Beneficial Effects of Statins on Seizures Independent of Their Lipid-Lowering Effect: A Narrative Review.

Among the many types of central nervous system (CNS) disorders, seizures and epilepsy severely affect the quality of life and routine daily activity of the sufferers. We aimed to review research studies that investigated the effect of statins on the prevention and treatment of seizures and epilepsy. Both animal models and human studies were included in this review. This article starts with a brief introduction about seizure, its prevalence, treatment, and various animal models of seizures and epilepsy. Next, we discuss statin's mechanism of action, side effects, and effects on neurological disorders with a specific focus on seizures. Finally, the effects of different types of statins on seizures are compared. The present review gives a better understanding of the therapeutic effects of statins on neurological disorders in animal models and human studies. This permits researchers to set up study designs to resolve current ambiguities and contradictions on the beneficial effects of statins on neurological disorders.

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.

Pentylenetetrazole preconditioning attenuates severity of status epilepticus induced by lithium-pilocarpine in male rats: evaluation of opioid/NMDA receptors and nitric oxide pathway.

BACKGROUND: Non-deleterious episodes of seizure preconditioning can efficiently increase the brain's resistance to the consequent severe status epilepticus (SE). In the present investigation, we intended to elucidate further (i) the effects of preconditioning with pentylenetetrazole (PTZ) in the lithium-pilocarpine model of SE in male rats, along with (ii) the possible contribution of opioid, N-Methyl-D-aspartate (NMDA) receptors, and nitric oxide (NO) signaling transduction. METHODS: In male Wistar rats, the SE was incited by lithium administration (127 mg/kg, ip) 20 h before pilocarpine (60 mg/kg, ip). PTZ preconditioning was induced via a low-dose injection of PTZ (25 mg/kg) for 5 repeated days. To investigate the underlying signaling pathway, naltrexone (NTX; a non-specific opioid receptor antagonist), MK-801 (NMDA antagonist), L-NAME (a non-specific nitric oxide synthase (NOS) inhibitor), aminoguanidine (AG; a specific inducible NOS inhibitor), and 7-Nitroindazole (7-NI; a specific neuronal NOS inhibitor) were administered 15 min before PTZ injection. RESULTS: Preconditioning with PTZ successfully ameliorates the increased SE scores due to lithium-pilocarpine-induced SE (p < 0.05). None of the drugs given without PTZ preconditioning had an impact on SE outcomes. The observed anti-convulsant effect of PTZ preconditioning is reversed by the opioid receptor antagonists and NOS inhibitors. Conversely, the NMDA receptor antagonist enhanced the anti-convulsion activity caused by PTZ preconditioning. Quantifying nitrite level in the hippocampus showed a significant NO level decline in the PTZ-preconditioned animals. CONCLUSIONS: Therefore, PTZ preconditioning generates endogenous protection against SE, possibly through targeting opioid/NMDA receptors and NO signaling transduction in the animal model of lithium-pilocarpine-induced SE.

Phenothiazine as novel human superoxide dismutase modulators: discovery, optimization, and biological evaluation.

Superoxide dismutases (SODs) are regarded as important antioxidants for protecting cells against damage arising from oxidative stress. Much research is focused on finding new chemicals with an ability to boost human SOD activity. In the research described herein a structure-based approach was used to identify new human Cu-Zn superoxide dismutase (SOD1) modulators based on previously reported plasmodium falciparum iron SOD inhibitors using induced fit docking and molecular dynamic (MD) protocols. The compound with the highest docking binding energy was selected for further structure simplification followed by structural similarity and MD in order to find a new activator/inhibitor scaffold of the SOD1 enzyme. According to the docking survey of the mentioned series, 1,4-bis(3-(1,4,8-trichloro-10Hphenothiazin-10-yl) propyl) piperazine (DS88) was the top scoring compound interacting with the SOD1 active site channel. Following structure simplification and similarity search, the most promising scaffold which is closely related to the phenothiazine antipsychotic class, was identified. Compared with the normal blood SOD1 activity, the percent of O2 production increased with trifluoperazine, while it decreased with the chlorpromazine. The molecular dynamic investigation shows that trifluoperazine exerts its SOD1 activating effect by stabilizing electrostatic loop while chlorpromazine employs SOD1 inhibition activity through repositioning of the electrostatic loop and increasing its distance from the catalytic metal site which diminished substrate specificity and catalytic activity of the SOD1 enzyme. The results identified the preferred region, orientation, and types of interaction for each activator or inhibitor compound.

Anticonvulsive evaluation and histopathological survey of thalidomide synthetic analogs on lithium-pilocarpine-induced status epilepticus in rats.

BACKGROUND AND PURPOSE: Status epilepticus is a severe neurological disorder that can be life-threatening. Thalidomide and its analogs have shown promising results to confront pentylenetetrazole-induced seizures. This study aimed to evaluate the potential effects of three synthesized thalidomide derivatives on lithium-pilocarpine-induced status epilepticus. EXPERIMENTAL APPROACH: To induce status epilepticus, rats received lithium chloride (127 mg/kg, i.p.) and pilocarpine HCl (60 mg/kg, i.p.) 20 h after lithium chloride injection. Thirty min before pilocarpine HCl administration, rats received hyoscine N-butyl bromide (1 mg/kg, i.p.) and concurrently one of the test compounds (5B, 5C, and 5D), diazepam, thalidomide, or vehicle (4% DMSO) to evaluate their anti-epileptic effects. Epileptic seizures scores were assessed through the Racine scale. Twenty-four h after injection of pilocarpine, brain samples were extracted for further histopathological evaluation. FINDINGS/RESULTS: Results revealed that among tested compounds (5B, 5C, and 5D), only compound 5C (1 mg/kg) exhibited excellent anti-epileptic activity comparable to diazepam (10 mg/kg). Compound 5D (100 mg/kg) only demonstrated comparable anti-epileptic activity to thalidomide (1 mg/kg). Compound 5B did not have any anti-epileptic activity even at the dose of 100 mg/kg. The histopathological survey showed that compound 5C has more neuroprotective effects than diazepam and thalidomide in the cortex of the brain. In the cornu ammonis 1 region, thalidomide had higher protective properties and in the cornu ammonis 3 and dentate gyrus areas, diazepam had higher efficacy to prevent necrosis. CONCLUSION AND IMPLICATIONS: Compound 5C is a good candidate for further studies regarding its potency, compared to thalidomide and diazepam.

Tankyrase Inhibitor for Cardiac Tissue Regeneration: an In-silico Approach.

Myocardial infarction causes heart tissue damages; therefore, using non-invasive methods to regenerate the heart tissue could be very helpful. Recent studies claimed that the inhibition of the Wnt signaling could promote cardiac remodeling and induce cardiac regeneration. Therefore, a tankyrase inhibitor to stabilize the AXIN and inhibit the Wnt/ß-catenin signaling pathway will induce cardiac regeneration after injury. In this regard, virtual screening procedure, using molecular docking of 9127 FDA and world approved drugs, including herbal medicine, was done over the crystal structures of tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2) catalytic poly (ADP-ribose) polymerase (PARP) domains with PDB ID: 2RF5 and 3KR7, respectively, to find potential small molecule inhibitors to regenerate injured heart tissue. Subsequently, molecular dynamics simulations were done to assess the stability of selected ligands phenothrin and ethyl rosinate in the binding pocket of TNKS1 and TNKS2 for 100 ns, respectively. Both compounds show suitable interaction in their binding pocket. The molecular dynamics simulation results confirm their stability. The binding free energy of complexes was carried out by the MM-PBSA method. ADME properties also indicate the potential of drug-likeness of both compounds. Taking together both drugs may be promising for inducing cardiac regeneration after injury. Nevertheless, clinical approval remains.

Tetracyclines as a potential antiviral therapy against Crimean Congo hemorrhagic fever virus: Docking and molecular dynamic studies.

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is one of the deadliest human diseases with mortality rate near 50%. Special attention should be paid to this virus since there is no approved treatment for it. On the other hand, the recent outbreak of Ebola virus which is a member of hemorrhagic fever viruses shows this group of viruses can be extremely dangerous. Previous studies have indicated that nucleoprotein of CCHFV, a pivotal protein in virus replication, is an appropriate target for antiviral drug development. The aim of this study is finding inhibitor(s) of this protein. Herein, a virtual screening procedure employing docking followed by molecular dynamic was used to identify small molecule inhibitors of the nucleoprotein from FDA-approved drugs. Regarding CCHFV, using in-silico method is a safe way to achieve its inhibitor(s) since this virus is categorized as a World Health Organization (WHO) biosafety level 4 pathogen and therefore investigation in general laboratories is restricted. In conclusion, considering docking and molecular dynamic results alongside with bioavailability of FDA-approved drugs, doxycycline and minocycline are proposed as potential inhibitors of CCHFV nucleoprotein. There is hope, this study encourage other research groups for in-vitro and in-vivo studies about the efficacy of those two medicines in CCHFV treatment.

Determination of hydrogen cyanide concentration in mainstream smoke of tobacco products by polarography.

BACKGROUND: There has been a worldwide concern for the health risks of cigarette smoking and hydrogen cyanide (HCN) considered as one of the hazardous tobacco compounds which is needed to be determined in order to reduce the dose related to smoke disease risk. In this study, we prepare the experimental procedure to entrap the HCN from mainstream smoke of different brands of Tehran cigarette, through simulating human inhalation and determine its concentration applying polarography. RESULTS: The HCN level of the 50 commonly consumed tobacco products (47 cigarettes and 3 cigars) obtained from local store is ranged between 17.56 ± 1.02 and 1553.98 ± 0.56 µg per stick, this acquired amount is more than FDA approval (10 µg per stick), so the harmful effects of smoking is indicative. CONCLUSIONS: The comparative study of the results shows that the price and the weight of each product do not indicate HCN level. As can be seen, R(2) value which is a statistical measure of how close the data are to the fitted regression line is low (R(2) < 0.2). So it should not be deceived by names such as ultra light or infinite gravity to suck, because this names or the price haven(')t effect on the amount of HCN and its destructive effects.

A preliminary investigation of anticholinesterase activity of some Iranian medicinal plants commonly used in traditional medicine.

BACKGROUND: The aim of this study was to evaluate acetylcholinesterase inhibitory activity of some commonly used herbal medicine in Iran to introduce a new source for management of Alzheimer's disease. A total of 18 aqueous-methanolic extract (1:1; v/v) from the following plants: Brassica alba, Brassica nigra, Camellia sinensis, Cinchona officinalis, Citrus aurantifolia, Citrus x aurantium, Ferula assafoetida, Humulus lupulus, Juglans regia, Juniperus sabina, Myristica fragrans, Pelargonium graveolens, Pistacia vera, Punica granatum, Rheum officinale, Rosa damascena, Salix alba, and Zizyphus vulgaris were prepared and screened for their acetylcholinesterase inhibitory activity using in vitro Ellman spectrophotometric method. RESULTS: According to the obtained results, the order of inhibitory activity (IC50 values, µg /ml) of extracts from highest to the lowest was: C. sinensis (5.96), C. aurantifolia (19.57), Z. vulgaris (24.37), B. nigra (84.30) and R. damascena (93.1). CONCLUSIONS: The results indicated and confirmed the traditional use of these herbs for management of central nervous system disorders. C. sinensis showed the highest activity in inhibition of acetylcholinesterase. However, further investigations on identification of active components in the extracts are needed.