Comparative Anticonvulsant Activity and Neurotoxicity of 4–Amino‐<i>N</i>‐(2,6‐Dimethylphenyl)Phthalimide and Prototype Antiepileptic Drugs in Mice and Rats

Summary:Purpose: Nefiracetam (NEF) is a novel pyrrolidone-type nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognitionenhancing effects. The present study focused on the anticonvulsant effect of NEF and its potential for antiepileptic therapy.Methods: The anticonvulsant properties of NEF were investigated in experimental seizure models of mice and rats, compared with levetiracetam (LEV) and other standard antiepileptic drugs [AEDs; zonisamide (ZNS), phenytoin (PHT), carbamazepine (CBZ), valproic acid (VPA), diazepam (DZP), and ethosuximide (ESM)]. With reference to standard programs for evaluating potential AEDs, the study included the traditional maximal electroshock seizure and subcutaneous chemoconvulsant (pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate) seizure tests and two threshold models (the increasing-current electroshock seizure test and intravenous pentylenetetrazole seizure threshold test). Neurotoxic activities were examined with the rotarod test and traction test.Results: NEF inhibited electroshock-induced seizures at nontoxic doses, whereas it had no effect on seizures chemically induced by pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate. The anticonvulsant spectrum of NEF paralleled that of ZNS, PHT, and CBZ. The anticonvulsant efficacy of NEF was comparable with that of ZNS and less potent than that of PHT, CBZ, and DZP. However, the safety margin of NEF was superior to that of ZNS, CBZ, VPA, and DZP. LEV showed only slight anticonvulsant effects in threshold models, and it was not effective in conventional screening models.Conclusions: These results suggest that NEF has distinct anticonvulsant spectrum and mechanisms from those of LEV. NEF is an orally active and safe AED, and it possesses a potential for antiepileptic therapy. Key Words: NefiracetamLevetiracetam-Nootropic-Seizure-Antiepileptic.Cognition-enhancing agents (or nootropics) are drugs used for the treatment of impaired brain function resulting from cerebral deficiencies such as senile dementia or cerebral vascular disorders (1-3). Nefiracetam [NEF; N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, DM-9384] is a novel pyrrolidone-type nootropic and has been reported to enhance learning acquisition and to improve experimentally induced amnesia in various animal models (4-7). Electrophysiologic and neurochemical studies have demonstrated that NEF activates N/L-type Ca 2+ channels (8,9), and cholinergic, monoaminergic and γ -aminobutyric acid (GABA)ergic systems (10-15).Some pyrrolidone derivatives such as piracetam and oxiracetam have been reported to possess anticonvulsant activities (16) or synergistic effects in combination with antiepileptic drugs (AEDs) (17,18). Piracetam has been Accepted February 6, 2005. Address correspondence and reprint requests to Dr. Y. Kitano at New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. E-mail: kitanpm...

Section: Methodsmentioning

confidence: 99%

Anticonvulsant Properties of the Novel Nootropic Agent Nefiracetam in Seizure Models of Mice and Rats

Kitano

Komiyama²,

Makino³

et al. 2005

“…PHT, for example, has a time to peak neurotoxic effect of 30 min compared with a time to peak anticonvulsant effect of 2 h (23). For VPA, however, the neurotoxic and anticonvulsant times to peak effects are both 15 min (22). Therefore, for VPA, we completed behavioral testing immediately before seizure testing, whereas seizure testing for PHT was done 90 min after neurotoxicity evaluation.…”

Section: Methodsmentioning

confidence: 99%

Comparison of the Anticonvulsant Efficacies and Neurotoxic Effects of Valproic Acid, Phenytoin, and the Ketogenic Diet

Bough

Eagles

2001

Summary:Purpose: The purpose of this study was to measure quantitatively the effectiveness of the ketogenic diet (KD) in comparison to two clinically important anticonvulsant drugs (AEDs), valproic acid (VPA) and phenytoin (PHT), and to evaluate possible associated neurotoxicity.Methods: Rats were maintained on either a calorie-restricted, KD or calorie-restricted, rodent-chow diet for 3-5 weeks, after which neurobehavioral and seizure testing was completed. AEDs (either VPA or PHT) were injected acutely at the time to peak effect before neurotoxic and seizure assessment. Seizures were induced by timed infusion of pentylenetetrazole (PTZ) and maximal electroshock (MES).Results: VPA protected from both MES-and PTZ-induced seizures, whereas the KD only elevated PTZ seizure threshold; PHT only attenuated MES-induced seizures. The KD was as effective as a high dose of VPA (i.e., 300 mg/kg) and combined treatment (i.e., KD + VPA) showed an additive increase in PTZ seizure threshold. No observed neurobehavioral deficits were associated with either diet treatment; however, drug-related side effects were noted with high doses of either VPA or PHT.Conclusions: These data suggest that the KD ranks among VPA and PHT as an effective treatment for seizures, without observed drug-associated neurobehavioral contraindications. In combination with AEDs, our results indicate that the KD plus VPA work synergistically to increase seizure threshold, whereas the KD plus PHT may be complementary, elevating seizure threshold (KD) and reducing seizure severity (PHT). These findings may provide insights into future directions for rational polytherapy; however, it is important to be aware that the KD has been shown to elevate VPA-induced hepatotoxicity. Key Words: Ketongenic diet-Epilepsy-PhenytoinValproic acid-Neurotoxicity-Rat.The ketogenic diet (KD) is a dietary treatment for human epilepsy that has been shown to be an effective means of managing difficult-to-control seizures for nearly 70 years (1-8). As Geyelin (9) reported that abstinence from food and drink could attenuate seizure activity, Wilder (1) subsequently developed a high-fat diet in an effort to mimic the physiology of fasting, circumvent the self-limiting nature of starvation, and attain the benefits of improved seizure control. The KD is predominantly fat (by weight and caloric content), with minimal proteins and carbohydrates. Historical reports of clinical efficacy have described a >50% reduction in seizure activity for 44-95% of the patients to whom the diet was administered (10). More recent, prospective KD studies show similar findings and indicate that the KD provides protection from various types of seizure activity (8,11).Initial experimental studies focused on characterizing the putative anticonvulsant action of KD (e.g., 12). Early studies in mice (4,12) and rats (13) provided evidence that the KD attenuated seizure activity. There were no systematic studies of the KD in a single model, and generalizations have proven difficult. Since 1994, however, there has ...

“…), BM 11, BM 27, and BM 34 did not protect mice against convulsions induced by subcutaneous (s.c.) injection of pentetrazole (PTZ), strychnine (STR), bicuculline (BIC), picrotoxine (PIC) or NMLDA ( Table 2). Their profile appeared, therefore, similar to that of phenytoin (14,18). The sulfonyl-urea and -thiourea functions of BM derivatives could be regarded chemically as bioisosteres of the cyclic acylurea moiety of phenytoin.…”

Section: Resultsmentioning

confidence: 72%

Anticonvulsant Activity of Pyrid‐3‐yl‐Sulfonyl Ureas and Thioureas

Masereel

Lambert²,

Dogné

et al. 1997

Summary:The N-[(4-cycloheptylaminopyrid-3-yl)sulfonyl]-N'-cycloheptyl urea, a neuroprotective agent, and 10 chemically related sulfonyl(thio)ureas were evaluated in the maximal electroshock seizure test in mice. This sulfonylurea, BM 27, and two stucturally related sulfonylthioureas, BM 11 and BM 34, emerged with a 50% effective dose (ED,,) of 2.87, 1.72, and 1.19 mg/kg, respectively. Their anticonvulsant profiles were found to be similar to that of phenytoin: active in the maximal electroshock seizure (MES) test and inactive in chemically induced seizures (pentetrazole, strychnine, bicuculline, picrotoxine, N-methyl-D,L-aspartic acid). These compounds exhibited a higher protective index and potency than those of phenytoin. Additional work remains necessary, however, to determine whether BM 27 is of clinical interest. Key Words: Sulfonylurea-Sulfonylthiourea-Epilepsy-Anticonvulsan-BM 34. N-[ (4-cycloheptylaminopyrid-3-yl)sulfonyl]-N'-cycbheptyl urea, called BM 27, (Table 1) is a sulfonylurea that exhibits neuroprotective properties against normobaric hypoxia in mice (0.1-1 mg/kg) and cerebral ischemia in gerbils (1-2.5 mg/kg) (1). It is structurally related to torasemide (a loop diuretic) acting, as does furosemide (2), by the inhibition of the Na+ 2 HC1-K+ cotransporter of the thick ascending limb of Henle's loop (3). The central properties of BM 27 probably can be attributed to its ability to inhibit the astrocytic Na+ 2 HC1-K+ cotransporter (1). As furosemide blocks kainic acid-induced electrical discharges recorded from cortex (4), and in view of the antiepileptic properties attributed to the neuroprotective agents such as the antagonists of the N-methyl-D-aspartate (NMDA) and non-NMDA receptors (5-9), we investigated the anticonvulsant activity of BM 27 and some related substances. In this study, BM 27 and two sulphonylthioureas, BM 11 and BM 34, were selected to be tested in several classic anticonvulsant assays to define their pharmacologic profile. METHODS ChemistryAll compounds were synthesized as described previously (1). Their elemental analyses for C, H, N, and S were within 0.4% of the theoretic values. 'H-nuclear magnetic resonance (NMR) and IR spectra were in complete agreement with their chemical structure. LipophilicityThe lipophilicity of compounds (log P) was measured at pH 7.4 and expressed as the logarithm of their partition coefficient in the n-octanollphosphate buffer system. The log P of a series of standards chosen in a wide range of log P values (from +0.16 to +2.0) was determined by using the shake-flask method (10). As reported (1,l l), a reverse-phase high performance liquid chromatography system was used to determine their capacity factor (log k') which corresponds to log (~-t,)/t,)] where t, is the drug retention time and t, is the void volume. A calibration curve calculated from log P and log k' of standards was used to interpolate the log P of the studied compounds. Pharmacology Anticonvulsant activityAll compounds were administered to OF1 male mice (22-25 g; Iffa-Credo, Les Onci...