed to examine FNDC5 gene expression. RESULTS: Our study showed that the administration of vitamin D (4300 IU/kg/week) in a streptozotocin-diabetic rat model resulted in increased serum vitamin D levels, FNDC5 gene expression and muscle irisin levels. However, the levels of serum irisin were not significantly changed by the administration of vitamin D. CONCLUSION: In conclusion, we show that vitamin D supplementation enhances serum vitamin D levels, FDNC5 gene expression and muscle irisin levels in the streptozotocin-diabetic rat model. Our study highlights the potential therapeutic effect of vitamin D supplementation for diabetes mellitus.

Foeniculum vulgare essential oil ameliorates acetic acid-induced colitis in rats through the inhibition of NF-kB pathway.

AIM: The aim of the present study is to investigate the protective effects of Foeniculum vulgare essential oil on intestinal inflammation through the inhibition of NF-kB pathway in acetic acid-induced rat colitis. METHODS: Acute colitis was induced by intra-rectal administration of 2 mL of diluted acetic acid (4%) solution. Two hours after the induction of colitis, 0.2% tween 80 in normal saline, dexamethasone (2 mg/kg) and F. vulgare essential oil (100, 200, 400 mg/kg) were administered to the animals by oral gavage and continued for 5 consecutive days. Assessment of macroscopic and microscopic lesions was done. MPO activity was evaluated by biochemical method. Furthermore, TNF-α activity was detected by immunohistochemistry (IHC) and the expression level of p-NF-kB p65 protein was measured by western blot analysis. RESULTS: Dexamethasone and F. vulgare essential oil (200, 400 mg/kg) reduced the macroscopic and microscopic lesions compared to the acetic acid group (p < 0.01, p < 0.001). In addition, these agents decreased the activity of MPO (p < 0.01, p < 0.001) and the expression of TNF-α positive cells (p < 0.05, p < 0.01, p < 0.001) in the colon tissue compared to acetic acid group. Furthermore, they inhibited acetic acid-induced expression of p-NF-kB p65 protein (p < 0.05, p < 0.001). CONCLUSION: It is proposed that the anti-inflammatory activity of F. vulgare essential oil on acetic acid-induced colitis in rats may involve the inhibition of NF-kB pathway.

Involvement of NMDA receptors in the antidepressant-like effect of tramadol in the mouse forced swimming test.

Tramadol is an analgesic agent that is mainly used to treat moderate to severe pain. There is evidence that tramadol may have antidepressant property. However, the mechanisms underlying the antidepressant effects of tramadol have not been elucidated yet. Considering that fact that N-methyl-d-aspartate (NMDA) receptor signaling may play an important role in the pathophysiology of depression, the aim of the present study was to investigate the role of NMDA receptor signaling in the possible antidepressant-like effects of tramadol in the mouse forced swimming test (mFST). We found that tramadol exerted antidepressant-like effects at high dose (40mg/kg, intraperitoneally [i.p.]) in the mFST. Co-administration of non-effective doses of NMDA receptor antagonists (ketamine [1mg/kg, i.p.], MK-801 [0.05mg/kg, i.p.], or magnesium sulfate [10mg/kg, i.p.]) with sub-effective dose of tramadol (20mg/kg, i.p.) exerted significant antidepressant-like effects in the mFST. The antidepressant-like effects of tramadol (40mg/kg) was also inhibited by pre-treatment with non-effective dose of the NMDA receptor agonist NMDA (75mg/kg, i.p.). Our data suggest a role for NMDA receptor signaling in the antidepressant-like effects of tramadol in the mFST.

Evaluation of the Wound Healing Activity of a Traditional Compound Herbal Product Using Rat Excision Wound Model.

Iranian Traditional Medicine (ITM) manuscripts contain prescriptions that have long been used for healing of wounds. The present study evaluates the healing effect of a poly herbal paste (PHP), retrieved from ITM sources, containing Aloe vera, Commiphora myrrha and Boswellia carteri using rat excision wound model. Excision wounds were induced in six groups consisting of six rats each. Group 1 received no treatment, while groups 2 and 6 received tetracycline ointment, Alpha ointment, PHP 40%, PHP 10% and paste base every day, respectively. The percentage of wound contraction on days 2, 7, 14 and 21 and histopathology parameters of healed wounds on 14th and 21st days were evaluated. Moreover, antioxidant activity of PHP was evaluated using DPPH method. There was a significant improvement in wound healing in PHP 10% group on the 7th day of the treatment (p<0.05). Moreover, the healing effect of PHP 10% was significantly greater than the control, tetracycline and paste base groups on the 2nd, 14th and 21st days (p<0.05). On day 14, PHP 40% showed significant healing effect compared to the control, tetracycline and paste base groups (p<0.05). Fewer inflammatory cells were observed in PHP 10%-treated animals and this group demonstrated better re-epithelialization with remarkable neovascularization. Besides, the PHP 10% formulation exhibited antioxidant activity. In vivo and histopathologic examinations showed considerable wound healing in PHP 10% group. This finding could probably be due to the antioxidant, anti-inflammatory and antimicrobial activities of phytoconstituents of A. vera, B. carteri and C. myrrha.

A Wound Healing Formulation Based on Iranian Traditional Medicine and Its HPTLC Fingerprint.

Herbal therapy was the common treatment prescribed by Iranian physicians for wound healing. "Zemad" was the most ancient pharmaceutical dosage form used in Iranian Traditional Medicine (ITM) for skin diseases. In the present research, formulation of a traditionally used Poly Herbal Paste (PHP) for wound healing was performed. Moreover, the fingerprint of the product was prepared by HPTLC method for identification and quality assessment of the formulation. 3.33 % of each plant materials containing Aloe vera, Boswellia carteri and Commiphora myrrha were used in a hydrophilic base. The physical stability and rheological behavior of the formulation was evaluated. Moreover, microbiological tests was performed. Methanol fraction of A. vera, C. myrrha and B. carterri were used as standard materials in HPTLC method. Stability and rheological behavior evaluations as well as microbiological tests showed that the prepared formulation was stable towards physical changes with no growth of pathogenic microorganisms and suitable for topical application. HPTLC fingerprinting of PHP confirmed the presence of compounds corresponding to the plants used in the formula. Regarding to the antioxidant, anti-inflammatory and antimicrobial effects of the constituents of PHP, the product could be an appropriate candidate for wound healing with respect to its traditional use in ITM. In addition, HPTLC fingerprinting could be used as an applicable method for quality control assessment of the prepared formulation.

Therapeutic potential of cannabinoids in counteracting chemotherapy-induced adverse effects: an exploratory review.

Cannabinoids (the active constituents of Cannabis sativa) and their derivatives have got intense attention during recent years because of their extensive pharmacological properties. Cannabinoids first developed as successful agents for alleviating chemotherapy associated nausea and vomiting. Recent investigations revealed that cannabinoids have a wide range of therapeutic effects such as appetite stimulation, inhibition of nausea and emesis, suppression of chemotherapy or radiotherapy-associated bone loss, chemotherapy-induced nephrotoxicity and cardiotoxicity, pain relief, mood amelioration, and last but not the least relief from insomnia. In this exploratory review, we scrutinize the potential of cannabinoids to counteract chemotherapy-induced side effects. Moreover, some novel and yet important pharmacological aspects of cannabinoids such as antitumoral effects will be discussed.