scholarly journals S(+)-(2E)-N-(2-Hydroxypropyl)-3-Phenylprop-2-Enamide (KM-568): A Novel Cinnamamide Derivative with Anticonvulsant Activity in Animal Models of Seizures and Epilepsy

2020 ◽  
Vol 21 (12) ◽  
pp. 4372
Author(s):  
Agnieszka Gunia-Krzyżak ◽  
Ewa Żesławska ◽  
Karolina Słoczyńska ◽  
Dorota Żelaszczyk ◽  
Aleksandra Sowa ◽  
...  
Keyword(s):  
Mouse Model ◽  
Anticonvulsant Activity ◽  
Treatment Options ◽  
Seizure Threshold ◽  
Base Substitution ◽  
Maximal Electroshock ◽  
Susceptible Mouse ◽  
Acute Seizures ◽  
Seizure Model

Epilepsy is one of the most frequent neurological disorders affecting about 1% of the world’s human population. Despite availability of multiple treatment options including antiseizure drugs, it is estimated that about 30% of seizures still remain resistant to pharmacotherapy. Searching for new antiseizure and antiepileptic agents constitutes an important issue within modern medicinal chemistry. Cinnamamide derivatives were identified in preclinical as well as clinical studies as important drug candidates for the treatment of epilepsy. The cinnamamide derivative presented here: S(+)-(2E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide (S(+)-N-(2-hydroxypropyl)cinnamamide, compound KM-568) showed anticonvulsant activity in several models of epilepsy and seizures in mice and rats. It was active in a genetic animal model of epilepsy (Frings audiogenic seizure-susceptible mouse model, ED50 = 13.21 mg/kg, i.p.), acute seizures induced electrically (maximal electroshock test ED50 = 44.46 mg/kg mice i.p., ED50 = 86.6 mg/kg mice p.o., ED50 = 27.58 mg/kg rats i.p., ED50 = 30.81 mg/kg rats p.o., 6-Hz psychomotor seizure model 32 mA ED50 = 71.55 mg/kg mice i.p., 44 mA ED50 = 114.4 mg/kg mice i.p.), chronic seizures induced electrically (corneal kindled mouse model ED50 = 79.17 mg/kg i.p., hippocampal kindled rat model ED50 = 24.21 mg/kg i.p., lamotrigine-resistant amygdala kindled seizure model in rats ED50 = 58.59 mg/kg i.p.), acute seizures induced chemically (subcutaneous metrazol seizure threshold test ED50 = 104.29 mg/kg mice i.p., ED50 = 107.27 mg/kg mice p.o., ED50 = 41.72 mg/kg rats i.p., seizures induced by picrotoxin in mice ED50 = 94.11 mg/kg i.p.) and the pilocarpine-induced status epilepticus model in rats (ED50 = 279.45 mg/kg i.p., ED97 = 498.2 mg/kg i.p.). The chemical structure of the compound including configuration of the chiral center was confirmed by NMR spectroscopy, LC/MS spectroscopy, elemental analysis, and crystallography. Compound KM-568 was identified as a moderately stable derivative in an in vitro mouse liver microsome system. According to the Ames microplate format mutagenicity assay performed, KM-568 was not a base substitution or frameshift mutagen. Cytotoxicity evaluation in two cell lines (HepG2 and H9c2) proved the safety of the compound in concentrations up to 100 µM. Based on the results of anticonvulsant activity and safety profile, S(+)-(2E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide could be proposed as a new lead compound for further preclinical studies on novel treatment options for epilepsy.

scholarly journals Reductions in Hydrogen Sulfide Precede Onset of Mitochondrial Quality Control in the Corneal Kindled Mouse Model of Epilepsy

2021 ◽  
Author(s):  
Christi Cho ◽  
Maxwell Zeigler ◽  
Stephanie Mizuno ◽  
Richard S. Morrison ◽  
Rheem Totah ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Mouse Model ◽  
Membrane Integrity ◽  
Brain Homogenate ◽  
Maximal Electroshock ◽  
Maximal Electroshock Seizure ◽  
Mitochondrial Stress ◽  
Acute Seizures ◽  
Related Proteins

Epilepsy is a heterogenous neurological disorder characterized by recurrent unprovoked seizures, mitochondrial stress, and neurodegeneration. Hydrogen sulfide (H2S), a gasotransmitter, promotes mitochondrial function and biogenesis, elicits neuromodulation and neuroprotection, and may acutely suppress seizures. A major gap in knowledge remains in understanding the role of mitochondrial dysfunction and progressive changes in H2S levels following acute seizures and during epileptogenesis. We thus sought to quantify changes in H2S and its methylated metabolite (MeSH) via LC-MS/MS subsequent to acute maximal electroshock and 6 Hz 44 mA seizures in mice, as well as in the corneal kindled mouse model of chronic seizures. Plasma H2S was acutely reduced after a maximal electroshock seizure. H2S or MeSH levels in whole brain homogenate and expression of related genes in corneal kindled mice were not altered. However, plasma H2S and MeSH levels were significantly lower during kindling, but not after established kindling. Morever, we demonstrated a time-dependent increase in expression of mitochondrial membrane integrity-related proteins, Opa1, Mfn2, Drp1, and Mff during kindling, which did not correlate with gene expression. Taken together, short-term reductions in plasma H2S could be a novel biomarker for seizures. Future studies should further define the role of H2S and mitochondrial stress in epilepsy.

scholarly journals Evaluation of Anticonvulsant and Antioxidant Activity of Senna occidentalis Seeds Extracts

2019 ◽  
Vol 9 (2) ◽  
pp. 183-187
Author(s):  
Vijay Vikram Singh ◽  
Jainendra Jain ◽  
Arun Kumar Mishra
Keyword(s):  
Antioxidant Activity ◽  
Ascorbic Acid ◽  
Anticonvulsant Activity ◽  
Future Research ◽  
Maximal Electroshock ◽  
Formulation Development ◽  
Dpph Method ◽  
Dose Dependent Fashion ◽  
Seizure Model ◽  
Dose Dependent

Aim: The aim of present work was to determine the anticonvulsant and antioxidant activity of Senna occidentalis L. ethanolic seed extract by different mod­els. Methods: For evaluation of anticonvulsant activity, Pentylenetetrazole (PTZ) seizure model and Maximal electroshock (MES) seizure model were used. For antioxidant activity, (1, 1-diphenyl - 2-picryl hydrazine (DPPH) and hydrogen peroxide (H2O2) method were used. Results: The finding suggested that the ethanolic extract (EAE) of Senna occidentalis in the dose 400 mg/kg body weight posses potent anticonvulsant activity. The EAE showed anticonvulsant action in dose dependent fashion. It was observed that upon increasing the concentration of extract, it showed reduced absorbance and increased free radical inhibition, and when comparison was made with Ascorbic acid, it showed marked antioxidant property in DPPH as well as H2O2 method. The IC50 of Ascorbic acid and EAE by DPPH method were found to be 14.56 and 14.8 respectively whereas the IC50 of Ascorbic acid and EAE by H2O2 method were found that 14.3and 14.8 respectively. Conclusion: The results of the present study concluded hat the EAE of Senna occidentalis L. possesses significant antioxidant and anticonvulsant activity. The activity was in dose dependent fashion. This study will assist in future research associated with formulation development of seeds of Senna occidentalis L. Keyword: Senna occidentalis L., Anticonvulsant, Antioxidant, DPPH model

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

2021 ◽  
Vol 22 (23) ◽  
pp. 13092
Author(s):  
Michał Abram ◽  
Marcin Jakubiec ◽  
Anna Rapacz ◽  
Szczepan Mogilski ◽  
Gniewomir Latacz ◽  
...  
Keyword(s):  
Water Soluble ◽  
Calcium Currents ◽  
In Vitro Studies ◽  
Maximal Electroshock ◽  
Induction Effect ◽  
Potential Candidate ◽  
Seizure Models ◽  
Seizure Model

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.

scholarly journals D-limonene Inhibits Pentylenetetrazole-Induced Seizure via Adenosine A2A Receptor Modulation on GABAergic Neuronal Activity

2020 ◽  
Vol 21 (23) ◽  
pp. 9277
Author(s):  
Sowoon Seo ◽  
Yunjeong Song ◽  
Sun Mi Gu ◽  
Hyun Kyu Min ◽  
Jin Tae Hong ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hippocampal Neurons ◽  
Anticonvulsant Activity ◽  
High Performance ◽  
Gamma Aminobutyric Acid ◽  
Receptor Modulation ◽  
Ptz Kindling ◽  
Study Results ◽  
Adenosine A2a

Background: Epilepsy is a chronic neurological disorder characterized by the recurrence of seizures. One-third of patients with epilepsy may not respond to antiseizure drugs. Purpose: We aimed to examine whether D-limonene, a cyclic monoterpene, exhibited any antiseizure activity in the pentylenetetrazole (PTZ)-induced kindling mouse model and in vitro. Methods: PTZ kindling mouse model was established by administering PTZ (30 mg/kg) intraperitoneally to mice once every 48 h. We performed immunoblot blots, immunohistochemistry (IHC), and high-performance liquid chromatography (HPLC) analysis after the behavioral study. Results: An acute injection of PTZ (60 mg/kg) induced seizure in mice, while pretreatment with D-limonene inhibited PTZ-induced seizure. Repeated administration of PTZ (30 mg/kg) increased the seizure score gradually in mice, which was reduced in D-limonene (10 mg/kg)-pretreated group. In addition, D-limonene treatment increased glutamate decarboxylase-67 (GAD-67) expression in the hippocampus. Axonal sprouting of hippocampal neurons after kindling was inhibited by D-limonene pretreatment. Moreover, D-limonene reduced the expression levels of Neuronal PAS Domain Protein 4 (Npas4)-induced by PTZ. Furthermore, the adenosine A2A antagonist SCH58261 and ZM241385 inhibited anticonvulsant activity and gamma-aminobutyric acid (GABA)ergic neurotransmission-induced by D-limonene. Conclusion: These results suggest that D-limonene exhibits anticonvulsant activity through modulation of adenosine A2A receptors on GABAergic neuronal function.

Synthesis and Evaluation of N-substituted (Z)-5-(Benzo[d][1,3]dioxol-5- ylmethylene)-2-Thioxothiazolidin-4-one Derivatives and 5-Substituted- Thioxothiazolidindione Derivatives as Potent Anticonvulsant Agents

2020 ◽  
Vol 18 (10) ◽  
pp. 798-807
Author(s):  
Shiyang Dong ◽  
Yanhua Liu ◽  
Jun Xu ◽  
Yue Hu ◽  
Limin Huang ◽  
...  
Keyword(s):  
Anticonvulsant Activity ◽  
Structural Modification ◽  
Docking Study ◽  
Maximal Electroshock ◽  
Molecular Docking Study ◽  
Rotarod Test ◽  
Protective Index ◽  
Channel Inhibition ◽  
Anticonvulsant Activities

Background: Epilepsy is a serious and common neurological disorder threatening the health of humans. Despite enormous progress in epileptic research, the anti-epileptic drugs present many limitations. These limitations prompted the development of more safer and effective AEDs. Methods: series of N-substituted (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)- 2-thioxothiazolidin-4- one derivatives and 5-substituted-thioxothiazolidindione derivatives were designed, synthesized and tested for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ). Neurotoxicity was determined by the rotarod test. Results: Among them, the most potent 4e displayed high protection against MES-induced seizures with an ED50 value of 9.7 mg/kg and TD50 value of 263.3 mg/kg, which provided 4e with a high protective index (TD50/ED50) of 27.1 comparable to reference antiepileptic drugs. 4e clearly inhibits the NaV1.1 channel in vitro. The molecular docking study was conducted to exploit the results. Conclusion: Stiripentol is a good lead compound for further structural modification. Compound 4e was synthesized, which displayed remarkable anticonvulsant activities, and the NaV1.1 channel inhibition was involved in the mechanism of action of 4e.

Captopril potentiates the anticonvulsant activity of carbamazepine and lamotrigine in the mouse maximal electroshock seizure model

2010 ◽  
Vol 117 (10) ◽  
pp. 1161-1166 ◽  
Author(s):  
Krzysztof Łukawski ◽  
Tomasz Jakubus ◽  
Grzegorz Raszewski ◽  
Stanisław J. Czuczwar
Keyword(s):  
Anticonvulsant Activity ◽  
Maximal Electroshock ◽  
Maximal Electroshock Seizure ◽  
Seizure Model

Synthesis and Anticonvulsant Activity of α-Amino Acid Amide Derivatives

2019 ◽  
Vol 15 (5) ◽  
pp. 547-561
Author(s):  
Valerie Currier ◽  
Maryam Molki ◽  
Katelyn Fryman ◽  
Lacey D. Rodgers ◽  
A. Michael Crider
Keyword(s):  
Amino Acid ◽  
Side Effects ◽  
Anticonvulsant Activity ◽  
Acid Amide ◽  
New Drugs ◽  
Seizure Threshold ◽  
Maximal Electroshock ◽  
Maximal Electroshock Seizure ◽  
Maximal Electroshock Seizure Test ◽  
Amide Derivatives

Background: Epilepsy is a disease of the central nervous system that affects approximately 50 million individuals worldwide. Although several new drugs have been marketed in the last 25 years, almost one-third of patients are not protected. In many cases, currently available drugs produce undesirable side effects. As a result, a need exists for novel anticonvulsants with unique mechanisms of action and minimal side effects. Methods: A mixed anhydride coupling procedure and standard deprotection procedures were utilized to prepare 36 α-amino acid amides. All final products were evaluated in mice and rats utilizing a standard battery of anticonvulsant tests. Results: α-Amino acids containing a 2,6-dimethylanilide group exhibited anticonvulsant activity in the maximal electroshock seizure test and 6 Hz test in mice and rats. A small, branched-chain on the α- carbon generally maintained or enhanced anticonvulsant activity in the maximal electroshock seizure test. The (R)-α-amino acid amides were typically more potent and slightly more neurotoxic than the corresponding (S)-enantiomers. The valine dimethylanilide (R)-42 was highly active in the MES test in mice (ED50 = 3.6mg/kg) and rats (ED50 = 3.8 mg/kg). (R)-42 also demonstrated excellent anticonvulsant activity in the 6 Hz, picrotoxin, and corneal kindled mouse tests. Furthermore, (R)-42 did not lower seizure threshold when evaluated in the intravenous metrazol seizure test. Conclusion: α-Amino acid 2,6-dimethylanilides exhibited potent activity in a variety of anticonvulsant tests in mice and rats. The valine derivative (R)-42 represents a promising compound for potential use in complex partial seizures.

Synthesis and biological evaluation of 4-aminoantipyrine analogues

2020 ◽  
Vol 16 ◽  
Author(s):  
Houwei Ren ◽  
Premnath Dhanaraj ◽  
Israel V M V Enoch ◽  
Mosae Selvakumar Paulraj ◽  
Indiraleka M
Keyword(s):  
Cervical Cancer ◽  
Dna Cleavage ◽  
Anticonvulsant Activity ◽  
Biological Activities ◽  
Biological Evaluation ◽  
In Vitro Cytotoxicity ◽  
Dilution Method ◽  
Maximal Electroshock ◽  
Protein Receptors

Objectives: The aim of the present study is to carry out a simple synthesis of aminoantipyrine analogues and exploration of their antibacterial, cytotoxic, and anticonvulsant potential. Methods: The compounds were characterized employing multi-spectroscopic methods. The in vitro pharmacological response of a series of bacteria were screened employing serial dilution method. The derivatives were screened against maximal electro-shock for their anticonvulsant activity. Molecular docking was carried out to optimize the interaction of the compounds with HPV16-E7 receptors. Further, the in vitro cytotoxicity was tested against human cervical cancer (SiHa) cell lines. Results: The compounds show protection against maximal electroshock, esp. 3-nirto- and 4-methyl-3-nitrobenzamido derivatives. In addition, they reveal appreciable DNA cleavage activities and interactions with HPV16-E7 protein receptors, esp. 3,5-dinitro- and 4-methyl-3-nitrobenzamido derivatives. Furthermore, they show potent activity against cervical cancer cells (LD50 value up to 1200 in the case of 4-methyl-3-nitrobenzamido derivative and an inhibition of a maximum of 97% of cells). Conclusions: The simply synthesized aminoantipyrine derivatives show a variety of biological activities like antibacterial and anticancer effects. In addition, this is the first study demonstrating that 4-aminoantipyrine derivatives shows an anticonvulsant activity.

Synthesis and Biological Evaluation of Amino Acid Based Mutual Amide Prodrugs of Phenytoin as Anticonvulsant Agents

2020 ◽  
Vol 20 ◽  
Author(s):  
Sampada Jangam ◽  
Meenakshi Deodhar ◽  
Sagar Wankhede
Keyword(s):  
Amino Acid ◽  
Anticonvulsant Activity ◽  
Water Solubility ◽  
Biological Evaluation ◽  
Proton Nuclear Magnetic Resonance ◽  
Log P ◽  
Maximal Electroshock ◽  
Sprague Dawley ◽  
Anticonvulsant Agents

Background: Phenytoin (5,5-diphenyl hydantoin) has poor water solubility which results in incomplete oral availability. Other problems associated with the oral and intramuscular administration of phenytoin are gastric irritation and inflammation at the site of injection. Objective: The purpose of this study was to synthesize mutual amide prodrugs of phenytoin by using amino acids like glycine, L-tryptophan, L-lysine and taurine. Methods: These prodrugs were synthesized and characterized by Fourier Transform Infrared (FTIR), Proton nuclear magnetic resonance (1 H NMR) and Mass Spectra. Physical and spectral characterization was performed by determination of solubility, maximum wavelength, partition coefficient (log P), ionization constant (pKa), specific (α) and molar rotation (µ), refractive index (n), specific refraction (RS) and molar refraction (RM). Results: The results obtained from solubility and log P values determination indicated that phenytoin prodrugs can be administered by oral as well as a parenteral route by minimizing the limitations associated with phenytoin. Anticonvulsant activity of prodrugs (4a-4d) was performed by using maximal electroshock (MES) and strychnine induced seizure test on albino mice of either sex weighing 25-30 g in which 4b and 4d were found to have significant anticonvulsant activity for MES and strychnine induced seizure test. In vitro enzymatic hydrolysis study of 4b and 4d was performed on liver, intestinal mucosa and plasma sample of male Sprague Dawley rats weighing 280-300 g in which phenytoin was eluted at 10.13 to 10.68 minute at 220 nm. Conclusion: The results obtained from the present work showed that amino acid based mutual prodrug strategy can be a promising method to increase the solubility and anticonvulsant activity of phenytoin for the development of anticonvulsant agents.

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