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Aims Although approving new anticonvulsants was a major breakthrough in the field of epilepsy control, so far we have met limited success in almost one third of patients suffering from epilepsy and a definite and reliable method is yet to be found. Levosimendan demonstrated neuroprotective effects and reduced mortality in conditions in which seizure can be an etiology of death; however, the underlying neuroprotective mechanisms of levosimendan still eludes us. In the light of evidence suggesting levosimendan can be a K ATP channel opener and nitrergic pathway activator, levosimendan may exert antiseizure effects through K ATP channels and nitrergic pathway. Main methods In this study, the effects of levosimendan on seizure susceptibility was studied by PTZ-induced seizures model in mice. Key findings Administration of a single effective dose of levosimendan significantly increased seizures threshold and the nitrite level in the hippocampus and temporal cortex. Pretreatment with noneffective doses of glibenclamide (a K ATP channel blocker) and L-NAME (a non-selective NOS inhibitor) neutralize the anticonvulsant and nitrite elevating effects of levosimendan. While 7-NI (a neural NOS inhibitor) blocked the anticonvulsant effect of levosimendan, Aminoguanidine (an inducible NOS inhibitor) failed to affect the anticonvulsant effects of levosimendan. Cromakalim (a K ATP channel opener) or l -arginine (an NO precursor) augmented the anticonvulsant effects of a subeffective dose of levosimendan. Moreover, co-administration of noneffective doses of Glibenclamide and L-NAME demonstrated a synergistic effect in blocking the anticonvulsant effects of levosimendan. Significance Levosimendan has anticonvulsant effects possibly via K ATP /nNOS/NO pathway activation in the hippocampus and temporal cortex.

Objective To assess the role of transition zone prostate-specific antigen density (TZPSAD) in determining rebiopsy strategy in men with prostate inflammation at initial biopsy. Materials and Methods Analysis was performed on data derived from transrectal ultrasound–guided prostate biopsy registry containing 2461 men who underwent biopsy between March 2005 and January 2015. Eligible patients were divided into 2 groups based on the presence of chronic inflammation in prostate. Group 1 consisted of 920 patients with histopathologic evidence of chronic inflammation and group 2 consisted of 1287 patients with no evidence of inflammation. Receiver operating characteristic curve analysis was performed to evaluate the accuracy of PSA, PSA density (PSAD), and TZPSAD for detecting prostate cancer (PCa) in each group. Patients who underwent rebiopsy during the study period were further assessed to determine factors that may predict the presence of PCa on subsequent biopsies. Results In group 1 patients, at 90% sensitivity for detecting PCa, PSAD and TZPSAD showed 19.7% and 37.8% specificity at cutoff values of 0.10 and 0.27 ng/mL/mL respectively, whereas in group 2 patients, PSAD and TZPSAD revealed 29.8% and 31.4% specificity, respectively. Chronic inflammation at initial biopsy was associated with a significant decrease in the likelihood of cancer detection during rebiopsy (odds ratio, 0.42; 95% confidence interval, 0.18-0.99). TZPSAD was found to be capable of sparing 39.8% of unnecessary rebiopsies in group 1 patients, whereas it spared 20.5% of unnecessary rebiopsies in group 2 patients. Conclusion Applying TZPSAD is advantageous in determining rebiopsy strategy in patients with proven inflammation of prostate at initial biopsy.

Cannabinoid and PPAR receptors show well established interactions in a set of physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study aimed to evaluate the roles of the PPAR-gamma, PPAR-alpha and CB1 receptors on the anticonvulsant effects of WIN 55,212-2 (WIN, a non selective cannabinoid agonist). The clonic seizure thresholds after intravenous administration of pentylenetetrazole (PTZ) were assessed in mice weighing 23-30 g. WIN increased the seizure threshold dose dependently. Pretreatment with pioglitazone, as a PPARγ agonist, potentiated the anticonvulsant effects of WIN, while PPARγ antagonist inhibited these anticonvulsant effects partially. On the other hand PPARα antagonist reduced the anticonvulsant effects of WIN significantly. Finally the combination of CB1 antagonist and PPARα antagonist could completely block the anticonvulsant properties of WIN. Taken together, these results show for the first time that a functional interaction exists between cannabinoid and PPAR receptors in the modulation of seizure susceptibility.

Stroke is a leading cause of death, disability, and socioeconomic loss worldwide. All attempts at pharmacological reduction of the complications of stroke (e.g. post-stroke seizure, and brain׳s vulnerability to hypoxic/ischemic injury) have failed. Endogenous opioids and nitric oxide (NO) overproduction has been documented in brain hypoxia/ischemia (H/I), which can exert pro-convulsive effects. In this study, we aimed to examine the possible involvement of opioidergic and nitrergic pathways in the pathogenesis of post-stroke seizure. H/I was induced by right common carotid ligation and sham-operated mice served as controls. We demonstrated that right common carotid ligation decreases the threshold for clonic seizures induced by pentylenetetrazole (PTZ), a GABA antagonist. Furthermore, pro-convulsive effect of H/I following right common carotid ligation was blocked by naltrexone (NTX) (3mg/kg), NG-Nitro-l-arginine methyl ester (l-NAME) (10mg/kg), and aminoguanidine (AG) (100mg/kg) administration (P

Sumatriptan has been among the top choices in the management of migraine headaches. The association between migraine and epilepsy highlights the possible effect of sumatriptan on seizures. In this regard, we investigated sumatriptan effects on PTZ-induced seizures thresholds and delineated the modulatory role of 5-HT1B/D receptors and NOS/NO pathway. Our data revealed the anti-convulsant effects of lower doses of sumatriptan, and pro-convulsant effects of higher doses of sumatriptan. GR 127935, a selective 5-HT1B/D antagonist, could abolish the sumatriptan anti-convulsant effects, but it was ineffective against the sumatriptan pro-convulsant effects. Serotonin depletion by consecutive administration of p-CPA, a selective irreversible inhibitor of tryptophan hydroxylase, could not affect the anti-convulsant effects of sumatriptan. The anti-convulsant effects of sumatriptan was potentiated by L-NAME, a non-selective NOS inhibitor, 7-NI, a selective nNOS inhibitor, but not AG, an iNOS inhibitor. It was also neutralized by L-ARG, a NO precursor. The pro-convulsant effects of sumatriptan were blocked by L-NAME and AG, but not 7-NI. It was also potentiated by L-ARG. Our data revealed that anti-convulsive effects of sumatriptan is mediated by interaction between non-serotonergic 5-HT1B/D receptors and nNOS/NO pathway. Besides, the pro-convulsive effect of sumatriptan is mediated by iNOS/NO pathway independent of 5-HT1B/D receptors. For the first time, this study reported the biphasic effect of sumatriptan on an animal model of GCS and its modulatory pathways.

Probiotics are live microorganisms, conferring a health benefit on the host when administered in a sufficient amount. Generally, Lactobacilli, Bifidobacteria, and Saccharomyces are recognized as “Generally Regarded As Safe by the WHO.” However, further caution is needed to administer probiotics to patients with compromised immune systems, leaky gut, or critical illnesses. Different strains of probiotics have different safety profiles, which should be taken into account, and generalizations in relation to all probiotics should be avoided. Particularly, the safety of probiotics in an at-risk population should be categorized as strain-by-strain basis, dose and interaction with other strains and pathologic conditions.

Influenza virus belongs to orthomyxoviridae family. This virus is a major public health problems, with high rates of morbidity and mortality. Despite a wide range of pharmacotherapeutic choices inhibiting specific sequences of pathological process of influenza, developing more effective therapeutic options is an immediate challenge. In this paper, a comprehensively review of natural polyphenolic products used worldwide for the management of influenza infection is presented. Cellular and molecular mechanisms of the natural polyphenols on influenza infection including suppressing virus replication cycle, viral hemagglutination, viral adhesion and penetration into the host cells, also intracellular transductional signaling pathways have been discussed in detail. Based on cellular, animal, and human evidence obtained from several studies, the current paper demonstrates that natural polyphenolic compounds possess potential effects on both prevention and treatment of influenza, which can be used as adjuvant therapy with conventional chemical drugs for the management of influenza and its complications.

Histamine regulates release of neurotransmitters such as dopamine, serotonin, gamma-aminobutyric acid (GABA), glutamate and also is involved in several functions in central nervous system (CNS). It has been shown that histamine participates in disorders like seizure. It has been well documented that morphine dose-dependently induces anti or proconvulsant effects. In the current study, we firstly showed that morphine (1mg/kg) exerts anticonvulsant effects which significantly reversed by naltrexone administration. Secondly, we determined seizure threshold for H1 and H3 receptors agonists and antagonists in mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. Our results showed that activation of H1 receptors by 2-(2-Pyridyl)-ethylamine exerts anticonvulsant properties while inhibition of H1 receptors by pyrilamine maleate induced proconvulsant effects. Furthermore, we showed that immepip dihydrobromide, a H3 receptor agonist, increased seizure susceptibility to PTZ whereas thioperamide, a H3 receptor antagonist increased seizure threshold. We also revealed that pretreatment with morphine potently reversed the effects of histaminergic system on seizure threshold suggesting the involvement of opioid system in alteration of seizure threshold by histaminergic drugs.

Aim Aluminum phosphide (AlP) is a widely used fumigant and rodenticide. While AlP ingestion leads to high mortality, its exact mechanism of action is unclear. There are ample evidences suggesting cardioprotective effects of triiodothyronine (T3). In this study, we aimed to examine the potential of T3 in the protection of a rat model of AlP induced cardiotoxicity. Main methods In order to induce AlP intoxication animals were intoxicated with AlP (12 mg/kg; LD50) by gavage. In treatment groups, T3 (1, 2 and 3 μg/kg) was administered intra-peritoneally 30 min after AlP administration. Animals were connected to the electronic cardiovascular monitoring device simultaneously after T3 administration. Then, electrocardiogram (ECG), blood pressure (BP), and heart rate (HR) were monitored for 180 min. Additionally, 24 h after AlP intoxication, rats were deceased and the hearts were dissected out for evaluation of oxidative stress, cardiac mitochondrial function (complexes I, II and IV), ATP/ADP ratio, caspases 3 & 9, and apoptosis by flow cytometry. Key findings The results demonstrated that AlP intoxication causes cardiac toxicity presenting with changes in ECG patterns such as decrement of HR, BP and abnormal QRS complexes, QTc and ST height. T3 at a dose of 3 μg/kg significantly improved ECG and also oxidative stress parameters. Furthermore, T3 administration could increase mitochondrial function and ATP levels within the cardiac cells. In addition, administration of T3 showed a reduction in apoptosis through diminishing the caspase activities and improving cell viability. Significance Overall, the present data demonstrate the beneficial effects of T3 in cardiotoxicity of AlP.

AIM: To investigate the efficacy and adverse effects of antioxidant therapy in acute pancreatitis (AP), chronic pancreatitis (CP) and post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). METHODS: PubMed, Scopus, Google Scholar, Cochrane library database, and Evidence-based medicine/clinical trials published before August 2014 were searched. Clinical and laboratory outcomes of randomized trials of antioxidant therapy in patients with AP, CP and PEP were included. The methodological quality of the trials was assessed by the Jadad score based on the description of randomization, blinding, and dropouts (withdrawals). The results of the studies were pooled and meta-analyzed to provide estimates of the efficacy of antioxidant therapy. RESULTS: Thirty four trials out of 1069 potentially relevant studies with data for 4898 patients were eligible for inclusion. Antioxidant therapy significantly reduced the length of hospital stay in AP patients {mean difference -2.59 d (95%CI: -4.25-(-0.93)], P = 0.002}. Although, antioxidant therapy had no significant effect on serum C reactive protein (CRP) after 5-7 d in AP patients [mean difference -9.57 (95%CI: -40.61-21.48, P = 0.55], it significantly reduced serum CRP after 10 d {mean difference -45.16 [95%CI: -89.99-(-0.33)], P = 0.048}. In addition, antioxidant therapy had no significant effect on CP-induced pain [mean difference -2.13 (95%CI: -5.87-1.6), P = 0.26]. Antioxidant therapy had no significant effects on the incidence of all types of PEP [mean difference 1.05 (95%CI: 0.74-1.5), P = 0.78], severe PEP [mean difference 0.92 (95%CI: 0.43-1.97), P = 0.83], moderate PEP [mean difference 0.82 (95%CI: 0.54-1.23), P = 0.33], and mild PEP [mean difference 1.33 (95%CI: 0.99-1.78), P = 0.06]. Furthermore, while antioxidant therapy had no significant effect on serum amylase after less than 8 h sampling [mean difference -20.61 (95%CI: -143.61-102.39), P = 0.74], it significantly reduced serum amylase close to 24-h sampling {mean difference -16.13 [95%CI: -22.98-(-9.28)], P < 0.0001}. CONCLUSION: While there is some evidence to support antioxidant therapy in AP, its effect on CP and PEP is still controversial.