Piracetam: Novelty in a Unique Mode of Action

Müller, Wernér E.G.; Eckert, Gunter P.; Eckert, Anne

doi:10.1055/s-2007-979230

Cited by 75 publications

(59 citation statements)

References 23 publications

(28 reference statements)

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“…Piracetam is an agent thought to act as a modifier of membrane fluidity (Muller et al, 1999), cognition-and microcirculation-enhancer, neuroprotectant, and anticonvulsant (Winblad, 2005). A phase III trial of piracetam was conducted in 927 acute stroke patients randomized to treatment within 12 hours of onset.…”

Section: A Miscellany Of Other Agents Studied Without Success In Largmentioning

confidence: 99%

Neuroprotection for ischemic stroke: Past, present and future

2008

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Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safetyfeasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6 hour therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials.This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized. Part I: Neuroprotection -from Past to the PresentNeuroprotection for ischemic brain injury has emerged only recently as a topic of serious biomedical inquiry. A MEDLINE survey (PubMed, 2007) reveals virtually no publications on this topic until the early 1990's but a remarkable surge in publications over the past 10 years Correspondence and reprint requests to:

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Section: A Miscellany Of Other Agents Studied Without Success In Largmentioning

confidence: 99%

Neuroprotection for ischemic stroke: Past, present and future

2008

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“…[3,5,[33][34][35][36]76,85,89,90,96,111,134]). Of particular interest are those studies that show that not only an increase in the level of cholesterol, but also in the level of the toxic metabolite, 24S-hydroxycholesterol (cerebrosterol) [32,64].…”

Section: Membrane Fluidity In Aging-cholesterolmentioning

confidence: 99%

The role of polyunsaturated fatty acids in restoring the aging neuronal membrane

Yehuda¹,

Rabinovitz²,

Carasso³

et al. 2002

Neurobiology of Aging

348

200

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In addition to a gradual loss of neurons in various brain regions, major biochemical changes in the brain affect the neuronal membrane that is the "site of action" for many essential functions including long-term potentiation (LTP), learning and memory, sleep, pain threshold, and thermoregulation. Normal physiological functioning includes the transmission of axonal information, regulation of membrane-bound enzymes, control of ionic channels and various receptors. All are highly dependent on membrane fluidity, where rigidity is increased during aging. The significantly higher level of cholesterol in aging neuronal membrane, the slow rate of cholesterol turnover, and the decreased level of total polyunsaturated fatty acids (PUFA) may result from poor passage rate via the blood-brain barrier, or from a decreased rate of incorporation into the membrane, or a decrease in the activities of delta-6 and delta-9 desaturase enzymes. The added oxidative stress, which leads to an increase of free radicals leading to a decrease in membrane fluidity, may respond to a restricted diet, and thereby overcome the damaging effects of the free radicals. A central focus of this review is that a specific ratio of n-3/n-6 PUFA can restore many of these age-related effects.

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“…These drugs, with the only exception of nefiracetam, which shows high affinity for the GABA A receptors, do not seem to act at any wellcharacterized receptor system [Gouliaev and Senning, 1994]. Indeed, as already postulated for nootropic compounds [Mondadori et al, 1991;Muller et al, 1999], the DM232 effects on the cholinergic system might be of secondary origin.…”

Section: Discussionmentioning

confidence: 84%

The novel nootropic compound DM232 (UNIFIRAM) ameliorates memory impairment in mice and rats

Ghelardini

Galeotti

Gualtieri

et al. 2002

Drug Development Research

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The favorable pharmacological profile exhibited by piracetam stimulated the synthesis of related compounds potentially endowed with a higher nootropic potency. The antiamnesic and procognitive activity of DM232 (unifiram), a new compound structurally related to piracetam, was investigated. Mouse passive avoidance and rat Morris water maze and Social learning tests were employed. DM232 (0.001-1 mg kg À1 i.p. -0.01-0.1 1 mg kg À1 p.o.) prevented amnesia induced by scopolamine (1.5 mg kg À1 i.p.), mecamylamine (20 mg kg À1 i.p.), baclofen (2 mg kg À1 i.p.), and clonidine (0.125 mg kg À1 i.p.). Furthermore, The antiamnesic effect of the investigated compound was comparable to that exerted by well-known nootropic drugs such as piracetam (30-100 mg kg À1 i.p.), aniracetam (100 mg kg À1 p.o.), rolipram (30 mg kg À1 p.o.), and nicotine (5 mg kg À1 i.p). DM232 (0.1 mg kg À1 i.p.) was also able to prevent amnesia induced by scopolamine (0.8 mg kg À1 i.p.) in the rat Morris watermaze test. In the rat social learning test, DM232 (0.1 mg kg À1 i.p.) injected in adults rats reduced the duration of active exploration of the familiar partner in the second session of the test. DM232, similarly to piracetam, reduced the duration of hypnosis induced by pentobarbital. At the highest effective doses, the investigated compound did not impair motor coordination (rota rod test), nor modified spontaneous (Animex). These results indicate DM232 (unifiram) as a novel cognition enhancer, strictly related to piracetam-like compounds, able to ameliorate memory impairment at doses about 1,000 times lower than the most active available nootropic compounds. Drug Dev.

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Piracetam: Novelty in a Unique Mode of Action

Cited by 75 publications

References 23 publications

Neuroprotection for ischemic stroke: Past, present and future

Neuroprotection for ischemic stroke: Past, present and future

The role of polyunsaturated fatty acids in restoring the aging neuronal membrane

The novel nootropic compound DM232 (UNIFIRAM) ameliorates memory impairment in mice and rats

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