Nefiracetam

The cholinergic and glutamatergic systems are known to be downregulated in the brain of Alzheimer's disease patients. Galantamine and nefiracetam have been shown to potentiate the phasic activity of nicotinic acetylcholine receptors (nAChRs) in the brain. Stimulation of nAChRs is also known to cause release of various neurotransmitters including glutamate and gamma-aminobutyric acid (GABA). We have previously reported that nefiracetam and galantamine potentiate the activity of nAChRs. Therefore, nefiracetam and galantamine are hypothesized to cause stimulations of the glutamate and GABA systems via stimulation of nAChRs...

Olfactory bulbectomized (OBX) mice exhibit depressive-like behaviors as assessed by the tail suspension test (TST) and the forced swim test (FST). Interestingly, chronic intraperitoneal administration (1 mg/kg/day) of nefiracetam (DM-9384), a prototype cognitive enhancer, significantly improved depressive-like behaviors as well as spatial reference memory assessed by Y-maze task. As previously reported (Moriguchi, S., Han, F., Nakagawasai, O., Tadano, T., Fukunaga, K., 2006. Decreased calcium/calmoculin-dependent protein kinase II and protein kinase C activities mediate impairment of hippocampal long-term potentiation in the olfactory bulbectomized mice...

In preliminary trials, nefiracetam, a gamma aminobutyric compound, enhanced blood flow and improved mood following stroke. Within 3 months following stroke with major depression, 159 patients were enrolled in a double-blind trial of nefiracetam or placebo. Repeated measures analysis of covariance failed to show a significant time-by-treatment interaction. Response rates were greater than 70% and remission rates were greater than 40% for nefiracetam and placebo. The top quintile of Hamilton Depression Rating Scale scores showed significant effect after 900 mg of nefiracetam versus 600 mg or placebo...

Nefiracetam is a pyrrolidine-related nootropic drug exhibiting various pharmacological actions such as cognitive-enhancing effect. We previously showed that nefiracetam potentiates NMDA-induced currents in cultured rat cortical neurons. To address questions whether nefiracetam affects NMDA receptor-dependent synaptic plasticity in the hippocampus, we assessed effects of nefiracetam on NMDA receptor-dependent long-term potentiation (LTP) by electrophysiology and LTP-induced phosphorylation of synaptic proteins by immunoblotting analysis...

UNLABELLED: Recent studies have shown that nefiracetam ameliorates cognitive dysfunction because of ischemia when behavioral testing occurs during treatment. We sought to determine if there was a persistent effect after treatment, by testing spatial learning of embolized rats after nefiracetam therapy. METHODS: Male Sprague Dawley rats (250 to 300 g) were divided into 3 categories. The control group (n = 5) underwent no surgery or cerebral embolism. The vehicle group (n = 12) was anesthetized with halothane, underwent surgery, injected with intracarotid microspheres, and given orally 5 mL/kg of the vehicle (0...

Nicotinic acetylcholine receptors and N-methyl-D-aspartate (NMDA) receptors are known to be down-regulated in the brain of Alzheimer's disease patients. We have previously demonstrated that the nootropic drug nefiracetam potentiates the activity of both nicotinic acetylcholine and NMDA receptors and that nefiracetam modulates the glycine binding site of the NMDA receptor. Because the NMDA receptor is also modulated by Mg2+ and protein kinases, we studied their roles in nefiracetam action on the NMDA receptor by the whole-cell patch-clamp technique and immunoblotting analysis using rat cortical or hippocampal neurons in primary culture...

Animal models of drug discrimination have been used to examine the subjective effects of addictive substances. The cAMP system is a crucial downstream signaling pathway implicated in the long-lasting neuroadaptations induced by addictive drugs. We examined effects of rolipram, nefiracetam, and dopamine D2-like receptor antagonists, all of which have been reported to modulate cAMP level in vivo, on the discriminative-stimulus effects of methamphetamine (METH) and morphine in rats. All these compounds inhibited the discriminative-stimulus effects of METH, while only rolipram and nefiracetam attenuated the discriminative-stimulus effects of morphine...

PURPOSE: Nefiracetam (NEF) is a novel pyrrolidonetype nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition-enhancing effects. The present study focused on the effects of NEF in amygdala-kindled seizures and its potential for antiepileptic therapy. METHODS: Effects of NEF on fully amygdala-kindled seizures and development of amygdala-kindled seizures were investigated in rats and compared with those of levetiracetam (LEV), a pyrrolidone-type antiepileptic drug (AED)...

Nefiracetam is a novel pyrrolidone-type nootropic agent, and it has been reported to possess a potential for antiepileptic therapy as well as cognition-enhancing effects. We investigated the anticonvulsant and neuroprotective effects of nefiracetam in kainic acid-induced seizures of rats, compared with levetiracetam and standard antiepileptic drugs. Subcutaneous injection of kainic acid (10 mg/kg) induced typical behavioral seizures such as wet dog shakes and limbic seizures and histopathological changes in the hippocampus (degeneration and loss of pyramidal cells in CA1 to CA4 areas)...

To ascertain the early pathophysiological features in canine renal papillary necrosis (RPN) caused by the neurotransmission enhancer nefiracetam, male beagle dogs were orally administered nefiracetam at 300 mg/kg/day for 4 to 7 weeks in comparison with ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), at 50 mg/kg/day for 5 weeks. During the dosing period, the animals were periodically subjected to laboratory tests, light-microscopic, immunohistochemical, and electron-microscopic examinations and/or cyclooxygenase (COX)-2 mRNA analysis...

The occurrence of renal papillary necrosis (RPN), seen only in dogs after repeated oral administration of nefiracetam, a neurotransmission enhancer, at a relatively high dose, is because of inhibition of renal prostaglandin synthesis by the nefiracetam metabolite M-18. In this study, analyses of urinary proteins and renal mRNA expression were performed to investigate the possible existence of a specific protein expressing the characteristics of RPN evoked by nefiracetam. In the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of urinary proteins from male dogs given nefiracetam at 300 mg kg(-1) day(-1) over weeks 5-11, a protein of approximately 40 kDa, which was not seen in control urine, and protein of approximately 30 kDa emerged as distinct bands...

Enhancing the release of acetylcholine (ACh) in the brain is one approach to increasing neuronal activity, restoring central cholinergic tone and improving attention and cognition. ACh release is modulated by both ligand-gated (gamma-amino butyric acid A receptors/benzodiazepine [GABA(A)/BDZ], nicotinic-acetylcholine and serotonin, 5-HT3) and voltage-gated (calcium and potassium) ion channels. Of the ligand-gated channel modulators, the BDZ receptor (BDZR) inverse agonists (beta-CCM, ZK 93426) enhance activity-dependent release in animals, whereas S-8510, a partial inverse agonist, and the BDZR antagonist, flumazenil, show enhancement regardless of the behavioural state of the animal...

Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a disease-modifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing...

Nicotinic acetylcholine receptors and N-methyl-D-aspartate (NMDA) receptors are known to be down-regulated in the brain of patients with Alzheimer's disease. It was previously shown that the nootropic drugs nefiracetam and galantamine potentiate the activity of both nicotinic and NMDA receptors. We hypothesized that donepezil, a nootropic with a potent anticholinesterase activity, might also affect the NMDA system. NMDA-induced currents were recorded from rat cortical neurons in primary culture using the whole-cell patch-clamp technique at a holding potential of -70 mV in Mg2+-free solutions...

PURPOSE: Nefiracetam (NEF) is a novel pyrrolidone-type nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition-enhancing 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)]...

Our recent study demonstrated that nefiracetam, N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, prevented impairment of the cyclic AMP (cAMP)/cAMP-responsive element binding (CREB) protein signaling pathway in sustained cerebral ischemia. The purpose of the present study was to determine whether nefiracetam has an effect on the expression of brain-derived neurotrophic factor (BDNF) and synapsin I mRNAs that are believed to be produced via CREB, and the alteration in their protein contents in the hippocampus after cerebral ischemia...

It has recently been reported that nefiracetam, a nootropic agent, is capable of attenuating the development of morphine dependence and tolerance in mice. The mechanism of this antimorphine action is not clear. The present study was designed to address this issue using Xenopus oocytes expressing delta-opioid receptors, G proteins (G(i3alpha) or G(o1alpha)), and N-type (alpha1B) Ca2+ channels. Membrane currents through Ca2+ channels were recorded from the oocytes under voltage-clamp conditions. The Ca2+ channel currents were reduced reversibly by 40-60% in the presence of 1 microM leucine-enkephalin (Leu-Enk)...

Nefiracetam has been reported to increase intracellular cyclic AMP levels and enhance calcium channel current. Since the cAMP cascade is involved in the development of drug dependence, we investigated whether nefiracetam attenuates the methamphetamine (MAP)-induced discriminative responses in rats. Nefiracetam (50 mg/kg) inhibited MAP-induced discriminative responses. Furthermore, rolipram, raclopride, and L-745870, all of which can enhance cAMP activity, disrupted MAP-paired lever press of rats. Nifedipine and neomycin, which are blockers of voltage-sensitive calcium channels (VSCCs), decreased MAP-induced discriminative responses...

Piracetam and structurally related nootropics are known to potentiate the anticonvulsant effects of antiepileptic drugs. It remains to be seen, however, whether these nootropics inhibit proconvulsant actions of many toxic agents including Ro 5-4864, a specific agonist for peripheral-type benzodiazepine receptors (PBR). The present study was designed to address this issue using EL mice, an animal model of epilepsy. In behavioral pharmacological experiments, EL mice were highly susceptible to convulsions induced by Ro 5-4864 (i...

No strategies for curing Alzheimer's disease have been developed yet as we do not know the exact cause of the disease. The only therapy that is available for patients is symptomatic treatment. Since Alzheimer's disease is associated with downregulation of the cholinergic system in the brain, its stimulation is expected to improve the patients' cognition, learning, and memory. Four anticholinesterases have been approved in the U.S.A. for the treatment of Alzheimer's disease patients. However, because of the inhibition of cholinesterases, these drugs have side effects and their effectiveness does not last long...