Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-Acetamides

We report herein a series of water-soluble analogues of previously described anticonvulsants and their detailed in vivo and in vitro characterization. The majority of these compounds demonstrated broad-spectrum anticonvulsant properties in animal seizure models, including the maximal electroshock (MES) test, the pentylenetetrazole-induced seizure model (scPTZ), and the psychomotor 6 Hz (32 mA) seizure model in mice. Compound 14 showed the most robust anticonvulsant activity (ED50 MES = 49.6 mg/kg, ED50 6 Hz (32 mA) = 31.3 mg/kg, ED50scPTZ = 67.4 mg/kg). Notably, it was also effective in the 6 Hz (44 mA) model of drug-resistant epilepsy (ED50 = 63.2 mg/kg). Apart from favorable anticonvulsant properties, compound 14 revealed a high efficacy against pain responses in the formalin-induced tonic pain, the capsaicin-induced neurogenic pain, as well as in the oxaliplatin-induced neuropathic pain in mice. Moreover, compound 14 showed distinct anti-inflammatory activity in the model of carrageenan-induced aseptic inflammation. The mechanism of action of compound 14 is likely complex and may result from the inhibition of peripheral and central sodium and calcium currents, as well as the TRPV1 receptor antagonism as observed in the in vitro studies. This lead compound also revealed beneficial in vitro ADME-Tox properties and an in vivo pharmacokinetic profile, making it a potential candidate for future preclinical development. Interestingly, the in vitro studies also showed a favorable induction effect of compound 14 on the viability of neuroblastoma SH-SY5Y cells.

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The Search for New Anticonvulsants in a Group of (2,5-Dioxopyrrolidin-1-yl)(phenyl)Acetamides with Hybrid Structure—Synthesis and In Vivo/In Vitro Studies

International Journal of Molecular Sciences ◽

10.3390/ijms21228780 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8780

Author(s):

Michał Abram ◽

Marcin Jakubiec ◽

Anna Rapacz ◽

Szczepan Mogilski ◽

Gniewomir Latacz ◽

...

Keyword(s):

Liver Microsomes ◽

Coupling Reaction ◽

Calcium Currents ◽

Maximal Electroshock ◽

Preclinical Development ◽

Toxic Dose ◽

Pain Model ◽

Seizure Models

Epilepsy belongs to the most common and debilitating neurological disorders with multifactorial pathophysiology and a high level of drug resistance. Therefore, with the aim of searching for new, more effective, and/or safer therapeutics, we discovered a focused series of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant properties. We applied an optimized coupling reaction yielding several hybrid compounds that showed broad-spectrum activity in widely accepted animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure model in mice. The most potent anticonvulsant activity and favorable safety profile was demonstrated for compound 30 (median effective dose (ED50) MES = 45.6 mg/kg, ED50 6 Hz (32 mA) = 39.5 mg/kg, median toxic dose (TD50) (rotarod test) = 162.4 mg/kg). Anticonvulsant drugs often show activity in pain models, and compound 30 was also proven effective in the formalin test of tonic pain, the capsaicin-induced pain model, and the oxaliplatin (OXPT)-induced neuropathic pain model in mice. Our studies showed that the most plausible mechanism of action of 30 involves inhibition of calcium currents mediated by Cav1.2 (L-type) channels. Importantly, 30 revealed high metabolic stability on human liver microsomes, negligible hepatotoxicity, and relatively weak inhibition of CYP3A4, CYP2D6, and CYP2C9 isoforms of cytochrome P450, compared to reference compounds. The promising in vivo activity profile and drug-like properties of compound 30 make it an interesting candidate for further preclinical development.

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Immunomodulatory and antioxidant effects of polysaccharides from the parasitic fungus Cordyceps kyushuensis

10.21203/rs.3.rs-26190/v1 ◽

2020 ◽

Author(s):

Jianya LING ◽

Jinjuan Su ◽

Guoying Zhang ◽

Jing Sun

Keyword(s):

Antioxidant Activities ◽

Structural Information ◽

Deae Cellulose ◽

Peritoneal Macrophages ◽

Water Soluble ◽

Parasitic Fungus ◽

Potential Candidate ◽

Mouse Splenocytes

Abstract Ascomycete Cordyceps genus has been used as valued traditional Chinese medicines. Cordyceps kyushuensis is a unique species of Cordyceps, which parasitizes on the larvae of Clanis bilineata Walker, and its major component cordycepin and aqueous extract are known to have many pharmacological effects. However, the physiological function of water soluble polysaccharides has not been explored in detail. In this study, to resolve these doubts, we extracted and separated Cordyceps-derived polysaccharides, then evaluated the immunomodulatory and antioxidant activities. Four polysaccharide fractions were purified from Cordyceps cultured stroma by DEAE-cellulose 23 and Sephadex G-150 column chromatography. Basic structural information was elucidated on the basis of physicochemical property and spectroscopic evidences. The antioxidant activities were evaluated by DPPH radical method and protective effect of DNA damage. The qualified immunologic activities were also determined in vivo and in vitro. The polysaccharides could stimulate the proliferation of mouse splenocytes whether ConA and LPS existed or not, strengthen peritoneal macrophages to devour neutral red, and increase the content of IL-2 and TNF-α in serum. The research provides the corresponding evidence for Cordyceps polysaccharides as a potential candidate for functional foods and therapeutic agents.

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NEUROPROTECTIVE AND COGNITIVE ENHANCING EFFECT OF METHANOLIC MORUS ALBA LEAF FRACTION IN U87MG CELL LINES AND EXPERIMENTAL RAT MODEL

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2019.v12i4.32359 ◽

2019 ◽

pp. 238-243

Author(s):

ANJALI RAJ ◽

SUMIT DEY ◽

SUBBA RAO VENKATA MADHUNAPANTULA ◽

MANJULA SN

Keyword(s):

Cell Lines ◽

Neuronal Damage ◽

Morus Alba ◽

In Vitro Studies ◽

Potential Candidate ◽

Protective Effects ◽

U87mg Cell ◽

Standard Drug

Objective: The present study aims to investigate the protective effect of methanol fraction of Morus alba (MEMA) leaves against hydrogen peroxide (H2O2)-induced U87MG cell toxicity and aluminum fluoride (ALF)-induced rat toxicity. Methods: The study was divided into in vitro and in vivo sections. U87MG cell lines were pre-treated with different fractions of MEMA for 20 h and further tested against 1000 ϻM of H2O2. The best fraction from in vitro studies was used to study the protective effects against ALF-induced neurotoxicity. Rats were divided i nto five different groups, and MEMA (200 and 400 mg/kg p.o) was administered for 14 days to the animals with α-tocopherol as the standard drug treatment. Behavioral studies were assessed using Barnes maze. The major biochemical measurements included catalase, superoxide dismutase and glutathione reductase, lipid peroxidation (LPO), and acetylcholinesterase (AchE) levels. Results: In vitro studies indicated MEMA as a potential candidate followed by AQMA and ethyl acetate. The MEMA fraction was able to ameliorate ALF-induced neurotoxicity in the behavioral assessment. The higher antioxidant content in the fraction decreased the LPO levels from 250±4.07 to 115±3.22 as well as elevated the levels of most of the endogenous antioxidant enzyme levels. AchE levels were also decreased to 33.89±0.71 from 38.94±0.64. Conclusion: Although the results obtained indicate that MEMA could significantly suppress oxidative stress-induced central neuronal damage both in vitro and in vivo, further mechanistic studies are required to delineate its neuroprotective pathway.

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Studies on Anticonvulsant Effects of Novel Histamine H3R Antagonists in Electrically and Chemically Induced Seizures in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms19113386 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3386 ◽

Cited By ~ 10

Author(s):

Alaa Alachkar ◽

Dorota Łażewska ◽

Gniewomir Latacz ◽

Annika Frank ◽

Agata Siwek ◽

...

Keyword(s):

Clonic Seizure ◽

Maximal Electroshock ◽

Protective Effects ◽

Chemically Induced ◽

Seizure Models ◽

Dose Dependent Fashion ◽

Full Protection ◽

Anticonvulsant Effects

A newly developed series of non-imidazole histamine H3 receptor (H3R) antagonists (1–16) was evaluated in vivo for anticonvulsant effects in three different seizure models in Wistar rats. Among the novel H3R antagonists examined, H3R antagonist 4 shortened the duration of tonic hind limb extension (THLE) in a dose-dependent fashion in the maximal electroshock (MES)-induced seizure and offered full protection against pentylenetetrazole (PTZ)-induced generalized tonic-clonic seizure (GTCS), following acute systemic administration (2.5, 5, 10, and 15 mg/kg, i.p.). However, only H3R antagonist 13, without appreciable protective effects in MES- and PTZ-induced seizure, fully protected animals in the strychnine (STR)-induced GTCS following acute systemic pretreatment (10 mg/kg, i.p.). Moreover, the protective effect observed with H3R antagonist 4 in MES-induced seizure was completely abolished when animals were co-administered with the H3R agonist (R)-α-methylhistamine (RAMH, 10 mg/kg, i.p.). However, RAMH failed to abolish the full protection provided by the H3R antagonist 4 in PTZ-induced seizure and H3R antagonist 13 in STR-induced seizure. Furthermore, in vitro antiproliferative effects or possible metabolic interactions could not be observed for compound 4. Additionally, the predictive in silico, as well as in vitro, metabolic stability for the most promising H3R antagonist 4 was assessed. The obtained results show prospective effects of non-imidazole H3R antagonists as innovative antiepileptic drugs (AEDs) for potential single use against epilepsy.

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Abnormal Sensitivity of Cortisol-Producing Adrenocortical Adenomas to Serotonin: In Vivo and in Vitro Studies

Yearbook of Endocrinology ◽

10.1016/s0084-3741(08)70169-0 ◽

2007 ◽

Vol 2007 ◽

pp. 358-361

Author(s):

D.E. Schteingart

Keyword(s):

In Vitro Studies ◽

Adrenocortical Adenomas

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The Venom of the Boomslang (Dispholidus Typus): In Vivo and in Vitro Studies

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653532 ◽

1969 ◽

Vol 21 (02) ◽

pp. 234-244 ◽

Cited By ~ 5

Author(s):

N Mackay ◽

J.C Ferguson ◽

Antonia Bagshawe ◽

A.T.T Forrester ◽

G.P Mcnicol

Keyword(s):

In Vitro Studies

SummaryAn account is given of the effects of boomslang venom in man. Evidence was found of a fibrinolytic state apparently secondary to the coagulant action of the venom. These features rapidly responded to the administration of specific antivenom. In vitro studies, using a homogenate of boomslang parotids, confirmed the coagulant properties of the venom and showed them to be of much greater potency than the proteolytic actions.

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