Neuropharmacological effects of lipoic acid and ubiquinone on the mRNA level of interleukin‐1β and acetylcholinesterase activity in rat hippocampus after seizures

The purpose of this study was to investigate the neuroprotective effects of lipoic acid and ubiquinone on interleukin‐1β (IL‐1β) mRNA levels and acetylcholinesterase (AChE) activities in rat hippocampus after pilocarpine‐induced seizures. Wistar rats were intraperitoneally administered with either 0.9% saline (icontrol group), LA (10 or 20 mg/kg, LA10 or LA20 groups), UQ (20 or 40 mg/kg, UQ20 and UQ40 groups), pilocarpine (400 mg/kg, P400 group), or co‐administration of pilocarpine with LA or UQ groups 30 min prior to LA or UQ administration. After the treatments, all groups were observed for 1 h. IL‐1β mRNA and AChE activity in rat hippocampus at 1 h after SE onset was determined. Results showed that rats pretreated with LA or UQ developed less seizures and SE more slowly and has less number than animals treated with pilocarpine alone. Reduced IL‐1β mRNA and marked AChE activities in the hippocampus were significantly higher in rats pretreated with LA or UQ in comparison with the values of the control and seized groups. Our findings strongly support the hypothesis that an increase on IL‐1β mRNA levels in hippocampus occurs during seizures induced by pilocarpine, which indicates that inflammatory process plays a crucial role in seizures pathogenic consequences. Our result also suggests that LA or UQ can exert significant neuroprotective effects, at least in part, because of the increase in the AChE activities in rat hippocampus that will be useful in the treatment of neurodegenerative diseases.     

Na+‐K+‐ATPase,a potent neuroprotective modulator against Alzheimer disease

Alzheimer disease (AD) is a neurodegenerative disorder clinically characterized by progressive cognitive and memory dysfunction, which is the most common form of dementia. Although the pathogenesis of neuronal injury in AD is not clear, recent evidences suggest that Na⁺‐K⁺‐ATPase plays an important role in AD, and may be a potent neuroprotective modulator against AD. This review aims to provide readers with an in‐depth understanding of Na⁺‐K⁺‐ATPase in AD through these modulations of some factors that are as follows, which leads to the change of learning and memory in the process of AD.

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(E)‐2‐benzylidene‐4‐phenyl‐1,3‐diselenole has antioxidant and hepatoprotective properties against oxidative damage induced by 2‐nitropropane in rats

The in vitro effect of (E)‐2‐benzylidene‐4‐phenyl‐1,3‐diselenole (BPD) was evaluated through iron/EDTA‐induced thiobarbituric acid reactive species (TBARS) and reactive species (RS) determinations as well as of the scavenging 2,2′‐diphenyl‐1‐picrylhydrazyl (DPPH) radical quantification. BPD at the concentrations of 10 and 50 μΜ decreased RS and TBARS levels, respectively. The antioxidant activity was not related to the scavenging DPPH radical mechanism. A second objective of this study was to investigate the hepatoprotective action of BPD, administered by oral route, against oxidative damage induced by 2‐nitropropane (2‐NP) (100 mg/kg of body weight) in liver of rats. At the dose of 50 mg/kg, BPD protected against the increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) activities induced by 2‐NP. BPD (10 and 50 mg/kg) protected against the increase in TBARS levels and alkaline phosphatase (ALP) activity. Sections of liver from 2‐NP‐exposed rats presented intense infiltration of inflammatory cells and loss of cellular architecture. BPD (10 and 50 mg/kg) attenuated 2‐NP‐induced hepatic histological alterations. The inhibition of δ‐aminolevulinic dehydratase (δ‐ALA‐D), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S‐transferase (GST) activities and the decreased GSH levels caused by 2‐NP were protected by BPD (50 mg/kg). Catalase activity and ascorbic acid levels were not altered by 2‐NP. These results demonstrated the antioxidant and hepatoprotective effects of BPD in liver of rats.     

Sumatriptan reduces severity of status epilepticus induced by lithium–pilocarpine through nitrergic transmission and 5‐HT1B/D receptors in rats: A pharmacological‐based evidence

Status epilepticus (SE) is a life‐threatening neurologic disorder that can be as both cause and consequence of neuroinflammation. In addition to previous reports on anti‐inflammatory property of the anti‐migraine medication sumatriptan, we have recently shown its anticonvulsive effects on pentylenetetrazole‐induced seizure in mice. In the present study, we investigated further (i) the effects of sumatriptan in the lithium–pilocarpine SE model in rats, and (ii) the possible involvement of nitric oxide (NO), 5‐hydroxytryptamin 1B/1D (5‐HT_1B/1D) receptor, and inflammatory pathways in such effects of sumatriptan. Status epilepticus was induced by lithium chloride (127 mg/kg, i.p) and pilocarpine (60 mg/kg, i.p.) in Wistar rats. While SE induction increased SE scores and mortality rate, sumatriptan (0.001‐1 mg/kg, i.p.) improved it (P < 0.001). Administration of the selective 5‐HT_1B/1D antagonist GR‐127935 (0.01 mg/kg, i.p.) reversed the anticonvulsive effects of sumatriptan (0.01 mg/kg, i.p.). Although both tumor necrosis factor‐α (TNF‐α) and NO levels were markedly elevated in the rats' brain tissues post‐SE induction, pre‐treatment with sumatriptan significantly reduced both TNF‐α (P < 0.05) and NO (P < 0.001) levels. Combined GR‐127935 and sumatriptan treatment inhibited these anti‐inflammatory effects of sumatriptan, whereas combined non‐specific NOS (L‐NAME) or selective neuronal NOS (7‐nitroindazole) inhibitors and sumatriptan further reduced NO levels. In conclusion, sumatriptan exerted a protective effect against the clinical manifestations and mortality rate of SE in rats which is possibly through targeting 5‐HT_1B/1D receptors, neuroinflammation, and nitrergic transmission.     

Lack of efficacy of alpha‐lipoic acid in burning mouth syndrome: A double‐blind,randomized, placebo‐controlled study

Background: A systematic review from the Cochrane Collaboration stated that alpha‐lipoic acid (ALA) may help in the management of burning mouth syndrome (BMS). Because all of the data on ALA came from a single group, it has been stressed that its effectiveness should be reproduced in other populations. Aim: A double‐blind, randomized, placebo‐controlled study, including two test groups (Group A and Group B) and one control group (Group C), was carried out to evaluate the efficacy of systemic ALA (400mg) and ALA (400mg) plus vitamins in the treatment of BMS. Methods: Sixty‐six patients (54 females and 12 males) were included in an 8‐week trial. Symptoms were evaluated by using a visual analogue scale (VAS) and the McGill Pain Questionnaire (MPQ) at 0, 2, 4, 8 and 16 weeks. Results: Fifty‐two patients (43 females and 9 males, aged 67.3±11.9 years) completed the study. All three groups had significant reductions in the VAS score and in the mixed affective/evaluative subscale of the MPQ; the responders’ rate (at least 50% improvement in the VAS score) was about 30%. No significant differences were observed among the groups either in the response rate or in the mean latency of the therapeutic effect. Conclusions: The fairly high placebo effect observed is very similar to data obtained from patients affected by atypical facial pain. This study failed to support a role for ALA in the treatment of BMS, and further investigations are needed to identify the cause of BMS in order to develop efficacious therapies.     

Na+/Ca2+‐exchanger‐mediated Mn2+‐enhanced 1H2O MRI in hypoxic,perfused rat myocardium

Paramagnetic Mn²⁺ has emerged in the search for non‐invasive magnetic resonance imaging (MRI) techniques to monitor Ca²⁺ in diagnostic and prognostic cardiovascular disease tests because it both alters MRI contrast and behaves as a Ca²⁺ ‘surrogate’ in vivo. However, the reliance on macroscopically averaged measurements to infer microscopic processes constitutes a major limitation of MRI. This investigation circumvents this limitation and contributes an MRI‐based myocardial Ca²⁺‐transporter assay, which probes the Na⁺/Ca²⁺‐exchanger involvement in Mn²⁺ (and presumably Ca²⁺) transport by virtue of its response to pharmacological inhibition. In the model employed herein, ex vivo arrested rat hearts underwent normoxia and then hypoxia while a constant (hyperkalemic) perfusion minimized flow (and uncontrolled Ca²⁺‐channel) contributions to Mn²⁺‐enhanced MRI measurements. The results (i) demonstrate that Mn²⁺ (and presumably Ca²⁺) accumulates via Na⁺/Ca²⁺‐exchanger‐mediated transport during hyperkalemic hypoxia and further, (ii) implicate hypo‐perfusion (rather than the diminished participation of an isolated sarcolemmal Ca²⁺‐transporter) as the mechanism that underlies the reported reductions of Mn²⁺ accumulation (relative to healthy myocardium) subsequent to myocardial insults in MRI studies. Although myriad studies have employed Mn²⁺‐enhanced MRI in myocardial investigations, this appears to be the first attempt to assay the Na⁺/Ca²⁺‐exchanger with MRI under highly circumscribed conditions. MRI‐based Ca²⁺‐transporter assays, such as the Na⁺/Ca²⁺‐exchanger assay utilized here, will inevitably impact disciplines in the medical sciences and beyond. Copyright © 2007 John Wiley & Sons, Ltd.     

Mobilization effects of G‐CSF,GM‐CSF,and darbepoetin‐α for allogeneic peripheral blood stem cell transplantation

The effects of GM‐/G‐CSF and darbepoetin‐α on stem cell mobilization were investigated. From February 2005 to March 2007, 30 allogeneic sibling donors were randomly assigned to a G‐CSF group (5 μg/kg/day for 5–7 days) or triple group (GM‐CSF 10 μg/kg/day on 1st and 2nd day, G‐CSF 5 μg/kg/day for 5–7 days, and darbepoetin‐α 40 mg on 1st day). The MNCs and CD34⁺ cells were not different between the two groups, although the doses (×10⁸/kg of recipient body weight) of CD3⁺ cells (3.64 ± 1.75 vs. 2.63 ± 1.36, P = 0.089) and CD8⁺ cells (1.07 ± 0.53 vs. 0.60 ± 0.30, P = 0.006) were lower in the triple group. The engraftments, frequency of RBC transfusions, and hemoglobin recovery were not different between the two groups. The cumulative incidence of overall and Grades II–IV aGVHD was 64.3% vs. 61.1% and 25.9% vs. 27.1% in the G‐CSF and triple regimen group, respectively, whereas the cumulative incidence of cGVHD was 20.8 ± 1.3% and 24.4 ± 1.7%, respectively. In conclusion, the triple regimen did not seem to be superior to G‐CSF alone in terms of the CD34+ cell dose, hemoglobin recovery, and GVHD. However, the CD8+ cell count was significantly lower in the triple regimen group. The role of a lower CD8+ cell count in the graft may need to be elucidated in the future. J. Clin. Apheresis, 2009. © 2009 Wiley‐Liss, Inc.     

Lipoic acid alters amino acid neurotransmitters content in rat hippocampus after pilocarpine‐induced seizures

This study was aimed at investigating the anticonvulsant activity of lipoic acid (LA) against pilocarpine‐induced seizures as well as the effects of this metabolic antioxidant on the hippocampal extracellular concentrations of amino acid neurotransmitters glutamate, aspartate, glycine and glutamate and γ‐aminobutyric acid (GABA). In vivo microdialysis demonstrated that an intraperitoneal administration of pilocarpine induced a pronounced increment of hippocampal glutamate and aspartate concentrations, whereas no significant change was observed in the levels of glycine or GABA. LA (10, 20 or 30 mg/kg) pretreatment completely blocked pilocarpine‐evoked increases in extracellular glutamate and aspartate concentrations. Significant reductions in hippocampal GABA and glycine concentrations were also observed although not as pronounced as those shown by glutamate and aspartate. Based on the finding that LA protected rats against pilocarpine‐induced seizures, it could be suggested that the reduction in inhibitory amino acid neurotransmitters levels was comparatively minor and offset by a more pronounced reduction in glutamate and aspartate extracellular concentrations. Therefore, the fact that LA could drastically reduce pilocarpine‐induced increases in glutamate and aspartate should account, at least partly, for its anticonvulsant activity observed in pilocarpine‐induced seizure in rats.     

Parachlorophenylalanine‐induced 5‐HT depletion alters behavioral and brain neurotransmitters levels in 6‐Hz psychomotor seizure model in mice

The present study was designed to investigate the role of serotonin and other neurotransmitters namely dopamine (DA), histamine, nor‐epinephrine (NE), glutamate, and γ‐aminobutyric acid (GABA) in the 6‐Hz‐induced psychomotor seizures in Swiss albino mice. Parachlorophenylalanine (PCPA, 300 mg/kg/day, i.p for 3 days)‐treated mice were given 6‐Hz stimulation. Sodium valproate (SVP) (200 mg/kg/day, p.o for 3 days) was used as a reference antiepileptic drug. The behavioral changes induced by 6 Hz including increased rearing and grooming, Straub's tail, behavioral arrest, stun position were amplified by PCPA. The 6‐Hz‐induced seizures were accompanied by reduced brain 5‐HT, DA, NE, histamine, GABA, and enhanced glutamate levels. PCPA facilitated further reduction of endogenous 5‐HT and DA levels but not NE, histamine, GABA, and glutamate levels. Pre‐ and post‐treatment with SVP protected the mice from 6‐Hz seizures and attenuated PCPA‐induced changes in the levels of 5‐HT and DA in the mice brain suggesting the protective effect of SVP in the pharmacoresistant model of epilepsy involving mainly serotonergic mechanism. However, the study also suggests modulation of other neurotransmitters both in 6‐Hz psychomotor seizures and in the action of SVP against such seizures.     

Capillary Endothelial Na+, K+, ATPase Transporter Homeostasis and a New Theory for Migraine Pathophysiology

(Headache 2010;50:459‐478) Background.— Cerebrospinal fluid sodium concentration ([Na⁺]_csf) increases during migraine, but the cause of the increase is not known. Objective.— Analyze biochemical pathways that influence [Na⁺]_csf to identify mechanisms that are consistent with migraine. Method.— We reviewed sodium physiology and biochemistry publications for links to migraine and pain. Results.— Increased capillary endothelial cell (CEC) Na⁺, K⁺, ‐ATPase transporter (NKAT) activity is probably the primary cause of increased [Na⁺]_csf. Physiological fluctuations of all NKAT regulators in blood, many known to be involved in migraine, are monitored by receptors on the luminal wall of brain CECs; signals are then transduced to their abluminal NKATs that alter brain extracellular sodium ([Na⁺]_e) and potassium ([K⁺]_e). Conclusions.— We propose a theoretical mechanism for aura and migraine when NKAT activity shifts outside normal limits: (1) CEC NKAT activity below a lower limit increases [K⁺]_e, facilitates cortical spreading depression, and causes aura; (2) CEC NKAT activity above an upper limit elevates [Na⁺]_e, increases neuronal excitability, and causes migraine; (3) migraine‐without‐aura may arise from CEC NKAT over‐activity without requiring a prior decrease in activity and its consequent spreading depression; (4) migraine triggers disturb, and treatments improve, CEC NKAT homeostasis; (5) CEC NKAT‐induced regulation of neural and vasomotor excitability coordinates vascular and neuronal activities, and includes occasional pathology from CEC NKAT‐induced apoptosis or cerebral infarction.     

Memantine delayed N‐methyl‐D‐aspartate ‐induced convulsions in neonatal rats

Memantine (1‐amino‐3,5‐dimethyladamantane) is a moderate‐affinity uncompetitive antagonist of N‐methyl‐d‐aspartate (NMDA) receptors. In this study, we have explored the effect of memantine against N‐methyl‐d‐aspartate (NMDA)‐induced seizures in neonatal rats. Here, we evaluated various behavioral seizure abnormalities in neonatal rats (Sprague–Dawley; postnatal day 9) after an intraperitoneal administration of NMDA. Further, we explored whether an acute administration of memantine could protect these neonates against different phases of convulsions induced by NMDA. In a separate study, we have compared the effect of levetiracetam in the same animal model. Exogenous administration of NMDA (30 mg/kg., i.p.) in neonatal rats resulted in arrest of activity, emprosthotonos curvature (trunk is bent forward by the entire muscles), myoclonic jerks, and forelimb/hindlimb clonus. The clonus phase in neonates was followed by loss of righting reflex and continuous seizures (for more than 5 min) suggesting status epilepticus, tonic extension, and death. Pretreatment of memantine hydrochloride (10–30 mg/kg., i.p.) dose‐dependently delayed the onset of different phases of convulsions induced by NMDA. Memantine at the highest dose was found to be ataxic in rat neonates, while lower doses were free of any observed behavioral signs of toxicity. Levetiracetam (25 mg/kg., i.p.) when administered 30 min before the NMDA challenge blocked only the jerk phase and did not affect other phases of NMDA‐induced convulsions. These data indicated that memantine and other safer uncompetitive NMDA receptor antagonists may be protective in the management of neonatal seizures.     

Appropriate timing of G‐CSF use after mobilization chemotherapy significantly increases the yield of CD34+ cells in autoPBSCT

The yield of CD34+ cells collected by apheresis for autologous peripheral blood stem cell (PBSC) transplantation was greatly increased when the appropriate timing was determined to begin using G‐CSF after COAEP (Cytoxan, Vinblastine, Arabinosylcytosin, Etoposide and Prednisone) mobilization. Twenty‐nine patients with lymphoma or multiple myeloma (MM) received the same mobilization chemotherapy, including cytoxan (CTX) 400 mg/m² d1; vinblastine (VLB) 2 mg/m² d1; Ara‐C 60 mg/m² × 5d; vp‐16 60 mg/m² × 5d; and prednisone 40 mg/m² × 5d. The historical control group (12 cases) received subcutaneous G‐CSF (filgrastim) at the first restoration after the initial nadir of the peripheral WBC count. The experimental group (17 cases) received G‐CSF during the steady rise of the WBC count (end of fluctuating after initial nadir). G‐CSF was given in a single daily subcutaneous dose of 5 μg/kg until the final PBSC apheresis. When the peripheral WBC and mononuclear cell (MNC) counts reached 10 × 10⁹/L and 1 × 10⁹/L, respectively, leukapheresis was carried out using the COBE Spectrablood cell separator. Despite comparable treatment with alkylating agents, a significantly increased yield of CD34‐positive cells was observed in the experimental group (32 × 10⁶/kg) compared with the historical control group (3.1 × 10⁶/kg) (P = 0.0182). This result indicates the importance of appropriate timing for the use G‐CSF after mobilization chemotherapy to increase the CD34+ cell yield. J. Clin. Apheresis, 2009. © 2009 Wiley‐Liss, Inc.     

Nerolidol exhibits antinociceptive and anti‐inflammatory activity: involvement of the GABAergic system and proinflammatory cytokines

Nerolidol, an acyclic sesquiterpene found as a major constituent of several essential oils, has several pharmacological activities, but its action in pain processes has never been studied. The purpose of our research was to evaluate the antinociceptive and anti‐inflammatory activities of nerolidol, as well as possible mechanisms of action, in experimental mouse models of pain. Antinociceptive activity was evaluated using the acetic acid‐induced writhing test, the formalin test, and the hot‐plate test. The nerolidol‐treated group showed lesser acetic acid‐induced abdominal contractions than the control group in all of the three doses tested (200, 300, and 400 mg/kg, p.o.). The formalin test doses of 300 and 400 mg/kg p.o. inhibited licking time, in both the first phase and the second phase. In the hot‐plate test, nerolidol did not alter latency at any of the observed time points. Motor coordination, evaluated through the rotarod test, was not hindered in animals treated with nerolidol. Regarding the mechanism of action, the antinociceptive activity of nerolidol is related to the GABAergic system, and not to the opioidergic or ATP‐sensitive K⁺ channels. Treatment with nerolidol reduced carrageenan‐induced paw edema. In the model of carrageenan‐induced peritonitis, nerolidol decreased the influx of polymorphonuclear cells and also reduced levels of tumor necrosis factor (TNF‐α) in peritoneal lavage. Nerolidol reduced production of interleukin 1 beta (IL‐1β) in LPS‐stimulated, peritoneal macrophages. Thus, these results showed that nerolidol has antinociceptive activity with possible involvement of the GABAergic system, and anti‐inflammatory activity, attributed to the suppression of TNF‐α and IL‐1β proinflammatory cytokines.     

Influence of arachidonyl‐2′‐chloroethylamide,a selective cannabinoid CB1 receptor agonist,on the anticonvulsant and acute side‐effect potentials of clobazam,lacosamide, and pregabalin in the maximal electroshock‐induced seizure model and chimney test in mice

The influence of arachidonyl‐2′‐chloroethylamide (ACEA – a selective cannabinoid CB₁ receptor agonist) on the anticonvulsant potency and acute adverse‐effect potentials of clobazam, lacosamide, and pregabalin was determined in the maximal electroshock‐induced seizure model and chimney test in mice. ACEA (2.5 mg/kg, i.p.) significantly enhanced the anticonvulsant potency of pregabalin in the mouse maximal electroshock‐induced seizure model by decreasing the median effective dose (ED₅₀) of pregabalin from 125.39 to 78.06 mg/kg (P < 0.05). In contrast, ACEA (2.5 mg/kg) had no significant impact on the anticonvulsant potency of clobazam and lacosamide in the mouse maximal electroshock‐induced seizure model. On the other hand, ACEA (2.5 mg/kg) did not affect acute adverse effects of clobazam, lacosamide or pregabalin, and the median toxic doses (TD₅₀) for the studied anti‐epileptic drugs in combination with ACEA did not differ from the TD₅₀ values as determined for the drugs administered alone in the chimney test. In conclusion, ACEA ameliorates the pharmacological profile of pregabalin, when considering both the anticonvulsant and the acute adverse effects of the drug in preclinical study on animals. The combination of pregabalin with ACEA can be of pivotal importance for patients with epilepsy as a potentially advantageous combination if the results from this study translate into clinical settings.     

Studies on the ATPase enzyme system in human intestinal epithelial cells

Human intestinal epithelial cells were fractionated to yield a soluble and particulate cell fraction, and a brush border fraction. (Na⁺-K⁺)-stimulated, ouabain sensitive ATPase (EC 3.6.1.4) was located in the brush border and soluble cell fraction. Mg²⁺-ATPase (EC 3.6.1.3) occurred throughout the epithelial cell. This enzyme was inhibited by Ca²⁺ in the brush border fraction, but was activated by Ca²⁺ and Mg²⁺ in the particulate cell fraction. The ATPase systems were separated and partially purified using Sephadex G-100. The molecular weights and enzymatic properties were examined. The results indicated that human intestinal epithelial cells contain two distinct types of (Na⁺-K⁺)-ATPase.     

Antidepressant‐like effect of bis‐eugenol in the mice forced swimming test: evidence for the involvement of the monoaminergic system

Dehydrodieugenol, known as bis‐eugenol, is a eugenol ortho dimer, and both compounds were able to exhibit anti‐inflammatory and antioxidant activities in previous studies. Furthermore, eugenol showed antidepressant‐like effect; however, the biological actions of bis‐eugenol on experimental models for screening antidepressant activity are still unknown. The present study investigated a possible antidepressant‐like activity of bis‐eugenol in the forced swimming test (FST) and tail suspension test (TST) in mice and the involvement in the monoaminergic system in this effect. In addition, a neurochemical analysis on brain monoamines of mice acutely treated with bis‐eugenol was also conducted. Bis‐eugenol decreased the immobility time in the FST and TST without accompanying changes in ambulation in the open field test at 10 mg/kg, i.p.. Nevertheless, it induced ambulation at 25 and 50 mg/kg doses. The anti‐immobility effect of bis‐eugenol (10 and 50 mg/kg, i.p.) was prevented by pretreatment of mice with p‐chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), yohimbine (1 mg/kg, i.p., an α2‐adrenoceptor antagonist), SCH23390 (15 μg/kg, s.c., a dopamine D1 receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist). Monoamines analysis using high‐performance liquid chromatograph revealed significant increase in the 5‐HT, NE and DA levels in brain striatum. The present study indicates that bis‐eugenol possesses antidepressant‐like activity in FST and TST by altering dopaminergic, serotonergic and noradrenergic systems function.