Anticonvulsant effects of desvenlafaxine on modulating brain monoamine and oxidative stress in mice

Desvenlafaxine succinate (DVS) inhibits serotonin reuptake selectively and is approved for major depressive disorders. This research investigated influence of DVS on modulating brain monoamine and oxidative stress in mice. The antiepileptic potential of DVS (10, 20, or 30 mg/kg/i.p.) in pentylenetetrazole (PTZ; 85 mg/kg) with i.p. route of administration, strychnine (STR; 75 mg/kg) with i.p. route, pilocarpine (400 mg/kg) with s.c. route and maximal electroshock MES-induced convulsion in mouse models. The activities of oxidative stress, i.e. superoxide dismutase (SOD), glutathione (GSH) and lipid peroxidation (LPO) as well as gamma-aminobutyric acid (GABA) in the brains of PTZ-induced convulsive mice. Treatment with DVS increased the latency to develop siezures and declined mortalities in rodents against PTZ, STR and pilocarpine-induced convulsions. Results of MES-leaded siezures revealed that DVS reduced tonic hind limb extension duration and mortalities significantly. Brain, SOD, GSH and GABA level were significantly (P<0.01) increased and LPO reduced significantly (P<0.01) after DVS treatment. Furthermore, the DVS did not show any motor coordination signs in the rotarod test. We demonstrated that the role of DVS in convulsion genesis in mice under control condition and attenuate the PTZ-induced oxidative damage.

The Effects and Mechanisms of Action of TC-G 1008, GPR39 Agonist, in Animal Models of Seizures and Epilepsy

Background and purpose: The G-protein coupled receptor 39 (GPR39) may be activated by zinc ions. Activation of GPR39 was suggested as a novel pharmacological strategy for treating seizures. Experimental approach: We utilized a specific agonist of GPR39, TC-G 1008, and the nonspecific agonist, zinc chloride and a variety of models of acute seizures or a chronic model of epilepsy which were induced in non-genetically modified mice, GPR39 knockout mice or in zebrafish larvae. We examined total serum zinc (by Inductively Coupled Plasma Optical Emission Spectrometry) as well as intracellular zinc ([Zn2+]I) (by Zinpyr-1 staining) concentrations and the expression of selected proteins (by Western blot) which are associated with GPR39 signaling in the hippocampus. Key results: Liquid chromatography tandem mass spectrometry analysis showed that TC-G 1008 is brain penetrant. TC-G 1008 decreased the seizure threshold in the maximal electroshock seizure (MES) threshold test, but it increased the seizure threshold in the 6-Hz induced seizure threshold test. The behavioral effects of TC-G 1008 and MES or 6-Hz seizure were accompanied by alterations in hippocampal [Zn2+]I. TC-G 1008 increased the mean duration of EEG discharges in response to pentylenetetrazole (PTZ) in zebrafish larvae and facilitated the development of PTZ kindling in mice. Using GPR39 knockout mouse line, generated by the CRISPR-Cas-9 method, we showed that GPR39 is a target for TC-G 1008 regarding PTZ-induced epileptogenesis. Conclusion and implications: Our in vivo data obtained using TC-G 1008 generally argue against GPR39 activation as a therapeutic strategy for alleviating seizures/epilepsy.

Evaluation of the Anticonvulsant Activities of Gastrodia Elata Bl.- Acorus Tatarinowii Decoction on Experimentally Induced Seizures in Mice

Epilepsy is a serious public health problem in the world. At present, the effect of drug treatment of epilepsy is are not satisfactory. Medicinal plants as pharmaceuticals and for healthcare treatments in the management of epilepsy in China for many centuries. Especially, Gastrodia elata Bl.-Acorus tatarinowii, as a classic and important herb pairs in folk medicine, has been used in folk medicine to control seizures. However, the animal experiment data of its anticonvulsant effect is limited in the literature. The objective of this study was to mainly analyze the anticonvulsant activity of Gastrodia elata-Acorus tatarinowii (GEAT) decoction in maximal electroshock (MES), pentylenetetrazole (PTZ) and trimercaptopropionic acid (3-MP) induced seizures in mice, providing scientific basis for the treatment of convulsive disorders in traditional medicine. In addition, the improvement effect were examined on seizure severity, anxiety, cognitive dysfunction, inflammation and oxidative stress in PTZ kindled mice. The results showed that GEAT decoction dose-dependently protected mice against MES, 3-MP and PTZ induced acute seizures. Meanwhile, GEAT decoction ameliorated seizure severity, decreased the accumulation of inflammatory mediators TNF-α, IL-1β, and IL-6, mitigated oxidative stress, as well as alleviated anxious-like behavior and cognitive deficits in PTZ-kindled mice. Our data evidenced that the anticonvulsant properties attributed to GEAT decoction as adjunctive therapy for epileptic patients in folk medicine.

Low-dose digoxin enhances the anticonvulsive potential of carbamazepine and lamotrigine in chemo-induced seizures with different neurochemical mechanisms

"Non-antiepileptic" drugs have a strong potential as adjuvants in multidrug-resistant epilepsy treatment. In previous study the influence of low doses of digoxin, which do not affect the myocardium, on the anticonvulsant potential of classical commonly used anti-epileptic drugs under conditions of seizures, induced by pentylenetetrazole and maximal electroshock, has been investigated. The aim of the study was to investigate the influence of digoxin at a sub-cardiotonic dose on the anticonvulsant potential of carbamazepine and lamotrigine in experimental seizures with different neurochemical mechanisms. Material and methods: A total of 192 random-bred male albino mice weighting 22–25 g were used. Carbamazepine and lamotrigine were administered intragastrically in conditionally effective (ED50) and sub-effective (½ ED50) doses: carbamazepine at doses of 100 and 50 mg/kg; lamotrigine at doses of 25 and 12.5 mg/kg. Digoxin was administered subcutaneously at a sub-cardiotonic dose of 0.8 mg/kg as an adjuvant to carbamazepine and lamotrigine in ½ ED50. Picrotoxin (2.5 mg/kg subcutaneously); thiosemicarbazide (25 mg/kg intraperitoneally); strychnine (1.2 mg/kg subcutaneously); camphor (1000 mg/kg intraperitoneally) were used as convulsant agents. Results: It was found that digoxin not only has its own permanent anticonvulsant effect on different models of paroxysms with different neurochemical mechanisms of development, but also significantly enhances the anticonvulsant potential of carbamazepine (to a lesser extent – lamotrigine) regardless of the pathogenesis of experimental paroxysms. Conclusion: Based on the results, it can be concluded that digoxin has a high potential as an adjuvant medicine in complex epilepsy treatment because it enhances the efficiency of low-dose traditional anticonvulsants carbamazepine and lamotrigine

Evaluation of Antiepileptic activity of Mosapride in Albino wistar rats

Serotonin causes a significant shift in the excitability of neurons and endogenous serotonin and drugs acting on serotonergic receptors play a role in pathogenesis of epilepsy. This study was done to study the effect of Mosapride, a serotonin receptor 5HT4 agonist, in animal models of epilepsy. Albino Wistar rats were divided into 5 groups with six animals in each group. Group 1 was control group, group 2 was standard group and group 3, 4 and 5 received test drug mosapride in low dose (3mg/kg), high dose (6mg/kg) and mosapride plus standard antiepileptic drug respectively. The antiepileptic efficacy was evaluated using Maximal Electroshock Seizure model (MES) and Pentylenetetrazole (PTZ) induced convulsions. Data was analysed using ANOVA followed by post hoc Tukeys test. Mosapride treated animals showed statistically significant decrease (p<0.001) in the duration of flexion, hind limb extension and post ictal depression in MES model which was comparable to phenytoin group. In PTZ model, mosapride alone did not show any significant difference as compared to control group in terms of latency and duration of seizures (p>0.05). The antiepileptic efficacy of mosapride is similar to phenytoin in MES model. However, in PTZ model mosapride did not show any beneficial antiepileptic effect

Therapeutic Effect of Novel Cyanopyrrolidine-Based Prolyl Oligopeptidase Inhibitors in Rat Models of Amnesia

Prolyl oligopeptidase (POP) is a large cytosolic serine peptidase that is altered in patients with Alzheimer’s disease, Parkinsonian syndrome, muscular dystrophies, and other denervating diseases. Thus, POP may represent a relevant therapeutic target for treatment of neuropsychiatric disorders and neurodegenerative diseases. Here, we report the characterization of five novel cyanopyrrolidine-based compounds (BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, CbzGlnPrdN, and CbzAlaPrdN) and show that they are potent inhibitors of POP and are predicted to penetrate the blood-brain barrier (BBB). Indeed, we show that CbzMetPrdN penetrates the rat BBB and effectively inhibits POP in the brain when administered intraperitoneally. Furthermore, molecular modeling confirmed these compounds likely inhibit POP via interaction with the POP catalytic site. We evaluated protective effects of the cyanopyrrolidine-based POP inhibitors using scopolamine- and maximal electroshock-induced models of amnesia in rats and showed that BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, and CbzGlnPrdN significantly prolonged conditioned passive avoidance reflex (CPAR) retention time when administered intraperitoneally (1 and 2 mg/kg) before evaluation in both models of amnesia, although CbzAlaPrdN was not effective in scopolamine-induced amnesia. Our data support previous reports on the antiamnesic effects of prolinal-based POP inhibitors and indicate an important role of POP in the regulation of learning and memory processes in the CNS.

Design and evaluation of pharmacological properties of a new 1,3,4-thiadiazolylamide derivative of 2-propylpentanoic acid

Introduction: The use of the pharmacophoric approach is a promising direction for modifying the chemical structure of 2-propylpentanoic (valproic) acid in order to obtain new drugs. Materials and methods: In the experiments on mice, acute toxicity, neurotoxicity, antiepileptic activity and analgesic effect of N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide (valprazolamide) were evaluated. LD50 was determined by probit analysis. Neurotoxicity was determined in a rotarod test and a bar test in mice. The effects of valprazolamide on the exploratory behavior of mice in open field test and in a light/dark transition test were evaluated. Its antiepileptic activity was tested in mice against seizures induced by maximal electroshock, pentylenetetrazole (scPTZ); isoniazid, thiosemicarbazide, pilocarpine, and camphor. The analgesic effect was studied in a hot plate test. Results and discussion: N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide was obtained by introducing pharmacophores into the structure of 2-propylpentanoic acid: a substituted amide group and an electron-donor domain of 1,3,4-thiadiazole. The LD50 value for intraperitoneal administration of a new 2-propylpentanoic acid: derivative to mice was 924.8 mg/kg, and the TD50 value in the rotarod test and the bar test were 456.7 mg/kg and 546.7 mg/kg, respectively. The suppression of orienting responses in the animals was noted when it was administered in neurotoxic doses. Valprazolamide showed the most antiepileptic activity on models of MES, scPTZ and isoniazid antagonism tests. The ED50 values were 138.4 mg/kg, 74.5 mg/kg, and 126.8 mg/kg, respectively. The therapeutic indices for these models of epilepsy were 6.7; 12.4; 7.3, and protective index – 3.3; 6.1 and 3.6, respectively. In the hot plate test, valprazolamide increased the latency period before a defensive response to a thermal stimulus (ED50 165 mg/kg). Conclusion: N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide is a new 1,3,4-thiadiazolylamide derivative of 2-propylpentanoic acid with antiepileptic and analgesic activities, which belongs to the group of low-toxic agents. Graphic abstract N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide (3D) LD50=924.8 mg/kg (mice, intraperitoneally) TD50=456.7 mg/kg (rotarod, mice, intraperitoneally) ED50=138.4 mg/kg (MES, mice, intraperitoneally) ED50=74.5 mg/kg (scPTZ, mice, intraperitoneally)

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.

Evaluation of Antiepileptic Activity of Flowers of Cocos nucifera L. Against Experimentally Induced Convulsions in Rats

The report used to be planned to analyze the antiepileptic activity of Cocos nucifera flowers against special experimentally induced convulsions in rats. In the present study, antiepileptic activity was assessed by following experimental models. Anti-convulsant in vivo models: Maximal electroshocks (MES) induced models in rats, Pentylenetetrazole (PTZ) induced in rats. Pretreatment of animals with Cocos nucifera flowers extract has reduced by half the general continuance of tonic hind leg extension, the most commonly used endpoint in assessing clonic convulsions. MES provokes repetitive neuronal firing indicates epileptic neurons. MES is the widely accepted model to demonstrate the antiepileptic property of a drug. This property is antagonistic of the plant extract could flow from to blockade of voltage-gated sodium channel or due to effect on NMDA receptors. The Cocos nucifera flowers extract was also demonstrated potential anticonvulsant activity in PTZ induced convulsions and this may be due to its agonistic activity on the GABAA receptor. This is further supported by an elevated level of GABA by the plant extract in the PTZ model. Methanolic extract of Cocos nucifera flowers has shown significant anticonvulsant activity against MES and Pentlylenetetrazole induced convulsion models. This observed activity could also be the referable presence of flavonoids and other phytochemical constituents found in the powerful extract. Keywords: Cocos nucifera, antiepileptic activity, Maximal electroshock, Pentlylenetetrazole, Flavonoids,

Combinatorial Regimen of Carbamazepine and Imipramine Exhibits Synergism against Grandmal Epilepsy in Rats: Inhibition of Pro-Inflammatory Cytokines and PI3K/Akt/mTOR Signaling Pathway

Epilepsy is a neurodegenerative disorder that causes recurring seizures. Thirty-five percent of patients remain refractory, with a higher prevalence of depression. We investigated the anticonvulsant efficacy of carbamazepine (CBZ; 20 and 50 mg/kg), imipramine (IMI; 10 and 20 mg/kg) alone, and as a low dose combination. This preclinical investigation included dosing of rats for 14 days followed by elicitation of electroshock on the last day of treatment. Along with behavioral monitoring, the rat hippocampus was processed for quantification of mTOR, IL-1β, IL-6 and TNF-α levels. The histopathological analysis of rat hippocampus was performed to ascertain neuroprotection. In vitro studies and in silico studies were also conducted. We found that the low dose combinatorial therapy of CBZ (20 mg/kg) + IMI (10 mg/kg) exhibits synergism (p < 0.001) in abrogation of maximal electroshock (MES) induced convulsions/tonic hind limb extension (THLE), by reducing levels of pro-inflammatory cytokines, and weakening of the PI3K/Akt/mTOR signal. The combination also exhibits cooperative binding at the Akt. As far as neuroprotection is concerned, the said combination increased cell viability by 166.37% compared to Pentylenetetrazol (PTZ) treated HEK-293 cells. Thus, the combination of CBZ (20 mg/kg) + IMI (10 mg/kg) is a fruitful combination therapy to elevate seizure threshold and provide neuroprotection.