Search

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.

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

Evolving data have shown that the toll like receptors (TLRs) family of innate immune receptors has an important role in driving the activation and inhibition of pathogenic pathways involved in multiple sclerosis (MS). While developing clinical trials targeting MS by TLRs modulators are of considerable interest, several of them have failed. Herein, the various consequences of TLRs pathways activation and the potential of targeting these receptors for therapeutic purposes are described. In particular, different aspects of TLR based therapies are discussed, in order to develop more efficacious and safe therapies targeting inflammatory and autoimmune diseases, especially MS.

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.

Osteoarthritis (OA) is a chronic condition in which imbalance between anabolic and catabolic mediators occurs leading to the destruction of homeostasis of articular cartilage. The current drugs in the management of OA can just alleviate symptoms. Hence, the research tendency toward exploration of novel sources has been grown up in order to achieve safe and efficacious drugs. Meanwhile, various components exist as novel natural drugs that may possess favorable properties for the management of OA. This review focuses on the most efficacious medicinal plants and their phytochemical agents, which have been consumed for the management of OA. Moreover, evaluation of their efficacy and molecular mechanisms of action are discussed based on numerous modern experimental investigations. More research is needed to develop therapeutic agents with disease-modifying properties to treat OA.

Thalidomide is an old glutamic acid derivative which was initially used as a sedative medication but withdrawn from the market due to the high incidence of teratogenicity. Recently, it has reemerged because of its potential for counteracting number of diseases, including neurodegenerative disorders. Other than the antiemetic and hypnotic aspects, thalidomide exerts some anticonvulsant properties in experimental settings. However, the underlying mechanisms of thalidomide actions are not fully realized yet. Some investigations revealed that thalidomide could elicit immunomodulatory or neuromodulatory properties by affecting different targets, including cytokines (such as TNF α), neurotransmitters, and nitric oxide (NO). In this regard, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of thalidomide is affected through modulation of the l-arginine-nitric oxide pathway or not. Injection of a single effective dose of thalidomide (10 mg/kg, i.p. or higher) significantly increased the seizure threshold (P0.05). On the one hand, pretreatment with low and per se noneffective dose of l-arginine [NO precursor] (10, 30 and 60 mg/kg) prevented the anticonvulsant effect of thalidomide. On the other hand, NOS inhibitors [l-NAME and 7-NI] augmented the anticonvulsant effect of a subeffective dose of thalidomide (1 and 5 mg/kg, i.p.) at relatively low doses. Meanwhile, several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of thalidomide significantly. In summary, our findings demonstrated that the l-arginine-nitric oxide pathway can be involved in the anticonvulsant properties of thalidomide, and the role of constitutive nNOS is prominent in the reported neuroprotective feature.

The interaction between the immune and nervous systems suggests invaluable mechanisms for several pathological conditions, especially neurodegenerative disorders. Multiple sclerosis (MS) is a potentially disabling chronic autoimmune disease, characterized by chronic inflammation and neurodegenerative pathology of the central nervous system. Toll-like receptors (TLRs) are an important family of receptors involved in host defense and in recognition of invading pathogens. The role of TLRs in the pathogenesis of autoimmune disorders such as MS is only starting to be uncovered. Recent studies suggest an ameliorative role of TLR3 and a detrimental role of other TLRs in the onset and progression of MS and experimental autoimmune encephalomyelitis, a murine model of MS. Thus, modulating TLRs can represent an innovative immunotherapeutic approach in MS therapy. This article outlines the role of these TLRs in MS, also discussing TLR-targeted agonist or antagonists that could be used in the different stages of the disease.