-
Archives of Razi Institute Aug 2023Ginseng is known as the king of all herbs in terms of antioxidant and anti-inflammatory activities and recently has become more involved in the treatment of neurological...
Ginseng is known as the king of all herbs in terms of antioxidant and anti-inflammatory activities and recently has become more involved in the treatment of neurological diseases. In this regard, this study aimed to determine the effects of on pentylenetetrazol-induced epilepsy during the estrus cycle. For this purpose, 30 rats were randomly divided into five groups, namely control (saline), valproic acid (VPA, 75 mg/kg), (50 mg/kg), (100 mg/kg), and (150 mg/kg) with four subgroups (proestrus, estrus, metestrus, and diestrus). Subsequently, the initiation time of myoclonic seizures (ITMS), initiation time of tonic-clonic seizures (ITTS), and seizure duration (SD) were determined. According to the results, ITMS and ITTS significantly increased in the VPA-treated group (<0.05). (100 and 150 mg/kg) administration significantly increased ITMS and ITTS (<0.05). Moreover, the ITMS and ITTS in -treated rats were significantly higher in luteal phases, compared to the follicular phase (<0.05). In addition, pretreatment with VPA significantly decreased SD, compared to the control group (<0.05). A significant decrease in SD was observed in the rats pretreated with (100 and 150 mg/kg) (<0.05). Seizure duration significantly decreased in animals that received in luteal phases, compared to the follicular phase (<0.05). These results suggested that have anticonvulsant effects that are more prominent during the luteal phase than the follicular phase.
Topics: Animals; Female; Rats; Anticonvulsants; Estrus; Ginsenosides; Pentylenetetrazole; Seizures; Valproic Acid
PubMed: 38226383
DOI: 10.32592/ARI.2023.78.4.1359 -
ENeuro May 2024The voltage-gated calcium channel subunit α2δ-2 controls calcium-dependent signaling in neurons, and loss of this subunit causes epilepsy in both mice and humans. To...
The voltage-gated calcium channel subunit α2δ-2 controls calcium-dependent signaling in neurons, and loss of this subunit causes epilepsy in both mice and humans. To determine whether mice without α2δ-2 demonstrate hippocampal activation or histopathological changes associated with seizure activity, we measured expression of the activity-dependent gene c and various histopathological correlates of temporal lobe epilepsy (TLE) in hippocampal tissue from wild-type (WT) and α2δ-2 knock-out ( KO) mice using immunohistochemical staining and confocal microscopy. Both genotypes demonstrated similarly sparse c- and expressions within the hippocampal dentate granule cell layer (GCL) at baseline, consistent with no difference in basal activity of granule cells between genotypes. Surprisingly, when mice were assayed 1 h after handling-associated convulsions, KO mice had fewer c--positive cells but dramatically increased expression in the dentate gyrus compared with WT mice. After administration of a subthreshold pentylenetetrazol dose, however, KO mice dentate had significantly more c- expression compared with WT mice. Other histopathological markers of TLE in these mice, including markers of neurogenesis, glial activation, and mossy fiber sprouting, were similar between WT and KO mice, apart from a small but statistically significant increase in hilar mossy cell density, opposite to what is typically found in mice with TLE. This suggests that the differences in seizure-associated dentate gyrus function in the absence of α2δ-2 protein are likely due to altered functional properties of the network without associated structural changes in the hippocampus at the typical age of seizure onset.
Topics: Animals; Mice, Knockout; Seizures; Hippocampus; Proto-Oncogene Proteins c-fos; Male; Calcium Channels; Mice, Inbred C57BL; Pentylenetetrazole; Mice; Disease Models, Animal; Neurons; Convulsants
PubMed: 38749701
DOI: 10.1523/ENEURO.0486-23.2024 -
The Journal of Pharmacy and Pharmacology Sep 2023In this study, tetramethylpyrazine (TMP) was evaluated for its therapeutic potential as an alternative therapy for epileptogenesis and its associated comorbidities in...
OBJECTIVES
In this study, tetramethylpyrazine (TMP) was evaluated for its therapeutic potential as an alternative therapy for epileptogenesis and its associated comorbidities in rats.
METHODS
The sub-convulsant dose of pentylenetetrazole (PTZ) (35 mg/kg, intraperitoneally) was injected on alternative days to produce kindling for 32 days and observed for seizure score percent of kindled animals in each group. After kindling, the animals were evaluated in models of anxiety, memory and predictive of depression. The neuroprotective effect of TMP was assessed by estimating the biochemical parameters in the cortex and hippocampus of the brain. Histopathological alterations were also observed in the cortex and hippocampus (CA1, CA3 and DG).
KEY FINDINGS
The administration of TMP reduced the seizure score and percentage of kindled animals dose-dependently. Furthermore, TMP significantly improved the behavioural parameters measured in the predictive models of depression but not in the anxiety and cognitive performances of the animals. The oxidative-nitrosative stress, excitotoxicity, neuroinflammation and histological alterations in the brain induced by PTZ were significantly mitigated by administering the TMP high dose of 60 mg/kg.
CONCLUSION
In conclusion, the TMP attenuated the depression behaviour in the PTZ-induced kindled rats, and reduced the oxidative-nitrosative stress, excitotoxicity, neuroinflammation and histological alterations of the brain.
Topics: Rats; Animals; Pentylenetetrazole; Neuroprotection; Rodentia; Neuroinflammatory Diseases; Kindling, Neurologic; Epilepsy; Seizures; Hippocampus
PubMed: 37100619
DOI: 10.1093/jpp/rgad022 -
Chinese Journal of Natural Medicines Feb 2024This study reports the isolation of four new β-carboline alkaloids (1-4) and six previously identified alkaloids (5-10) from the roots of Peganum harmala L. Among these...
This study reports the isolation of four new β-carboline alkaloids (1-4) and six previously identified alkaloids (5-10) from the roots of Peganum harmala L. Among these compounds, 1 and 2 were characterized as rare β-carboline-quinazoline dimers exhibiting axial chirality. Compound 3 possessed a unique 6/5/6/7 tetracyclic ring system with an azepine ring, and compound 4 was a novel annomontine β-carboline. The structures of these compounds were elucidated by spectroscopic data and quantum mechanical calculations. The biosynthetic pathways of 1-3 were proposed. Additionally, the cytotoxicity of some isolates against four cancer cell lines (HL-60, A549, MDA-MB-231, and DU145) was evaluated. Notably, compound 4 exhibited significant cytotoxicity against HL-60, A549, and DU145 cells with IC values of 12.39, 12.80, and 30.65 μmol·L, respectively. Furthermore, compound 2 demonstrated selective cytotoxicity against HL-60 cells with an IC value of 17.32 μmol·L.
Topics: Humans; Peganum; Alkaloids; Carbolines; HL-60 Cells
PubMed: 38342569
DOI: 10.1016/S1875-5364(24)60583-2 -
Advances in Therapy Apr 2024For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can... (Clinical Trial)
Clinical Trial
INTRODUCTION
For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts-non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety.
METHODS
The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2-14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases).
RESULTS
Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0-98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition.
CONCLUSIONS
Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment.
TRIAL REGISTRATION
ClinicalTrials.gov identifier, NCT04742699.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Japan; Prospective Studies; Triazoles; Azepines; Pyridines; Indenes; Pyrimidines
PubMed: 38460107
DOI: 10.1007/s12325-024-02811-2 -
Journal of Biochemistry Jul 2023Three dynamin isoforms play critical roles in clathrin-dependent endocytosis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells via...
Three dynamin isoforms play critical roles in clathrin-dependent endocytosis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells via clathrin-dependent endocytosis. We previously reported that 3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine (clomipramine) inhibits the GTPase activity of dynamin 1, which is in mainly neuron. Therefore, we investigated whether clomipramine inhibits the activity of other dynamin isoforms in this study. We found that, similar to its inhibitory effect on dynamin 1, clomipramine inhibited the l-α-phosphatidyl-l-serine-stimulated GTPase activity of dynamin 2, which is expressed ubiquitously, and dynamin 3, which is expressed in the lung. Inhibition of GTPase activity raises the possibility that clomipramine can suppress SARS-CoV-2 entry into host cells.
Topics: Humans; Dynamin I; Clomipramine; Serine; Clathrin; COVID-19; SARS-CoV-2; Dynamins; Endocytosis; Protein Isoforms
PubMed: 37137298
DOI: 10.1093/jb/mvad038 -
The International Journal of... Jun 2024Preterm neonates encounter hyperoxia relatively early, and are more exposed to hyperoxic stress due to their insufficient antioxidant defense mechanisms. This study was...
Preterm neonates encounter hyperoxia relatively early, and are more exposed to hyperoxic stress due to their insufficient antioxidant defense mechanisms. This study was planned around the hypothesis that this hyperoxic effect may cause a disposition to future acute seizures. This study was composed of two main groups Hyperoxy and Control (Room air with normal O levels) Groups. : The experimental group consisted of premature newborn rats exposed to hyperoxia with their dams from birth to postnatal day 5. The group was not exposed to hyperoxia and housed the same room air and temperature as their dams. Female, Acute Epilepsy Female, Male, Acute Epilepsy Male, and a total of eight subgroups were formed in both the control and hyperoxia groups. When the rats were two months old, intracranial electrodes were attached to obtain electrocorticography (ECoG) recordings. Pre-model recordings were taken, after which an acute pentylenetetrazole (PTZ) model of absence seizure was induced by the intraperitoneal administration of PTZ at 50 mg/kg. ECoG records were examined using the PowerLab system for 180 min. Spike wave number and duration, Spike wave frequency and amplitude data were evaluated. Seven female and three male rats were exposed to hyperoxia, and a control group of five female and three male rats were included in the study. The median interquartile range for spike wave latency in the hyperoxia and control groups were 1112 (644-1545) and 654 (408-1152), frequency 4476 (3120-7421) and 3934 (2264-4704), and amplitude data 0.68 (0.59-0.79) and 0.52 (0.37-0.67), respectively. Although a difference was observed in median values capable of constituting susceptibility to epilepsy, the difference was not statistically significant ( > 0.05). In terms of gender, spike-wave counts were significantly higher in female rats ( < 0.05). Females exposed to hyperoxia were more susceptible to epilepsy than both males and females in the control group ( < 0.05). Exposure to hyperoxia in the first days of life of premature neonates due to their susceptibility to oxidative stress and insufficient antioxidant mechanisms, can cause a disposition to acute seizures. As a result, females exposed to hyperoxia during the neonatal period may be prone to epilepsy in maturity.
Topics: Animals; Female; Male; Hyperoxia; Seizures; Animals, Newborn; Rats; Disease Models, Animal; Pentylenetetrazole; Disease Susceptibility; Electrocorticography; Rats, Wistar
PubMed: 36282040
DOI: 10.1080/00207454.2022.2140427 -
Journal of Ethnopharmacology Jun 2024Cynanchum otophyllum C.K.Schneid.PI.Wilson, commonly referred as ''Qingyangshen'' (QYS), is a traditional folk medicine from Yunnan, renowned for its efficacy in...
ETHNOPHARMACOLOGICAL RELEVANCE
Cynanchum otophyllum C.K.Schneid.PI.Wilson, commonly referred as ''Qingyangshen'' (QYS), is a traditional folk medicine from Yunnan, renowned for its efficacy in neurological and psychiatric disorders. Glycosides isolated from QYS have shown promise in alleviating epilepsy, however, mechanisms of action and specific molecular targets remain to be elucidated.
AIM OF THE STUDY
The study aimed to evaluate the anticonvulsant effects of Qingyangshen glycosides M1 (M1), a C steroidal glycoside from QYS, on pentylenetetrazol (PTZ)-induced convulsions in zebrafish (Danio rerio), and its neuroprotective effect on Glutamate (Glu)-induced damage to PC12 cells, and importantly to identify its potential molecular targets.
MATERIALS AND METHODS
To evaluate anticonvulsant activity of M1, 7 days-post-fertilization (7-dpf) animals were pretreated (by immersion) and then exposed to PTZ (10 mM) solution. Furthermore, Glu-induced PC12 cell damage was employed to investigate the neuroprotective and anti-apoptotic capacity. Cells were pretreated with various concentrations of M1 (0-10 μM) for 12 h and then co-treated with Glu (15 mM) for an additional 24 h. The cell viability, apoptosis rate and apoptosis-related proteins (p-PI3K, PI3K, Akt, p-Akt, CREB, p-CREB, BDNF, Bax and Bcl-2) were measured using CCK-8, annexin V/PI and Western blot assays. To model the expected interaction between M1 and candidate cannabinoid receptor type 1 (CBR), ERK phosphorylation, molecular docking, and drug affinity responsive target stability (DARTS) techniques were employed. Finally, CBR antagonist Rimonabant (Rim) was validated by co-administration in both zebrafish and cells to confirm the requirement of CBR for M1 efficacy.
RESULTS
At a concentration of 400 μM, M1 dramatically reversed PTZ-induced convulsive-like behaviors in zebrafish, as evidenced by a significant reduction in locomotor activity. In the context of Glu-induced cytotoxicity, M1 (10 μM) demonstrated a notable increase in cell viability and suppressed apoptosis through modulation of the Bax/Bcl-2 ratio and activation of the PI3K/Akt/CREB/BDNF signaling axis. These effects were facilitated through CBR activation. In contrast, Rim dampened the beneficial activities of M1 as a cannabinoid agonist.
CONCLUSIONS
These results demonstrated that M1 as a potential CBR activator, exhibiting anticonvulsive effects in a PTZ-induced zebrafish model and neuroprotective properties via the PI3K/Akt/CREB/BDNF signaling axis in a Glu-induced PC12 cell injury model. Notably, the observed seizure relief attenuated by CBR chemical antagonism.
Topics: Humans; Rats; Animals; Proto-Oncogene Proteins c-akt; Glycosides; Zebrafish; Anticonvulsants; Phosphatidylinositol 3-Kinases; bcl-2-Associated X Protein; Brain-Derived Neurotrophic Factor; Molecular Docking Simulation; China; Seizures; Apoptosis Regulatory Proteins; Apoptosis; Proto-Oncogene Proteins c-bcl-2; Pentylenetetrazole; Neuroprotective Agents
PubMed: 38423411
DOI: 10.1016/j.jep.2024.117982 -
Water Research May 2024Municipal wastewater treatment plants (WWTPs) play a crucial role in the collection and redistribution of plastic particles from both households and industries,...
Municipal wastewater treatment plants (WWTPs) play a crucial role in the collection and redistribution of plastic particles from both households and industries, contributing to their presence in the environment. Previous studies investigating the levels of plastics in WWTPs, and their removal rates have primarily focused on polymer type, size, shape, colour, and particle count, while comprehensive understanding of the mass concentration of plastic particles, particularly those <1 µm (nanoplastics), remains unclear and lacking. In this study, pyrolysis gas chromatography-mass spectrometry was used to simultaneously determine the mass concentration of nine selected polymers (i.e., polyethylene (PE), polypropylene (PP), polystyrene (PS), poly(ethylene terephthalate) (PET), nylon 6, nylon 66, polyvinylchloride (PVC), poly(methyl methacrylate) (PMMA) and polycarbonate (PC)) below 1 µm in size across the treatment processes or stages of three WWTPs in Australia. All the targeted nanoplastics were detected at concentrations between 0.04 and 7.3 µg/L. Nylon 66 (0.2-7.3 µg/L), PE (0.1-6.6 µg/L), PP (0.1-4.5 µg/L), Nylon 6 (0.1-3.6 µg/L) and PET (0.1-2.2 µg/L), were the predominant polymers in the samples. The mass concentration of the total nanoplastics decreased from 27.7, 18 and 9.1 µg/L in the influent to 1, 1.4 and 0.8 µg/L in the effluent, with approximate removal rates of 96 %, 92 % and 91 % in plants A, B and C, respectively. Based on annual wastewater effluent discharge, it is estimated that approximately 24, 2 and 0.7 kg of nanoplastics are released into the environment per year for WWTPs A, B and C, respectively. This study investigated the mass concentrations and removal rates of nanoplastics with a size range of 0.01-1 µm in wastewater, providing important insight into the pollution levels and distribution patterns of nanoplastics in Australian WWTPs.
Topics: Wastewater; Microplastics; Nylons; Pyrolysis; Gas Chromatography-Mass Spectrometry; Australia; Plastics; Polypropylenes; Polymethyl Methacrylate; Polyethylenes; Water Purification; Water Pollutants, Chemical; Environmental Monitoring; Caprolactam; Polymers
PubMed: 38461599
DOI: 10.1016/j.watres.2024.121397 -
Journal of Medicinal Chemistry Dec 2023To discover new multifunctional agents for the treatment of cardiovascular diseases, we designed and synthesized a series of compounds with a cyclopropyl alcohol moiety...
To discover new multifunctional agents for the treatment of cardiovascular diseases, we designed and synthesized a series of compounds with a cyclopropyl alcohol moiety and evaluated them in biochemical assays. Biological screening identified derivatives with dual activity: preventing Ca leak through ryanodine receptor 2 (RyR2) and enhancing cardiac sarco-endoplasmic reticulum (SR) Ca load by activation of Ca-dependent ATPase 2a (SERCA2a). The compounds that stabilize RyR2 at micro- and nanomolar concentrations are either structurally related to RyR-stabilizing drugs or Rycals or have structures similar to them. The novel compounds also demonstrate a good ability to increase ATP hydrolysis mediated by SERCA2a activity in cardiac microsomes, e.g., the half-maximal effective concentration (EC) was as low as 383 nM for compound 12a, which is 1,4-benzothiazepine with two cyclopropanol groups. Our findings indicate that these derivatives can be considered as new lead compounds to improve cardiac function in heart failure.
Topics: Calcium; Calcium Channel Blockers; Myocytes, Cardiac; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Thiazepines
PubMed: 37991191
DOI: 10.1021/acs.jmedchem.3c01235