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Metabolic Brain Disease Oct 2023Epilepsy, a chronic neurological condition, impacts millions of individuals globally and remains a significant contributor to both illness and mortality. Available...
Epilepsy, a chronic neurological condition, impacts millions of individuals globally and remains a significant contributor to both illness and mortality. Available antiepileptic drugs have serious side effects which warrants to explore different medicinal plants used for the management of epilepsy reported in Traditional Indian Medicinal System (TIMS). Therefore, we explored the antiepileptic potential of the Grewia tiliaefolia (Tiliaeceae) which is known for its neuroprotective properties. Aerial parts of G. tiliaefolia were subjected to extraction with increasing order of polarity viz. hexane, chloroform and methanol. Antioxidant potential of hexane, chloroform and methanol extracts of G. tiliaefolia was evaluated by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) assay, total antioxidant capacity (TAC) assay, reducing power assay (RPA) and DNA nicking assay. Additionally, quantitative antioxidant assays were also conducted to quantify total phenolic (TPC) and total flavonoid content (TFC). As revealed by in vitro assays, methanol extract was found to contain more phenolic content. Hence, the methanol extract was further explored for its anticonvulsant potential in pentylenetetrazole (PTZ) induced acute seizures in mice. The methanol extract (400 mg/kg) significantly increased the latency to occurrence of myoclonic jerks and generalized tonic clonic seizures (GTCS). Additionally, it also reduced duration and seizure severity score associated with GTCS. The Grewia tiliaefolia methanol extract was further screened by Ultra High-Performance Liquid Chromatography (UHPLC) for presence of polyphenolic compounds, among which gallic acid and kaempferol were present in higher amount and were further analysed by in silico study to predict their possible binding sites and type of interactions these compounds show with gamma amino butyric acid (GABA) receptor and glutamate α amino-3- hydroxyl-5-methyl-4-isoxazolepropionic acid (Glu-AMPA) receptor. It was revealed that gallic acid and kaempferol had shown agonistic interaction for GABA receptor and antagonistic interaction for Glu-AMPA receptor. We concluded that G. tiliaefolia showed anticonvulsant potential possibly because of gallic acid and kaempferol possibly mediated through GABA and Glu-AMPA receptor.
Topics: Mice; Animals; Anticonvulsants; Pentylenetetrazole; Grewia; Hexanes; Kaempferols; Antioxidants; Methanol; Chloroform; Receptors, AMPA; Seizures; Epilepsy; Plant Extracts; Gallic Acid; gamma-Aminobutyric Acid
PubMed: 37436587
DOI: 10.1007/s11011-023-01252-0 -
Clinical and Experimental Pharmacology... Dec 2023Epilepsy is caused by an excessive recurrent excitatory neuronal firing, characterized by motor, psychomotor, and sensory impairments. Current therapies fail to produce...
Epilepsy is caused by an excessive recurrent excitatory neuronal firing, characterized by motor, psychomotor, and sensory impairments. Current therapies fail to produce 100% outcomes because of the complexity of the disease, poor diagnosis, and upsurge to drug-resistant epilepsy. The study repurposed the drug 'noscapine' mainly known for its anti-tussive properties. For the management of epilepsy and its associated secondary complications. To confirm the effect of noscapine, adult mice were injected with pentylenetetrazole (PTZ) (35 mg/kg i.p.) on an alternate day for 29 days to induce epilepsy. Animals were pretreated with noscapine in three doses (5, 10, and 20 mg/kg i.p.) for 33 days. Various behavioural assessments like the open field test, Morris water maze, and tail suspension test were performed to observe animals' locomotor activity, spatial memory, and anxiety-depressive behaviour. On the 34th day, animals were sacrificed, and brains were removed for biochemical estimations. Prolonged PTZ treatment reduced locomotor, learning activity, and increased anxiety-depressive behaviour, which was further confirmed by reduced antioxidant levels such as reduced glutathione (GSH), superoxide dismutase (SOD), and catalase because of increased oxido-nitrosative stress, that is, malondialdehyde (MDA) and nitrite in the brain. In comparison, noscapine pretreatment attenuated PTZ-induced behavioural and biochemical changes in the animals. The results indicate that noscapine ameliorates the oxido-nitrosative stress. However, studies indicate that oxido-nitrosative stress is a significant concern for the GABAergic neurons and promotes the disease progression. Further studies are required to explore the molecular mechanism of noscapine, which might be a practical approach as a newer antiepileptic agent.
Topics: Mice; Animals; Pentylenetetrazole; Noscapine; Oxidative Stress; Epilepsy; Kindling, Neurologic; Anticonvulsants
PubMed: 37724453
DOI: 10.1111/1440-1681.13825 -
Journal of Ethnopharmacology Oct 2023Newbouldia laevis is a popular medicinal plant whose leaves and roots are used in Nigeria as ethnomedicinal prescriptions for pain, inflammation, convulsion, and...
Pharmacognostic profiles, evaluation of analgesic, anti-inflammatory and anticonvulsant activities of Newbouldia laevis (P. Beauv.) Seem. ex Bureau leaf and root extracts in Wistar rats.
ETHNOPHARMACOLOGICAL RELEVANCE
Newbouldia laevis is a popular medicinal plant whose leaves and roots are used in Nigeria as ethnomedicinal prescriptions for pain, inflammation, convulsion, and epilepsy. These claims have not been scientifically verified prior to this study.
AIM OF THE STUDY
To determine pharmacognostic profiles of the leaves and roots and evaluate the analgesic, anti-inflammatory, and anticonvulsant activities of methanol leaf and root extracts in Wistar rats.
MATERIAL AND METHODS
The pharmacognostic profiles of the leaves and roots were determined using standard procedures to serve as fingerprints for the plant. The methanol leaf and root extracts of Newbouldia laevis were tested for acute toxicity using the OECD's up and down method at the maximum dose of 2000 mg/kg (orally) in Wistar rats. Analgesic studies were carried out in acetic acid-induced writhing in rats and tail immersion. The anti-inflammatory activity of the extracts was evaluated using carrageenan-induced rat paw-oedema and formalin-induced inflammation in rats' mode. The anticonvulsant activity was determined using strychnine-induced, pentylenetetrazol-induced, and maximal electroshock-induced rat convulsion models. For each of these studies, the extracts doses of 100, 200 and 400 mg/kg were administered to the rats following the oral route.
RESULTS
The pharmacognostic profiles showed that the leaves possessed deep-sunken paracytic stomata (5-8-16 mm; adaxial, 8-11-24 mm; abaxial epidermis), vein islets (2-4-10 mm; adaxial), vein terminations (10-14-18 mm; adaxial), palisade ratio (8.3-12.5-16.4 mm; adaxial, 2.5-6.8-12.2 mm; adaxial), covering unicellular trichome (8-14; adaxial), spheroidal calcium oxalate crystals (3-5 μm), and oval-shaped striated starch grain with no hilum (0.5-4.3 μm). The transverse section of the leaf showed the presence of spongy and palisade parenchyma as well as a closed vascular bundle. The root powder showed the presence of brachy sclereid, fibers without lumen, and lignin. All physicochemical parameters fall within the acceptable limits, phytochemical contents showed mainly glycosides, alkaloids, and steroids while acute oral toxicity (LD) of the parts for 14 days did not produce any toxicity signs or mortality in the rats. The extracts produced dose-dependent (100-400 mg/kg) analgesic involving opioid receptors, anti-inflammatory, and anticonvulsant activities in the rats which were significant (p ≤ 0.05) when compared to the standard drugs. The leaf extract possessed the most potent analgesic and anti-inflammatory effects in the rats, while the most anticonvulsant effects were observed in rats treated with the leaf extract. Both extracts showed elevated levels of protection against strychnine-induced, pentylenetetrazol-induced, and maximal electroshock-induced seizure in rats.
CONCLUSION
Our study revealed some pharmacognostic profiles of Newbouldia laevis leaves and roots that are vital for its identification from closely related species often used for adulteration in traditional medicine. The study further showed that the leaf and root extracts of the plant possessed dose-dependent analgesics, anti-inflammatory and anti-convulsant activities in rats, thus, justifying its use for the treatment of these diseases in Nigerian traditional medicine. There is a need to further study its mechanisms of action towards drug discovery.
Topics: Rats; Animals; Rats, Wistar; Anticonvulsants; Plant Extracts; Methanol; Strychnine; Pentylenetetrazole; Analgesics; Anti-Inflammatory Agents; Inflammation; Seizures; Edema; Plant Leaves
PubMed: 37211190
DOI: 10.1016/j.jep.2023.116632 -
Phytotherapy Research : PTR Jun 2024Salidroside, a principal bioactive component of Rhodiola crenulata, is neuroprotective across a wide time window in stroke models. We investigated whether salidroside...
Salidroside, a principal bioactive component of Rhodiola crenulata, is neuroprotective across a wide time window in stroke models. We investigated whether salidroside induced neurogenesis after cerebral ischemia and aimed to identify its primary molecular targets. Rats, subjected to transient 2 h of middle cerebral artery occlusion (MCAO), received intraperitoneal vehicle or salidroside ± intracerebroventricular HSC70 inhibitor VER155008 or TrkB inhibitor ANA-12 for up to 7 days. MRI, behavioural tests, immunofluorescent staining and western blotting measured effects of salidroside. Reverse virtual docking and enzymatic assays assessed interaction of salidroside with purified recombinant HSC70. Salidroside dose-dependently decreased cerebral infarct volumes and neurological deficits, with maximal effects by 50 mg/kg/day. This dose also improved performance in beam balance and Morris water maze tests. Salidroside significantly increased BrdU/nestin, BrdU/DCX, BrdU/NeuN, BrdU/NeuN and BDNF cells in the peri-infarct cortex, with less effect in striatum and no significant effect in the subventricular zone. Salidroside was predicted to bind with HSC70. Salidroside dose-dependently increased HSC70 ATPase and HSC70-dependent luciferase activities, but it did not activate HSP70. HSC70 immunoreactivity concentrated in the peri-infarct cortex and was unchanged by salidroside. However, VER155008 prevented salidroside-dependent increases of neurogenesis, BrdU/NeuN cells and BDNF cells in peri-infarct cortex. Salidroside also increased BDNF protein and p-TrkB/TrkB ratio in ischemic brain, changes prevented by VER155008 and ANA-12, respectively. Additionally, ANA-12 blocked salidroside-dependent neurogenesis and increased BrdU/NeuN cells in the peri-infarct cortex. Salidroside directly activates HSC70, thereby stimulating neurogenesis and neuroprotection via BDNF/TrkB signalling after MCAO. Salidroside and similar activators of HSC70 might provide clinical therapies for ischemic stroke.
Topics: Animals; Phenols; Glucosides; Neurogenesis; Brain-Derived Neurotrophic Factor; Rats; Male; Infarction, Middle Cerebral Artery; Neuroprotective Agents; Rats, Sprague-Dawley; Brain Ischemia; HSC70 Heat-Shock Proteins; Signal Transduction; Doublecortin Protein; Rhodiola; Receptor, trkB; Disease Models, Animal; Azepines; Benzamides
PubMed: 38488455
DOI: 10.1002/ptr.8178 -
Journal of Medicinal Chemistry Aug 2023Because of the wide use of Fingolimod for the treatment of multiple sclerosis (MS) and its cardiovascular side effects such as bradycardia, second-generation sphingosine...
Because of the wide use of Fingolimod for the treatment of multiple sclerosis (MS) and its cardiovascular side effects such as bradycardia, second-generation sphingosine 1-phosphate receptor 1 (S1P1) agonist drugs for MS have been developed and approved by FDA. The issue of bradycardia is still present with the new drugs, however, which necessitates further exploration of S1P1 agonists with improved safety profiles for next-generation MS drugs. Herein, we report a tetrahydroisoquinoline or a benzo[]azepine core-based S1P1 agonists such as and after systematic examination of hydrophilic groups and cores. We investigated the binding modes of our representative compounds and their molecular interactions with S1P1 employing recent S1P1 cryo-EM structures. Also, favorable ADME properties of our compounds were shown. Furthermore, in vivo efficacy of our compounds was clearly demonstrated with PLC and EAE studies. Also, the preliminary in vitro cardiovascular safety of our compound was verified with human iPSC-derived cardiomyocytes.
Topics: Humans; Multiple Sclerosis; Sphingosine-1-Phosphate Receptors; Bradycardia; Receptors, Lysosphingolipid; Fingolimod Hydrochloride; Tetrahydroisoquinolines; Sphingosine
PubMed: 37489798
DOI: 10.1021/acs.jmedchem.3c00498 -
Scientific Reports Jul 2023In this study, a new series of spiro indolin-1,2-diazepine were designed, synthesized, and screened for their cholinesterase inhibitory activities. A novel, green,...
In this study, a new series of spiro indolin-1,2-diazepine were designed, synthesized, and screened for their cholinesterase inhibitory activities. A novel, green, high-yielding approach was constructed to synthesize spiro indolin-1,2-diazepine derivatives through a cascade reaction of different isatins, malononitrile and 1,1-enediamines (EDAMs) via sequential four-component reactions to produce the target compounds with good to excellent yields. Next the inhibitory potencies of all derivatives were determined spectroscopically at 415 nm using the modified Ellman method. The results of the in vitro screening indicated that 5l with spiroindolin-1,2-diazepine core bearing 5-NO at R and 4-OH at R was the most potent and selective AChE inhibitor with an IC value of 3.98 ± 1.07 µM with no significant inhibition against BChE while 5j was the most active analog against both AChE and BChE enzymes. The structure-activity relationships suggested the variation in the inhibitory activities of derivatives was affected by different substitutions on the indolinone ring as well as the phenyl moiety. The enzyme kinetic studies of the most potent compound 5l at five different concentrations and acetylthiocholine substrate (0.1-1 mM) by Ellman's method revealed that it inhibited AChE in a mixed mode with a K of 0.044 μM. A molecular docking study was performed via induced fit docking protocol to predict the putative binding interaction. It was shown that the moieties used in the initial structure design play a fundamental role in interacting with the enzyme's binding site. Further, molecular dynamics simulations with the Schrödinger package were performed for 5l in a complex with AChE and revealed that compound 5l formed the stable complex with the enzyme. The MTT toxicity assessments against the neuroblastoma cell line were executed, and no toxicity was seen for 5l under the tested concentrations.
Topics: Humans; Cholinesterase Inhibitors; Kinetics; Molecular Docking Simulation; Acetylthiocholine; Azepines; Pain
PubMed: 37488177
DOI: 10.1038/s41598-023-38236-0 -
The Journal of Organic Chemistry Feb 2024We describe a ReO-mediated intramolecular dehydrative Friedel-Crafts reaction for the efficient synthesis of various benzo-fused heterocycles such as benzazepines and...
We describe a ReO-mediated intramolecular dehydrative Friedel-Crafts reaction for the efficient synthesis of various benzo-fused heterocycles such as benzazepines and benzazocines. This process is characterized by a broad substrate scope, mild reaction conditions, high efficiency, and high atom economy. The potential application of this methodology was exemplified by the facile preparation of a NMDA antagonist as well as a key intermediate en route to SKF 38393.
PubMed: 38251420
DOI: 10.1021/acs.joc.3c01977 -
Asian Journal of Psychiatry Nov 2023The paper describes the introduction, and early use of chemically and electrically induced convulsive therapies, at the Mysore Government Mental Hospital (MGMH), now the...
OBJECTIVE
The paper describes the introduction, and early use of chemically and electrically induced convulsive therapies, at the Mysore Government Mental Hospital (MGMH), now the National Institute of Mental Health and Neuro Sciences, Bangalore, India. Cardiazol and ammonium chloride were used at MGMH before the introduction of electroconvulsive therapy (ECT). The study examines the early history, clinical correlates and outcome of convulsive therapies and attempts to contextualize how local conditions influenced implementation.
METHOD
Three sets of archival case-records from 1938 to 1948, each of a period of 9 months following the implementation of a particular mode of convulsive therapy were reviewed.
RESULTS
During the examined timeframe, 40 patients received cardiazol, 95 ammonium chloride and 50 unmodified ECT. Schizophrenia was the commonest clinical indication for convulsive therapy across all modalities of treatment. When outcomes were examined, 45%, 48.4% and 62% of patients were clinically reported to have been either cured/improved after receiving cardiazol, ammonium chloride and ECT respectively. Those receiving cardiazol had a high mortality of 22.5%, compared to 3.1% for ammonium chloride and 4% with ECT.
CONCLUSIONS
Convulsive therapies were one of the first somatic psychiatric treatments, introduced around 1930s and 1940s all over the world, including in India. Our archival records suggest that many international ideas about somatic treatments were quickly adopted in India. Electroconvulsive therapy and other novel neuromodulatory interventions continue to be used and actively researched in India.
Topics: Humans; Hospitals, Psychiatric; Pentylenetetrazole; Ammonium Chloride; India; Convulsive Therapy; Electroconvulsive Therapy
PubMed: 37647785
DOI: 10.1016/j.ajp.2023.103747 -
Organic Letters Oct 20235-Arylpyrrolidine-2-carboxylates with an -halogen substituent at 5-aryl and an electron-withdrawing group at the C position of the pyrrolidine ring were transformed into...
5-Arylpyrrolidine-2-carboxylates with an -halogen substituent at 5-aryl and an electron-withdrawing group at the C position of the pyrrolidine ring were transformed into 1-benzo[]azepine-2-carboxylates under Cu(I) promotion and microwave activation. Reaction promoter copper(I) thiophene-2-carboxylate has been generated in the reaction's environment from CuO and thiophene-2-carboxylic acid. Functionalized 1-benzo[]azepine-2-carboxylates were obtained in racemic and optically active forms in 67-89% yields. Subsequent stereoselective 1,3-dipolar cycloaddition and an Ullmann-type annulation/rearrangement cascade (UARC) ensure a synthetic route to oligomeric optically active benzazepine species with a well-defined 3D-structure.
PubMed: 37801732
DOI: 10.1021/acs.orglett.3c03030 -
European Journal of Medicinal Chemistry Jun 2024Azepanes or azepines are structural motifs of many drugs, drug candidates and evaluated lead compounds. Even though compounds having N-heterocyclic 7-membered rings are... (Review)
Review
Azepanes or azepines are structural motifs of many drugs, drug candidates and evaluated lead compounds. Even though compounds having N-heterocyclic 7-membered rings are often found in nature (e.g. alkaloids), the natural compounds of this group are rather rare as approved therapeutics. Thus, recently studied and approved azepane or azepine-congeners predominantly consist of semi-synthetically or synthetically-obtained scaffolds. In this review a comparison of approved drugs and recently investigated leads was proposed taking into regard their structural aspects (stereochemistry), biological activities, pharmacokinetic properties and confirmed molecular targets. The 7-membered N-heterocycles reveal a wide range of biological activities, not only against CNS diseases, but also as e.g. antibacterial, anticancer, antiviral, antiparasitic and against allergy agents. As most of the approved or investigated potential drugs or lead structures, belonging to 7-membered N-heterocycles, are synthetic scaffolds, this report also reveals different and efficient metal-free cascade approaches useful to synthesize both simple azepane or azepine-containing congeners and those of oligocyclic structures. Stereochemistry of azepane/azepine fused systems, in view of biological data and binding with the targets, is discussed. Apart from the approved drugs, we compare advances in SAR studies of 7-membered N-heterocycles (mainly from 2018 to 2023), whereas the related synthetic part concerning various domino strategies is focused on the last ten years.
PubMed: 38879971
DOI: 10.1016/j.ejmech.2024.116556