Neuroprotective effects of Lasmiditan and Sumatriptan in an experimental model of post-stroke seizure in mice: Higher effects with concurrent opioid receptors or KATP channels inhibitors.

BACKGROUND: Early post-stroke seizure frequently occurs in stroke survivors within the first few days and is associated with poor functional outcomes. Therefore, efficient treatments of such complications with less adverse effects are pivotal. In this study, we investigated the possible beneficial effects of lasmiditan and sumatriptan against post-stroke seizures in mice and explored underlying mechanisms in their effects. METHODS: Stroke was induced by double ligation of the right common carotid artery in mice. Immediately after the ligation, lasmiditan (0.1 mg/kg, intraperitoneally [i.p.]) or sumatriptan (0.03 mg/kg, i.p.) were administered. Twenty-four hours after the stroke induction, seizure susceptibility was evaluated using the pentylenetetrazole (PTZ)-induced clonic seizure model. In separate experiments, naltrexone (a non-specific opioid receptor antagonist) and glibenclamide (a KATP channel blocker) were administered 15 min before lasmiditan or sumatriptan injection. To evaluate the underlying signaling pathways, ELISA analysis of inflammatory cytokines (TNF-α and IL-1ß) and western blot analysis of anti- and pro-apoptotic markers (Bcl-2 and Bax) were performed on mice isolated brain tissues. RESULTS: Lasmiditan (0.1 mg/kg, i.p.) and sumatriptan (0.03 mg/kg, i.p.) remarkably decreased seizure susceptibility in stroke animals by reducing inflammatory cytokines and neuronal apoptosis. Concurrent administration of naltrexone (10 mg/kg, i.p.) or glibenclamide (0.3 mg/kg, i.p.) with lasmiditan or sumatriptan resulted in a higher neuroprotection against clonic seizures and efficiently reduced the inflammatory and apoptotic markers. CONCLUSION: Lasmiditan and sumatriptan significantly increased post-stroke seizure thresholds in mice by suppressing inflammatory cytokines and neuronal apoptosis. Lasmiditan and sumatriptan seem to exert higher effects on seizure threshold with concurrent administration of the opioid receptors or KATP channels modulators.

Montelukast suppresses the development of irritable bowel syndrome phenotype possibly through modulating NF-κB signaling in an experimental model.

Irritable bowel syndrome (IBS) is a functional gut disorder with multi-factorial pathophysiology that causes recurring pain or discomfort in the abdomen, as well as altered bowel habits. Montelukast, a well-known cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is widely used for the anti-inflammatory management of asthma. The present study aimed to evaluate the effects of pharmacological inhibition of CysLT1R on acetic acid-induced diarrhea-predominant IBS (D-IBS) in rats. Behavioral pain responses to noxious mechanical stimulation were decreased in the montelukast-treated rats as compared to the model animals following colorectal distension (CRD)-induced visceral hypersensitivity. Stool frequency decreased dose-dependently by montelukast in IBS rats exposed to restraint stress. A significantly shorter immobility time was also observed in IBS rats who received montelukast vs IBS group in the forced swimming test (depression-like behavior). Furthermore, there were significant decreases in the NF-κB protein expression, inflammatory cytokine (TNF-α, and IL-1ß) levels, and histopathological inflammatory injuries concomitant with increased anti-inflammatory cytokine, IL-10, in montelukast-treated rats compared with the IBS group. Cysteinyl leukotriene production and CysLT1R mRNA expression showed no remarkable differences among the experimental groups. The present results suggest the possible beneficial effects of montelukast in the management of D-IBS symptoms. The molecular mechanism underlying such effects, at least to some extent, might be through modulating CysLT1R-mediated NF-κB signaling. Yet, more studies are required to demonstrate the clinical potential of this drug for IBS therapy.

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.

The renin-angiotensin system in cutaneous hypertrophic scar and keloid formation.

Hypertrophic scar and keloid are two types of fibroproliferative conditions that result from excessive extracellular matrix production. The underlying pathological mechanism is not entirely clear. Activation of the renin-angiotensin system (RAS) is associated with fibrosis in various organs. RAS components including angiotensin II (Ang II), angiotensin AT1 and AT2 receptors, and angiotensin-converting enzyme (ACE) are expressed in the skin and act independently from the plasma RAS. AT1 receptors, which are usually the dominating receptor subtype, promote fibrosis and scar formation, while AT2 receptors inhibit the aforementioned AT1 receptor-coupled effects. Elevated angiotensin II (Ang II) levels acting on the AT1 receptor contribute to skin scar formation through increased expression of inflammatory factors such as interleukin-6 (IL-6), angiogenic factors such as vascular endothelial growth factor (VEGF) and fibrinogenic factors such as transforming growth factor-ß1 (TGF-ß1) and connective tissue growth factor (CTGF), while at the same time suppressing the anti-fibrotic tissue inhibitors of matrix metalloproteinase (TIMPs). First, small clinical trials have provided evidence that inhibition of the ACE/Ang II/ AT1 receptor axis may be effective in the treatment of hypertrophic scars/keloids. This review provides a detailed overview of the current literature on the RAS in skin, wound healing and scar formation and discusses the translational potential of targeting this hormonal system for treatment and prevention of hypertrophic scars and keloids.

Protective Effects of Spermidine Against Cirrhotic Cardiomyopathy in Bile Duct-Ligated Rats.

Cirrhotic cardiomyopathy is a critical factor that causes morbidity and mortality in crucial conditions such as liver transplantation. In animal model, the common pathophysiologic mechanisms of cirrhotic cardiomyopathy are similar to those associated with bile duct ligation (BDL). Overproduction of inflammatory and oxidant markers plays a crucial role in cirrhotic cardiomyopathy. Spermidine, a multifunctional polyamine, is known for its antioxidant and anti-inflammatory effects. In this study, we investigated the effects of spermidine on development of cirrhotic cardiomyopathy in BDL rats. Rats were randomly housed in 6 groups. Except the normal and sham groups, BDL was performed for all the control and spermidine groups. Seven days after operation, 3 different doses of spermidine (5, 10 and 50 mg/kg) were administrated until day 28, in spermidine groups. At the end of the fourth week, the electrocardiography (ECG) and papillary muscle isolation were performed. The serum level of tumor necrosis factor-a (TNF-α), interleukin-1ß (IL-1ß), and IL-10 and cardiac level of superoxide dismutase, glutathione (GSH). and malondialdehyde (MDA) were assessed. Furthermore, the nuclear factor-κB (NF-κB) expression was assessed by western blot. Cardiac histopathological changes were monitored. The serum levels of magnesium (Mg) and potassium (K) were investigated. Control group, exhibited exaggerated signs of cirrhotic cardiomyopathy in comparison with the sham group. Co-administration of spermidine at the dose of 10 mg/kg in BDL rats significantly improved the cardiac condition, reduced the inflammatory mediators, and increased antioxidant enzymes. In addition, the histopathologic findings were in accordance with the other results of the study. Besides, there was no significant alteration in serum levels of Mg and K. This study demonstrates that spermidine at the dose of 10 mg/kg significantly improved the cirrhotic cardiomyopathy in BDL model in rats.

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.

Risperidone attenuates acetic acid-induced colitis in rats through inhibition of TLR4/NF-kB signaling pathway.

AIM: The purpose of the present study is to explore the anti-inflammatory potential of risperidone in acetic acid-induced rat colitis through inhibition of TLR4/NF-kB pathway. METHODS: Acute colitis induction was done by intra-rectal administration of 2 mL of 4% diluted acetic acid solution. Two h after colitis induction, dexamethasone (2 mg/kg) as standard drugorrisperidone (2, 4 and 6 mg/kg) were administered orally to wistar rats for five consecutive days. 24 h after the last treatment, animals were sacrificed by cervical dislocation. Macroscopic and microscopic damage evaluation was done. Biochemical and ELISA methods were used to assess myeloid peroxidase (MPO) enzyme activity and tumor necrosis factor-α (TNF-α) level respectively. Moreover, immunohistochemistry (IHC) was performed to detect the expression of TLR4 and pNF-kBproteins. RESULTS: Dexamethasone (2 mg/kg) or risperidone (2, 4 and 6 mg/kg) improved acetic acid-induced macroscopic (p < .001) and microscopic lesions. Additionally, risperidone (2, 4 and 6 mg/kg) inhibited the activity of MPO and TNF-α (p < .01, p < .001) in the colon tissue compared to acetic acid group. Furthermore, bothdexamethasone and risperidone (2, 4 and 6 mg/kg) significantly reduced acetic acid-induced expression of TLR4and pNF-kB proteins (p < .05, p < .01, p < .001). CONCLUSION: The anti-inflammatory effect of risperidone on acetic acid-induced colitis in rats may involve inhibition of TLR4 and NF-kB signaling pathway.

Acute Activation of α7-Nicotinic Receptors by Nicotine Improves Rodent Skin Flap Survival Through Nitrergic System.

BACKGROUND: Recent reports have identified angiogenic, anti-inflammatory, and antioxidant properties of acute treatment with nicotine via activation of nicotinic acetylcholine receptors (nAChRs). In addition, the nitric oxide (NO) pathway is involved in ischemic reperfusion injuries. OBJECTIVES: We investigated the effects of acute pretreatment with nicotine in a rat model of random-pattern skin flap and the potential role of the NO pathway. METHODS: The Sprague-Dawley rats received increasing doses of (-)-nicotine (0.5, 1, 1.5, 2, and 3 mg/kg) before the procedure. Dorsal skin flaps with caudal pedicles were elevated at the midline, and flap survival was evaluated 7 days after surgery. In addition, animals received an α7-nAChR antagonist, methyllycaconitine, with nicotine. Quantitative reverse transcription polymerase chain reaction was also applied to measure the dermal expression of α7-nAChR. Next, a nonselective NO synthase inhibitor, N-nitro-L-arginine methyl ester hydrochloride; a selective inducible NO synthase inhibitor, aminoguanidine; and an NO precursor, L-arginine, were administered with nicotine. RESULTS: Nicotine at doses of 1, 1.5, and 2 mg/kg significantly increased flap survival, whereas the protective effects of nicotine disappeared at higher doses. Methyllycaconitine completely reversed the protective effects of nicotine and the elevated cutaneous expression of α7-nAChR in nicotine-pretreated rats. In addition, systemic administration of N-nitro-L-arginine methyl ester hydrochloride or aminoguanidine with an effective dose of nicotine caused a significant decrease in flap survival. Conversely, coinjection of a subeffective dose of L-arginine with the subeffective dose of nicotine significantly boosted its protective effects. CONCLUSIONS: Acute pretreatment with nicotine by stimulating the expression and activation of cutaneous α7-nAChR improves skin flap survival, which is partially mediated through modulation of the NO pathway.

Thymol reduces acetic acid-induced inflammatory response through inhibition of NF-kB signaling pathway in rat colon tissue.

AIM: The aim of the present study was to evaluate the anti-inflammatory effect of thymol in acetic acid-induced rat colitis through inhibiting the NF-κB signaling pathway. METHODS: Colitis was induced by intra-rectal administration of 2 mL of diluted acetic acid (4%) solution using a flexible plastic rubber catheter in Wistar rats. Colitis was induced on the first day and all treatments were applied 5 days after the induction of colitis. Thymol was dissolved in 0.2% tween 80 in saline and administered orally at doses of 10, 30, and 100 mg/kg per day. Macroscopic and histopathologic investigations were done. The expression of myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) was determined by immunohistochemistry (IHC) assay. The protein expression level of pNF-κB p65 was measured by the Western blot technique. RESULTS: Treatment with thymol reduced mucosal and histological damages compared to the acetic acid group. Our results showed that thymol markedly inhibited the production of MPO and TNF-α in the colon tissue of the acetic acid-induced group. In addition, thymol decreased acetic acid-induced up-regulation of pNFκB p65 protein. CONCLUSIONS: The results of our study suggest that thymol exerts an anti-inflammatory effect in acetic acid-induced rat colitis by inhibiting the NF-κB signaling pathway and downregulating TNF-α and MPO expressions.

Melatonin ameliorates TNBS-induced colitis in rats through the melatonin receptors: involvement of TLR4/MyD88/NF-κB signalling pathway.

AIM: The aim of the present study is to investigate the anti-inflammatory effect of melatonin in trinitrobenzene sulfonic acid (TNBS)-induced rat colitis through the inhibition of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signalling pathway and activation of melatonin receptor. METHODS: Colitis was induced in Wistar rats by administration of 100 mg/kg TNBS dissolved in 0.25 ml of 50% ethanol solution using a flexible plastic rubber catheter into the colon via the anus. This resulted in incidence of colitis on the first day, and all treatments were conducted for 10 days after induction of colitis. Melatonin was administered intraperitoneally (i.p.) at doses of 1, 5, and 10 mg/kg/day. Luzindole (non-selective MT1/MT2 receptor antagonist) was administered i.p. at dose of 5 mg/kg/day 15 min prior to melatonin injection. During the experiment, animals were monitored for the appearance of diarrhoea, body weight loss, and rectal bleeding. Myeloid peroxidase enzyme and tumour necrosis factor-α (TNF-α) activities were detected by immunohistochemistry. The protein expression level of TLR4, myeloid differentiation factor 88 (MyD88), NF-κB p65, and inhibitor of kappa B (I-κB) were detected by western blotting analysis. RESULTS: Treatment with melatonin improved weight loss, mucosal, and histological damage compared with TNBS group. In addition, melatonin decreased TNBS-induced up-regulation of TLR4, MyD88, and NF-κB p65, and increased down-regulation of I-κB proteins. On the other hand, the administration of luzindole resulted in the inhibition of melatonin effects. CONCLUSIONS: It seems that the inhibition of TLR4/NF-κB signalling pathway may mediate the anti-inflammatory effects of melatonin in TNBS-induced rat colitis.

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.

Possible involvement of ATP-sensitive potassium channels in the antidepressant-like effects of gabapentin in mouse forced swimming test.

Gabapentin as an anticonvulsant drug also has beneficial effects in treatment of depression. Previously, we showed that acute administration of gabapentin produced an antidepressant-like effect in the mouse forced swimming test (FST) by a mechanism that involves the inhibition of nitric oxide (NO). Considering the involvement of NO in adenosine triphosphate (ATP)-sensitive potassium channels (KATP), in the present study we investigated the involvement of KATP channels in antidepressant-like effect of gabapentin. Gabapentin at different doses (5-10 mg/kg) and fluoxetine (20 mg/kg) were administrated by intraperitoneal route, 60 and 30 min, respectively, before the test. To clarify the probable involvement of KATP channels, mice were pretreated with KATP channel inhibitor or opener. Gabapentin at dose 10 mg/kg significantly decreased the immobility behavior of mice similar to fluoxetine (20 mg/kg). Co-administration of subeffective dose (1 mg/kg) of glibenclamide (inhibitor of KATP channels) with gabapentin (3 mg/kg) showed a synergistic antidepressant-like effect. Also, subeffective dose of cromakalim (opener of KATP channels, 0.1 mg/kg) inhibited the antidepressant-like effect of gabapentin (10 mg/kg). None of the treatments had any impact on the locomotor movement. Our study, for the first time, revealed that antidepressant-like effect of gabapentin in mice is mediated by blocking the KATP channels.

Development of resistance to serotonin-induced itch in bile duct ligated mice.

Cholestatic itch can be severe and significantly impair the quality of life of patients. The serotonin system is implicated in cholestatic itch; however, the pruritogenic properties of serotonin have not been evaluated in cholestatic mice. Here, we investigated the serotonin-induced itch in cholestatic mice which was induced by bile duct ligation (BDL). Serotonin, sertraline or saline were administered intradermally to the rostral back area in BDL and sham operated (SHAM) mice, and the scratching behaviour was videotaped for 1 hour. Bile duct ligated mice had significantly increased scratching responses to saline injection on the seventh day after surgery. Additionally, serotonin or sertraline significantly induced scratching behaviour in BDL mice compared to saline at day 7 after surgery, while it did not induce itch at day 5. The scratching behaviour induced by serotonin or sertraline was significantly less in BDL mice compared to SHAM mice. Likewise, the locomotor activity of BDL or SHAM mice was not significantly different from unoperated (UNOP) mice on the fifth and seventh day, suggesting that the scratching behaviour was not affected by motor dysfunctions. Our data suggest that despite the potentiation of evoked itch, a resistance to serotonin-induced itch is developed in cholestatic mice.

Tropisetron attenuated the anxiogenic effects of social isolation by modulating nitrergic system and mitochondrial function.

BACKGROUND: Early social isolation stress (SIS) is associated with the occurrence of anxiety behaviors. It seems interaction between the nitrergic system and mitochondrial function plays a role in mediating the anxiety-like behaviors. In this study, we aimed to investigate the anxiolytic effects of tropisetron in animal model of SIS and we try to illustrate the possible role of nitrergic system and mitochondrial function. METHODS: We applied early social isolation paradigm to male NMRI mice. Animals treated with various doses of tropisetron, nitric oxide agents or their combination and anxiety-like behaviors of animals were assessed using valid behavioral tests including elevated plus maze (EPM), open-field test (OFT) and hole-board test (HBT) in their adulthood. Effects of housing conditions and drug treatments on the mitochondrial function were investigated in the hippocampus by assessing the ATP, GSH, ROS and nitrite levels. RESULTS: Anxiogenic effects of early SIS were assessed in the EPM, OFT, and HBT. Also, SIS disrupted mitochondrial function and caused oxidative stress in the hippocampus of stressed animals. Tropisetron showed an anxiolytic effect in the stressed mice. Also, these effects were mediated by nitrergic system by affecting mitochondrial function and modulating the oxidative stress. L-arginine, a nitric oxide precursor, abolished the anxiolytic effects of tropisetron in the behavioral tasks and blocked the protective effects of it against mitochondrial and oxidative challenge. CONCLUSIONS AND GENERAL SIGNIFICANCE: Our results demonstrated tropisetron attenuated the anxiogenic effects of SIS by mitigation of the negative effects of nitric oxide on mitochondrial function.

Are itch and scratching the nausea and vomiting of skin?

The physiologic similarities between itch and nausea may not be evident initially, but they share the role of repelling irritants and toxins from the body by inducting scratching and vomiting, respectively. In addition, itch and nausea frequently occur together in certain conditions such as uraemia. Here we show that the mechanisms underlying itch and nausea overlap and that advances in either field may influence the identification of novel drug targets, particularly for itch.

Anticonvulsant effect of dextrometrophan on pentylenetetrazole-induced seizures in mice: Involvement of nitric oxide and N-methyl-d-aspartate receptors.

Dextrometrophan (DM), widely used as an antitussive, has recently generated interest as an anticonvulsant drug. Some effects of dextrometrophan are associated with alterations in several pathways, such as inhibition of nitric oxide synthase (NOS) enzyme and N-methyl d-aspartate (NMDA) receptors. In this study, we aimed to investigate the anticonvulsant effect of acute administration of dextrometrophan on pentylenetetrazole (PTZ)-induced seizures and the probable involvement of the nitric oxide (NO) pathway and NMDA receptors in this effect. For this purpose, seizures were induced by intravenous PTZ infusion. All drugs were administrated by intraperitoneal (i.p.) route before PTZ injection. Our results demonstrate that acute DM treatment (10-100mg/kg) increased the seizure threshold. In addition, the nonselective NOS inhibitor L-NAME (10mg/kg) and the neural NOS inhibitor, 7-nitroindazole (40mg/kg), at doses that had no effect on seizure threshold, augmented the anticonvulsant effect of DM (3mg/kg), while the inducible NOS inhibitor, aminoguanidine (100mg/kg), did not affect the anticonvulsant effect of DM. Moreover, the NOS substrate l-arginine (60mg/kg) blunted the anticonvulsant effect of DM (100mg/kg). Also, NMDA antagonists, ketamine (0.5mg/kg) and MK-801 (0.05mg/kg), augmented the anticonvulsant effect of DM (3mg/kg). In conclusion, we demonstrated that the anticonvulsant effect of DM is mediated by a decline in neural nitric oxide activity and inhibition of NMDA receptors.

Fluoxetine reverses the behavioral despair induced by neurogenic stress in mice: role of N-methyl-d-aspartate and opioid receptors.

Opioid and N-methyl-d-aspartate (NMDA) receptors mediate different effects of fluoxetine. We investigated whether opioid and NMDA receptors are involved in the protective effect of fluoxetine against the behavioral despair induced by acute physical stress in male mice. We used the forced swimming test (FST), tail suspension test (TST), and open-field test (OFT) for behavioral evaluation. We used fluoxetine, naltrexone (opioid receptor antagonist), MK-801 (NMDA receptor antagonist), morphine (opioid receptor agonist), and NMDA (NMDA receptor agonist). Acute foot-shock stress (FSS) significantly induced behavioral despair (depressive-like) and anxiety-like behaviors in tests. Fluoxetine (5 mg/kg) reversed the depressant-like effect of FSS, but it did not alter the locomotion and anxiety-like behavior in animals. Acute administration of subeffective doses of naltrexone (0.3 mg/kg) or MK-801 (0.01 mg/kg) potentiated the antidepressant-like effect of fluoxetine, while subeffective doses of morphine (1 mg/kg) and NMDA (75 mg/kg) abolished this effect of fluoxetine. Also, co-administration of subeffective doses of naltrexone (0.05 mg/kg) and MK-801 (0.003 mg/kg) with fluoxetine (1 mg/kg) induced a significant decrease in the immobility time in FST and TST. Our results showed that opioid and NMDA receptors (alone or in combination) are involved in the antidepressant-like effect of fluoxetine against physical stress.

Involvement of opioid system in antidepressant-like effect of the cannabinoid CB1 receptor inverse agonist AM-251 after physical stress in mice.

Cannabinoid inverse agonists possess antidepressant-like properties, but the mechanism of this action is unknown. Numerous studies have reported the interaction between opioid and cannabinoid pathways. In this study, acute foot-shock stress was used in mice to investigate the involvement of the opioid pathway in the antidepressant-like effect of the cannabinoid CB1 receptor inverse agonist AM-251. Stress was induced by intermittent foot-shock stimulation for 30 min. Then, using the forced swimming test (FST) and tail suspension test (TST), the immobility time was measured. Results show that the immobility time was significantly prolonged in animals subjected to foot-shock stress, compared with non-stressed controls (P < 0.01). Also, the serum corticosterone level was significantly increased after stress induction (P < 0.001). Administration of AM-251 (0.5 and 0.3 mg/kg, intraperitoneally (i.p.)), significantly decreased the immobility time of stressed mice in the FST (P < 0.001 and P < 0.01, respectively) and TST (P < 0.01 and P < 0.05, respectively). The lowest dose of AM-251 (0.1 mg/kg), naltrexone (0.3 mg/kg), and morphine (1.0 mg/kg) did not show any significant effect on stressed animals (P > 0.05). Co-administration of AM-251 with sub-effective dose of naltrexone decreased the effective dose of this cannabinoid inverse agonist, to 0.1 mg/kg (P < 0.01). On the other hand, administration of the sub-effective dose of morphine reversed the anti-immobility effect of AM-251 (0.5 mg/kg; P < 0.001). In conclusion, the present study for the first time reveals the possible role of opioid signalling in the antidepressant-like properties of AM-251 in a foot-shock stress model.

Atorvastatin attenuates TNBS-induced rat colitis: the involvement of the TLR4/NF-kB signaling pathway.

AIM: The aim of the present study is to explore whether atorvastatin improves intestinal inflammation through the inhibition of the TLR4/NFkB signaling pathway in TNBS-induced rat colitis. METHODS: Acute colitis was induced by intra-rectal administration of 100 mg/kg TNBS dissolved in 0.25 ml of 50 % ethanol. Twenty four hours after colitis induction, saline, atorvastatin (20 and 40 mg/kg) and sulfasalazine (100 mg/kg) were given to the animals by oral route. This was repeated daily for 1 week. Body weight changes, macroscopic and microscopic lesions were assessed. MPO and TNF-α activities were detected by immunohistochemistry (IHC) and the expression level of TLR4, MyD88 and NF-κB p65 proteins were measured by western blotting analysis. RESULTS: Atorvastatin and sulfasalazine reduced the body weight loss, macroscopic and microscopic lesions. Additionally, both drugs decreased the expression of MPO and TNF-α positive cells in the colon tissue. Furthermore, they inhibited the TNBS-induced expression of TLR4, MyD88 and NF-κB p65 proteins. CONCLUSIONS: It is suggested that the anti-inflammatory effect of atorvastatin on TNBS-induced rat colitis may involve the inhibition of the TLR4/NFkB signaling pathway.

Development of Molecularly Imprinted Olanzapine Nano-particles: In Vitro Characterization and In Vivo Evaluation.

Molecularly imprinted nano-particles (MINPs) selective for olanzapine were prepared using methacrylic acid (MA) as monomer, ethylene glycol dimethacrylate (EGDMA) as a cross-linker, and 2,2-azobis (2-isobutyronitrile) (AIBN) as the initiator in 36 different ratios. The reaction runs with considerable fine powder formation were selected for further binding and selectivity studies. The MINP with the best selectivity (MINP-32) was chosen for further structural characterization by Fourier transform infrared spectroscopy (FT-IR), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM), adsorption-desorption isotherm for specific surface area, volume and average pore diameter determination. All characterization methods confirmed the successful formation of MINP. The optimum conditions for maximum template loading on the MINP-32 were found by experimental design using response surface methodology (RSM) and choosing absorbent amount, pH, and time as the main factors. MINPs with maximum template loading also indicated significant selectivity between template and its analog (clozapine). The release profile demonstrated a maximum release of about 95% after 288 h for MINP-32 in comparison with about 94% after 120 h for non-MINP-32. The same slow release of drug from MINP-32 was also observed during animal study of the plasma level of template, 20-28 µg/ml versus 5-10 µg/ml. The MINP-32 of this study represents a desirable ability to keep the memory of the template with significant selectivity and good capability to control the release of template in vitro and in vivo and hence could be a promising drug delivery system.