Disease relevance of CCRIS 6729

• The nefiracetam potentiating action was not affected by 24-h pretreatment of neurons with pertussis toxin, but was abolished by cholera toxin [1].
• Persistent effects of delayed treatment with nefiracetam on the water maze task in rats with sustained cerebral ischemia [2].
• In the thermal paw withdrawal test, p.o., s.c., i.t., and i.c.v. administration of nefiracetam dose dependently reversed the thermal hyperalgesia observed in nerve-injured mice [3].
• Effects of the nootropic drug nefiracetam on the GABAA receptor-channel complex in dorsal root ganglion neurons [4].
• Therefore, it is suggested that nefiracetam improves the dysfunction of cholinergic, GABAergic and/or monoaminergic neuronal function by acting at Ca2+ channel and enhancing the release of neurotransmitters, and modifies impairment of memory processes induced by drugs and hypoxia [5].

Psychiatry related information on CCRIS 6729

• Nefiracetam (DM-9384) is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and poststroke vascular-type dementia [1].
• Physostigmine and nefiracetam were tested alone and in combination in 104 rabbits with a mean age of 28 months conditioned in the 750 ms delay eyeblink classical conditioning procedure [6].
• Co-administration of nefiracetam with scopolamine was not necessary to achieve the antiamnesic action, as nefiracetam given during training significantly improved the memory deficits produced by scopolamine at the 6-h posttraining time [7].
• The results obtained indicate that the protective action of DM-9384 against scopolamine-induced amnesia is due to its ability to reverse the ACh depletion [8].
• 7. These results suggest that nefiracetam may be useful for the treatment of patients with Alzheimer's disease [9].

High impact information on CCRIS 6729

• No affinity for the alpha 1-, alpha 2-, beta-, muscarinic, 5-hydroxytryptamine-, dopamine, adenosine-A1-, mu-opiate, gamma-aminobutyric acid (GABA) (except for nefiracetam (GABAA)), benzodiazepine and glutamate receptors has been found [10].
• 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 [11].
• Nefiracetam at very high concentrations (approximately 10 microM) also potentiated alpha 4 beta 2-type currents but to a lesser extent, indicative of a bell-shaped dose-response relationship [1].
• Although nefiracetam and aniracetam inhibited alpha 7-type currents only weakly, these nootropic agents potentiated alpha 4 beta 2-type currents in a very potent and efficacious manner [1].
• Nefiracetam modulates acetylcholine receptor currents via two different signal transduction pathways [12].

Chemical compound and disease context of CCRIS 6729

• 2. In the present study, we investigated the effects of nefiracetam [N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384] on A beta-(1-42)-induced learning and memory deficits in rats [9].
• Nefiracetam suppression of GABA-induced currents was also abolished by KT 5720 or the pertussis toxin [4].
• The effects of N-(2,6-dimethyl-phenyl)-2-(2-oxo-1-pyrrolidinyl)-acetamide [DM-9384], a cyclic derivative of GABA, were investigated in the cycloheximide (CXM)-induced amnesia animal model using the passive avoidance task [13].
• In the absence of any evident effect on the onset or duration of anesthesia, nefiracetam prevented both forms of propofol-induced amnesia and preserved the learning-associated changes of neuronal polysialylation state [14].
• Thus, in the present report, we have studied the effects of nootropic drug nefiracetam on the thermal and mechanical hyperalgesia induced by partial sciatic nerve ligation or streptozotocin treatment in mice [3].

Biological context of CCRIS 6729

• In immunoblotting analysis, nefiracetam treatment increased the PKCalpha activity with a bell-shaped dose-response relationship peaking at 10 nM, thereby increasing phosphorylation of PKC substrate and NMDA receptor [11].
• 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 [11].
• Together, these findings suggest that nefiracetam, a new member of the piracetam group of cognition enhancers, could be a good therapeutic tool against neuropathic pain [3].
• All these findings suggest that nefiracetam inhibit necrosis and apoptosis occurred in the ischemic/hypoxic neuronal injury through an increase in Ca(2+) influx [15].
• The nefiracetam modulation of the GABAA receptor function will result in a nootropic effect on the central nervous system through modification of synaptic transmission [4].

Anatomical context of CCRIS 6729

• 5. Nefiracetam at a dose of 3 mg kg(-1) p.o. increased the activity of choline acetyltransferase in the hippocampus of A beta-(1-42)-infused rats [9].
• Nefiracetam, a nootropic (cognition-enhancing) agent, facilitated neurotransmission in the dentate gyrus of rat hippocampal slices in a dose-dependent manner at concentrations ranged from 1 nM to 1 microM, being evident at 60-min washing-out of the drug [16].
• In behavioral experiments in rats, nefiracetam (3 mg/kg) ameliorated amnesia induced by basal forebrain (BF) lesion or treatment of scopolamine [17].
• To delineate its pathogenesis, we established the primary culture of uroepithelial cells of the canine urinary bladder, and then explored the effect of nefiracetam on the cultured cells [18].
• In the Xenopus oocyte expression systems, nefiracetam potentiated currents through a variety of neuronal nicotinic ACh receptors (alpha 3beta 2, alpha 3beta 4, alpha 4 beta 2, alpha 4 beta 4, and alpha 7) to a different extent [16].

Associations of CCRIS 6729 with other chemical compounds

• The effect of a new cognition enhancer, DM-9384, N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, on regional acetylcholine (ACh) levels and against scopolamine-induced ACh depletion was examined in mouse brain [8].
• Finally, nefiracetam (p.o.)-induced analgesia in injured mice was not affected by opioid antagonist naloxone (s.c., i.t., and i.c.v.) but was dose dependently inhibited by nicotinic antagonist mecamylamine (i.t. and i.c.v.). The analgesic effect of i.t. nefiracetam was also blocked by i.t. mecamylamine pretreatment [3].
• When added to the internal pipette solution, the protein kinase A inhibitor KT 5720 (0. 6 microM), but not the protein kinase C inhibitor calphostin C (0.5 microM), abolished the nefiracetam stimulation of the ACh receptor [19].
• Nefiracetam, when administered orally t o EL mice, inhibited convulsions induced by the PBR agonist, Ro 5-4864, with an ED(50) of 17.2 mg/kg, whereas it did not inhibit the drug-induced convulsions in control DDY mice [20].
• Ultrastructurally, nefiracetam exhibited reductions of intracellular interdigitation and infoldings of epithelial cells in the papillary ducts, whereas ibuprofen showed no changes in the identical portions [21].

Gene context of CCRIS 6729

• We conclude that on average the formation of 5-OHN, the major metabolite of nefiracetam, is principally mediated by CYP3A4 with a relatively minor contribution by CYP1A2 [22].
• Nefiracetam inhibited both necrosis and apoptosis, whereas brain-derived neurotrophic factor (BDNF) inhibited only apoptosis [15].
• These results suggest that enhancement of BDNF and synapsin I expression by nefiracetam treatment may be, at least in part, due to the improvement in the CREB binding activity, contributing to the prevention of learning and memory dysfunction after sustained cerebral ischemia [23].
• Anticonvulsant actions of the nootropic drug nefiracetam were studied using EL mice, an animal model of epilepsy, in which peripheral-type benzodiazepine receptors (PBRs) might be involved in their epileptogenesis [20].
• Nefiracetam (DM-9384) preserves hippocampal neural cell adhesion molecule-mediated memory consolidation processes during scopolamine disruption of passive avoidance training in the rat [7].

Analytical, diagnostic and therapeutic context of CCRIS 6729

• These preclinical data in an animal model with clear parallels in humans suggest that nefiracetam may prove effective as a cognition enhancer in clinical trials [24].
• Daily oral administration of nefiracetam (10 mg kg(-1) day(-1)) was started from 15 h after the operation [25].
• The effects of nefiracetam on GABA-induced chloride currents were studied with rat dorsal root ganglion neurons in primary culture using the whole-cell patch-clamp technique [4].
• These results indicate that a persistent improvement of the spatial memory function impaired by sustained cerebral ischemia was achieved even after cessation of treatment with nefiracetam [2].
• Treatment with nefiracetam reduced the prolongation of the escape latency in the water maze test on days 7-9 after microsphere embolism-induced sustained cerebral ischemia, suggesting an improvement in the spatial learning function [23].

References