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Sergio E Starkstein, Simone Brockman, Katherine K Hatch, David G Bruce, Osvaldo P Almeida, Wendy A Davis, Robert G Robinson
BACKGROUND: To evaluate the efficacy of treatment with nefiracetam compared to placebo in poststroke apathy. METHODS: A parallel group, randomized, placebo-controlled, double-blind two-center trial in patients with recent stroke and apathy was conducted in 2 tertiary teaching hospitals in Perth, Western Australia, between March 2010 and October 2014. Consenting patients hospitalized with stroke were screened for participation at the time of hospitalization and, if diagnosed with apathy 8-36 weeks later, they were randomized to 12 weeks of 900 mg/day nefiracetam or placebo...
May 2016: Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association
Keita Sasaki, Olaposi Idowu Omotuyi, Mutsumi Ueda, Kazuyuki Shinohara, Hiroshi Ueda
BACKGROUND: Structural and functional changes of the hippocampus are correlated with psychiatric disorders and cognitive dysfunctions. Genetic deletion of heparin-binding epidermal growth factor-like growth factor (HB-EGF), which is predominantly expressed in cortex and hippocampus, also causes similar psychiatric and cognitive dysfunctions, accompanying down-regulated NMDA receptor signaling. However, little is known of such dysfunctions in hippocampus-specific Hbegf cKO mice. RESULTS: We successfully developed hippocampus-specific cKO mice by crossbreeding floxed Hbegf and Gng7-Cre knock-in mice, as Gng7 promoter-driven Cre is highly expressed in hippocampal neurons as well as striatal medium spiny neurons...
2015: Molecular Brain
Chuan-Yi Fu, Xu-Ying He, Xi-Feng Li, Xin Zhang, Zhi-Wei Huang, Jun Li, Min Chen, Chuan-Zhi Duan
BACKGROUND/AIMS: Prior studies demonstrated that pro-inflammatory cytokines (PICs) including IL-1β, IL-6 and TNF-α contribute to regulation of epilepsy-associated pathophysiological processes in the specific brain regions, namely the parietal cortex, hippocampus and amygdala. Moreover, GABA transporter type 1 and 3 (GAT-1 and GAT-3) modulating extracellular GABA levels are engaged in the role played by PICs in epileptogenesis. Note that brain ischemic injury also elevates cerebral PICs...
2015: Cellular Physiology and Biochemistry
Olaposi I Omotuyi, Hiroshi Ueda
Plastic changes in the brain required for memory formation and long-term learning are dependent on N-methyl-d-aspartic acid (NMDA) receptor signaling. Nefiracetam reportedly boosts NMDA receptor functions as a basis for its nootropic properties. Previous studies suggest that nefiracetam potentiates the NMDA receptor activation, as a more potent co-agonist for glycine binding site than glycine, though the underlying mechanisms remain elusive. Here, using BSP-SLIM method, a novel binding site within the core of spiral β-strands-1-5 of LBD-GLUN1 has been predicted in glycine-bound GLUN1 conformation in addition to the glycine pocket in Apo-GLUN1...
April 2015: Computational Biology and Chemistry
Oldřich Farsa
The log BB parameter is the logarithm of the ratio of a compound's equilibrium concentrations in the brain tissue versus the blood plasma. This parameter is a useful descriptor in assessing the ability of a compound to permeate the blood-brain barrier. The aim of this study was to develop a Hansch-type linear regression QSAR model that correlates the parameter log BB and the retention time of drugs and other organic compounds on a reversed-phase HPLC containing an embedded amide moiety. The retention time was expressed by the capacity factor log k'...
March 2013: Scientia Pharmaceutica
Xi-Chun May Lu, Jitendra R Dave, Zhiyong Chen, Ying Cao, Zhilin Liao, Frank C Tortella
AIMS: Stroke patients are at a high risk of developing post-ischemic seizures and cognitive impairment. Nefiracetam (NEF), a pyrrolidone derivative, has been shown to possess both anti-epileptic and cognitive-enhancing properties. In this study the anti-seizure effects of NEF were evaluated in a rat model of post-ischemic nonconvulsive seizures (NCSs). Its potential mechanisms were investigated in neuronal cell culture assays of neurotoxicity associated with ischemic brain injury and epileptogenesis...
June 13, 2013: Life Sciences
Rakesh Kumar, K H Reeta, Subrata Basu Ray
Morphine is a gold standard analgesic commonly used to alleviate pain. However, its use is associated with unavoidable side effects including the risk for addiction. Peripherally administered loperamide lacks effect on the central nervous system as it is a substrate for the permeability glycoprotein (P-gp) efflux pump which blocks its entry into brain. However, when administered intrathecally, loperamide has been reported to produce analgesia. The present study investigates the mechanism of the central analgesic effect of loperamide...
December 5, 2012: European Journal of Pharmacology
Shigeki Moriguchi
In the brain of Alzheimer's disease patients, down-regulation of both cholinergic and glutamatergic systems have been found and is thought to play an important role in impairment of cognition, learning, and memory. Nefiracetam is a pyrrolidine-related nootropic drug exhibiting various pharmacological actions such as a cognitive-enhancing effect. The present study was undertaken to elucidate mechanisms underlying the action of nefiracetam on glutamatergic receptors and intracellular protein kinases. N-Methyl-D-aspartate (NMDA)-evoked currents were recorded from rat cortical neurons in long-term cultured primary neurons using the whole-cell patch-clamp technique...
2011: Journal of Pharmacological Sciences
XingZhou Li, ChuangJiang Zhu, ChangHui Li, KeMei Wu, DaoFei Huang, Liang Huang
A practical synthesis of N-substituted Clausenamide analogues, including (-) and (+) CM1, Piracetam analogue 1 and Nefiracetam analogue 2, have been developed.
November 2010: European Journal of Medicinal Chemistry
Ricardo E Jorge, Sergio E Starkstein, Robert G Robinson
OBJECTIVE: We will review the available evidence on the frequency, clinical correlates, mechanism, and treatment of apathy following stroke. METHODS: We have explored relevant databases (that is, PubMed, MEDLINE, and PsycINFO) using the following key words and their combinations: apathy, motivation, abulia, stroke, cerebrovascular disease, basal ganglia, prefrontal cortex, anterior cerebral infarction, and thalamus. RESULTS: The frequency of apathy following stroke has been consistently estimated between 20% and 25%...
June 2010: Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie
Andrei G Malykh, M Reza Sadaie
There is an increasing interest in nootropic drugs for the treatment of CNS disorders. Since the last meta-analysis of the clinical efficacy of piracetam, more information has accumulated. The primary objective of this systematic survey is to evaluate the clinical outcomes as well as the scientific literature relating to the pharmacology, pharmacokinetics/pharmacodynamics, mechanism of action, dosing, toxicology and adverse effects of marketed and investigational drugs. The major focus of the literature search was on articles demonstrating evidence-based clinical investigations during the past 10 years for the following therapeutic categories of CNS disorders: (i) cognition/memory; (ii) epilepsy and seizure; (iii) neurodegenerative diseases; (iv) stroke/ischaemia; and (v) stress and anxiety...
February 12, 2010: Drugs
Robert G Robinson, Ricardo E Jorge, Kathleen Clarence-Smith, Sergio Starkstein
Nefiracetam is a novel pyrrolidone-type nootropic compound shown in preliminary trials to increase blood flow and improve patient outlook and energy following stroke. Of 137 stroke patients with major depression, 70 also met published diagnostic criteria for apathy (51.1%) and were randomly assigned either to placebo or 600 mg or 900 mg of nefiracetam per day, and received at least 4 weeks of treatment. Using the group with at least 4 weeks of treatment as the intention-to-treat sample with last observation carried forward, repeated measures analysis of variance of Apathy Scale scores demonstrated a significant time-by-treatment interaction...
2009: Journal of Neuropsychiatry and Clinical Neurosciences
Shigeki Moriguchi, Feng Han, Norifumi Shioda, Yui Yamamoto, Takeharu Nakajima, Osamu Nakagawasai, Takeshi Tadano, Jay Z Yeh, Toshio Narahashi, Kohji Fukunaga
Aberrant behaviors related to learning and memory in olfactory bulbectomized (OBX) mice have been documented in the previous studies. We reported that the impairment of long-term potentiation (LTP) of hippocampal CA1 regions from OBX mice was associated with down-regulation of CaM kinase II (CaMKII) and protein kinase C (PKC) activities. We now demonstrated that the nootropic drug, nefiracetam, significantly improved spatial reference memory-related behaviors as assessed by Y-maze and novel object recognition task in OBX mice...
July 2009: Journal of Neurochemistry
S Moriguchi, X Zhao, W Marszalec, J Z Yeh, K Fukunaga, T Narahashi
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...
May 5, 2009: Neuroscience
Feng Han, Tetsuo Nakano, Yui Yamamoto, Norifumi Shioda, Ying-Mei Lu, Kohji Fukunaga
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...
April 10, 2009: Brain Research
Robert G Robinson, Ricardo E Jorge, Kathleen Clarence-Smith
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...
2008: Journal of Neuropsychiatry and Clinical Neurosciences
Shigeki Moriguchi, Norifumi Shioda, Feng Han, Toshio Narahashi, Kohji Fukunaga
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...
August 2008: Journal of Neurochemistry
D T Le, C Shin, C Jackson-Friedman, P D Lyden
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...
May 2001: Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association
Shigeki Moriguchi, Norifumi Shioda, Hiroshi Maejima, Xilong Zhao, William Marszalec, Jay Z Yeh, Kohji Fukunaga, Toshio Narahashi
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...
February 2007: Molecular Pharmacology
Yijin Yan, Atsumi Nitta, Tomoko Mizuno, Akira Nakajima, Kiyofumi Yamada, Toshitaka Nabeshima
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...
October 2, 2006: Behavioural Brain Research
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