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  1. #21
    Senior Member spike77's Avatar
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    Aniracetam:



    Excitatory amino acids and neuronal plasticity: modulation of AMPA receptors as a novel substrate for the action of nootropic drugs.

    * Nicoletti F,

    * Casabona G,

    * Genazzani AA,

    * Copani A,

    * Aleppo G,

    * Canonico PL,

    * Scapagnini U.



    Institute of Pharmacology, University of Catania, School of Medicine, Italy.



    The nootropic drug, aniracetam, behaves as a positive modulator of AMPA-sensitive glutamate receptors in a variety of systems, including intact brain tissue, amphibian oocytes injected with rat brain mRNA, and cultured neurons. In electrophysiological studies, aniracetam both increases the peak amplitude and reduces the rate of decay of the ion current generated by AMPA or quisqualate. In cultured neurons, aniracetam (as well as oxiracetam and piracetam) enhances the stimulation of 45Ca2+ influx produced by AMPA but not that produced by kainate or NMDA. In addition, aniracetam (as other nootropic drugs) increases the maximal density of low affinity binding sites for [3H]AMPA in crude synaptic membranes. Positive modulation of AMPA receptors by aniracetam provides a novel molecular substrate which explains the clinical efficacy of nootropic drugs as memory and cognition enhancers.



    PMID: 1338053







    [3H]aniracetam binds to specific recognition sites in brain membranes.



    * Fallarino F,

    * Genazzani AA,

    * Silla S,

    * L'Episcopo MR,

    * Camici O,

    * Corazzi L,

    * Nicoletti F,

    * Fioretti MC.



    Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy.



    [3H]Aniracetam bound to specific and saturable recognition sites in membranes prepared from discrete regions of rat brain. In crude membrane preparation from rat cerebral cortex, specific binding was Na+ independent, was still largely detectable at low temperature (4 degrees C), and underwent rapid dissociation. Scatchard analysis of [3H]aniracetam binding revealed a single population of sites with an apparent KD value of approximately 70 nM and a maximal density of 3.5 pmol/mg of protein. Specifically bound [3H]aniracetam was not displaced by various metabolites of aniracetam, nor by other pyrrolidinone-containing nootropic drugs such as piracetam or oxiracetam. Subcellular distribution studies showed that a high percentage of specific [3H]aniracetam binding was present in purified synaptosomes or mitochondria, whereas specific binding was low in the myelin fraction. The possibility that at least some [3H]aniracetam binding sites are associated with glutamate receptors is supported by the evidence that specific binding was abolished when membranes were preincubated at 37 degrees C under fast shaking (a procedure that substantially reduced the amount of glutamate trapped in the membranes) and could be restored after addition of either glutamate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) but not kainate. The action of AMPA was antagonized by DNQX, which also reduced specific [3H]aniracetam binding in unwashed membranes. High levels of [3H]aniracetam binding were detected in hippocampal, cortical, or cerebellar membranes, which contain a high density of excitatory amino acid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)



    PMID: 7616253







    Excitatory amino acids and neuronal plasticity: modulation of AMPA receptors as a novel substrate for the action of nootropic drugs.



    Nicoletti F, Casabona G, Genazzani AA, Copani A, Aleppo G, Canonico PL, Scapagnini U.



    Institute of Pharmacology, University of Catania, School of Medicine, Italy.



    The nootropic drug, aniracetam, behaves as a positive modulator of AMPA-sensitive glutamate receptors in a variety of systems, including intact brain tissue, amphibian oocytes injected with rat brain mRNA, and cultured neurons. In electrophysiological studies, aniracetam both increases the peak amplitude and reduces the rate of decay of the ion current generated by AMPA or quisqualate. In cultured neurons, aniracetam (as well as oxiracetam and piracetam) enhances the stimulation of 45Ca2+ influx produced by AMPA but not that produced by kainate or NMDA. In addition, aniracetam (as other nootropic drugs) increases the maximal density of low affinity binding sites for [3H]AMPA in crude synaptic membranes. Positive modulation of AMPA receptors by aniracetam provides a novel molecular substrate which explains the clinical efficacy of nootropic drugs as memory and cognition enhancers.



    PMID: 1338053







    Aniracetam. An overview of its pharmacodynamic and pharmacokinetic properties, and a review of its therapeutic potential in senile cognitive disorders.



    * Lee CR,

    * Benfield P.



    Adis International Limited, Auckland, New Zealand.



    Aniracetam is a member of the nootropic class of drugs, which have possible cognition enhancing effects. It appears to positively modulate metabotropic glutamate receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-sensitive glutamate receptors, and may facilitate cholinergic transmission, effects which are possibly related to its mechanism of action. Results from trials in elderly patients with mild to moderate cognitive impairment due to senile dementia of the Alzheimer type suggest that aniracetam may be of benefit, with further trials required to confirm its efficacy profile and to define more precisely those patients most likely to respond to treatment. Aniracetam 1500 mg/day was significantly more effective than placebo in all tests at 4 and 6 months, and in a further 6-month trial was more effective than piracetam 2400 mg/day in 8 of 18 tests. Preliminary evidence in the treatment of patients with cognitive impairment of cerebrovascular origin suggests aniracetam may also be of benefit in this condition. Whilst incidence rates of adverse effects are not yet available, data from trials suggest aniracetam is well tolerated. In particular, aniracetam does not appear to cause increases in liver enzyme levels. The evaluation of drugs for patients with senile cognitive disorders is a difficult area and therapeutic options are currently limited. Preliminary evidence of the potential benefits and good tolerability profile of aniracetam support continued evaluation of its use in patients with mild to moderate senile dementia of the Alzheimer type.



    PMID: 8199398









    Piracetam:





    A 1979 study!



    Effects of piracetam on the incorporation of 32P into the phospholipids of neurons and glial cells isolated from rabbit cerebral cortex.



    Woelk H.



    In the search for the biochemical basis of the action of Piracetam, the effects of this encephalotropic substance on the neuronal and glial phospholipid metabolism was investigated. Piracetam increases the incorporation of 32P into phosphatidylinositol and phosphatidyl choline of both glia and neuronal cell bodies (Figs. 1 and 2). When taking the important role of phosphatidylinositol in the processes of synaptic transmission and axonal conduction into consideration, the data obtained in the present work suggest that piracetam may stimulate excitatory neurons and may be involved in the process of synaptic transmission. The stimulatory effect of piracetam on the incorporation of 32P into phosphatidylinositol and phosphatidyl choline appears to be mediated by noerpinephrine or another neurotransmitter. Glial cells, isolated from the cerebral cortex of a rabbit, contained approximately one-third more phospholipids per uint protein than the neuronal cell bodies. The distribution and pattern of phospholipid relative to the total amount, was rather similar in both cell types. The incorporation of 32P into phosphatidylinositol and phosphatidyl choline was somewhat faster in neurons than in glial cells. Compared to glial cells the neuronal cell fraction had a higher phospholipid turnover.



    PMID: 482348







    [A phase study of the glutamate-dependent EEG effects in the alpha- and beta-frequency ranges during the acute and subchronic administration of piracetam to rats]



    [Article in Russian]



    Kovalev GI, Vorob'ev VV, Akhmetova ER, Shibaev NV.



    Laboratory of Radioisotope Investigations, Russian Academy of Medical Sciences, Moscow, Russia.



    The glutamatergic component of the piracetam effect upon the EEG frequency spectrum was studied in wakeful rats with electrodes implanted into somatosensory cortex and hippocampus and a cannula in the lateral ventricle. Piracetam at a dose of 400 mg/kg enhanced the EEG activity in the range of 10.4-16.4 Hz in two phases: early (10-40 min) and late (above 50 min). Only the late phase was retained against the background of the NMDA receptor antagonist CPP (0.1 nmole). This stage was also retained upon the subchronic administration of piracetam. The AMPA-receptor agonist quisqualate (5 nmole) enhanced the EEG power in the range of 1.5-5 Hz and decreased the activity at 10.4-16.4 Hz. The AMPA-receptor antagonist glutamate diethyl ester (1 mumole) leveled the agonist effect, but enhanced the piracetam action in the late phase at frequencies in the alpha range.



    PMID: 10763101







    A very interesting study:



    AMPA receptor potentiators for the treatment of CNS disorders.



    * O'Neill MJ,

    * Bleakman D,

    * Zimmerman DM,

    * Nisenbaum ES.



    Eli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK. Oneill_Michael_J@Lilly.com



    Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF expression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the expression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin expression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMPA receptor potentiators have been reported. Data indicate that these molecules modulate glutamatergic transmission, enhance synaptic transmission, long-term potentiation (LTP) and increase neurotrophin expression. Therefore, these AMPA receptor potentiators offer an exciting new class of drugs with potential for treating (1) cognitive impairment associated with Alzheimer's disease and schizophrenia, (2) depression, (3) slowing the progression and potentially enhancing recovery from Parkinson's disease.



    PMID: 15180479







    Some new drugs:



    Pharmacological characterization of DM232 (unifiram) and DM235 (sunifiram), new potent cognition enhancers.



    * Romanelli MN,

    * Galeotti N,

    * Ghelardini C,

    * Manetti D,

    * Martini E,

    * Gualtieri F.



    Dipartimento di Scienze Farmaceutiche, University of Florence, Sesto Fiorentino, Italy. novella.romanelli@unifi.it



    DM232 (unifiram) and DM235 (sunifiram) are potent cognition-enhancers, which are four order of magnitude more potent than piracetam. These compounds, although not showing affinity in binding studies for the most important central receptors or channels, are able to prevent amnesia induced by modulation of several neurotransmission systems. These compounds are able to increase the release of acetylcholine from rat cerebral cortex, and, as far as unifiram is concerned, to increase the amplitude of fEPSP in rat hippocampal slices. In vitro experiments, performed on hippocampal slices, also supported the hypothesis of a role of the AMPA receptors for the cognition-enhancing properties of unifiram and sunifiram.



    PMID: 16834757







    Nefiracetam:



    Nefiracetam facilitates hippocampal neurotransmission by a mechanism independent of the piracetam and aniracetam action.



    * Nomura T,

    * Nishizaki T.



    Department of Physiology, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, 650-0017, Kobe, Japan.



    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. The facilitatory action was blocked by the nicotinic acetylcholine (ACh) receptor antagonists, alpha-bungarotoxin and mecamylamine. A similar facilitation was induced by the other nootropic agents, piracetam and aniracetam, but the facilitation was not inhibited by nicotinic ACh receptor antagonists and it did not occlude the potentiation induced by nefiracetam. 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. In contrast, neither piracetam nor aniracetam had any potentiating action on alpha 7 receptor currents. While aniracetam delayed the decay time of currents through the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, GluR1, -2, -3, expressed in oocytes, nefiracetam or piracetam had no effect on the currents. Nefiracetam, thus, appears to facilitate hippocampal neurotransmission by functionally targeting nicotinic ACh receptors, independently of the action of piracetam and aniracetam.



    PMID: 10869513







    Pir, Ani & Oxi:



    Nootropic drugs positively modulate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-sensitive glutamate receptors in neuronal cultures.



    * Copani A,

    * Genazzani AA,

    * Aleppo G,

    * Casabona G,

    * Canonico PL,

    * Scapagnini U,

    * Nicoletti F.



    Institute of Pharmacology, University of Catania School of Medicine, Italy.



    Micromolar concentrations of piracetam, aniracetam, and oxiracetam enhanced alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-stimulated 45Ca2+ influx in primary cultures of cerebellar granule cells. Nootropic drugs increased the efficacy but not the potency of AMPA and their action persisted in the presence of the voltage-sensitive calcium channel blocker nifedipine. Potentiation by oxiracetam was specific for AMPA receptor-mediated signal transduction, as the drug changed neither the stimulation of 45Ca2+ influx by kainate or N-methyl-D-aspartate nor the activation of inositol phospholipid hydrolysis elicited by quisqualate or (+-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid. Piracetam, aniracetam, and oxiracetam increased the maximal density of the specific binding sites for [3H]AMPA in synaptic membranes from rat cerebral cortex. Taken collectively, these results support the view that nootropic drugs act as positive modulators of AMPA-sensitive glutamate receptors in neurons.



    PMID: 1372342
    To cut the Gordian knot.

  2. #22
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    I'm taking aniracetma again and it def. affects my cognition and mood. good shit. different than piracetam but now I know where to look.
    Man on a mission

  3. #23
    Senior Member spike77's Avatar
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    Quote Originally Posted by liorrh' post='362641' date='Sep 21 2006, 03:56 AM

    I'm taking aniracetma again and it def. affects my cognition and mood. good shit. different than piracetam but now I know where to look.


    How would compare those 2 to you?
    To cut the Gordian knot.

  4. #24
    Senior Member ShuffleUp's Avatar
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    Quote Originally Posted by thrstn' post='354176' date='Aug 1 2006, 10:38 AM

    I remember reading -but I'd be happy to be corrected- that aniracetam could cause some issues long term.


    Bump to the question of negative long-term effects of Aniracetam.
    Smart people believe weird things because they are skilled at defending beliefs they arrived at for non smart reasons. - Michael Shermer, The Believing Brain

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    piracetam is more stimulating and adds more to "cholinergic" parts like processing speed, fluency, memory recall. aniracetam adds more too... cognition in general. hard to put it.
    Man on a mission

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    Board Sponsor D Sade's Avatar
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    Still interested in Nefiracetam anyone?
    Genomyx....Evolution in Action.

    "Blood, Sweat, and Tears doesn't mean crying while you struggle to put your tampon in." ~D Sade

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    Quote Originally Posted by ShuffleUp' post='362903' date='Sep 22 2006, 06:23 PM

    Bump to the question of negative long-term effects of Aniracetam.


    I'm sorry I'm so vague but I do recall reading a post (on this board most likely) pointing to the risks inherent in long term glutamatergic stimulation (which aniracetam does very well apparently). Maybe downregulation?

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    glutamate? sure doesn't feel like it...
    Man on a mission

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    Ampa is a subtype of glutamate receptors, but the mechanism by wich aniracetam and other ampakines increase glutamatergic neurotransmision is not an excitotoxyc one, they increase the duration of the stimulus, not the power, in fact they are neuroprotective because they seem to put a limit to the maximum power of activation in the calcium chanels, and also because of the increase in bdnf, and other neurotrophin independent neuroprotective actions of cetams.

    Of course that is my vague understanding of this all, but read the studies, they are out there demonstrating a neuroprotective and not neurotoxic effect.

    And about nefiracetam, sure I am stil interested, and also interestingly, nefiracetam doesn't seem to affect bdnf or other neurotrophins, but it is even more neuroprotective than neurotrophins!
    Ash nazg durbatulūk, ash nazg gimbatul, ash nazg thrakatulūk agh burzum-ishi krimpatul.

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