Giurgea, C.E.: The nootropic concept and its prospective implications. Drug. Dev. Res. 2:441^446, 1982.
The nootropic concept emerged about 10 years ago essentially from the unusual pharmacology of piracetam, which later on was confirmed and extended to human pharma-coclinics and therapeutics. A nootropic drug is characterized by a direct functional activation of the higher integrative brain mechanisms that enhances cortical vigilance, a telencephalic functional selectivity, and a particular efficiency in restoring deficient higher nervous activity. In contradistinction to other psychotropic drugs, nootropics do not induce direct reticular, limbic, or other subcortical events. Little is known with regard to nootropic, neurochemical mechanisms of action except that they interact with factors that contribute to the neuronal membrane stability, and possibly with the brain 5-HT. Main therapeutical indications seem to be in children with speech disorders, in the posttraumatic, and posthypoxic sequelae, in vertigo of central origin, and in geriatric, moderately impaired, possibly dysmnesic patients. Other drugs, such as pyritinol, meclofenoxate, and, to some extent, hydergine and vinca-mine, do show partially nootropic activities. The nootropic line of research is by now multifaceted to deepen the neurochemical and neurophysiologic comprehension of nootropics’ mode of action; to make clearer their clinical differential profile; to enlarge the nootropic framework to some other existing drugs, clinically if not pharmacologically related to piracetam; and to find new, more potent, and possibly more selective nootropic agents. The general aim of nootropic research is to find new drugs capable of enhancing directly the efficiency of the cognitive, noetic activity of the brain, thus compensating various neuro-psychologic deficits such as, but not exclusively, those related to aging.
Key words: piracetam, GABA, nystagmus, anticonvulsant activity, nootropics, psychotropics classification
Received April 22. 1982; accepted June 12, 1982.
Address reprint requests to Prof. C.E. Giurgea, UCB Dept, of Neuropharmacology, 1060 Brussels, Belgium.
Within the marble itself, thought Michelangelo, lies the beauty; it is not created by the sculptor, who only takes out the excess of stone and makes beauty available to our eyes.
Scientific creativity can usually be considered along the same line: we only remove a bit of misunderstanding, and even so only for a certain time before new data will reject our former concept or, at best, will show how crude and incomplete it was. Of course, this was also the case with the nootropic research which we have considered, for almost 10 years now [Giurgea, 1972], as a potential new approach to the pharmacology of the integrative activity of the brain.
It is therefore a great pleasure and honor for me—and I would like to address my most sincere thanks to Professor Itil for giving me the opportunity—to close this symposium with a retrospective-prospective flash on the nootropic saga.
It all started with a wrong hypothesis, namely, that by working with cyclic GABA derivatives we should find new sedative hypnotics because, we thought, we would provide an “extra amount” of inhibition to the brain. During 1963-1964, Strubbe and Cyprysiak , on the ground of this idea, synthesized several compounds, including piracetam (UCB 6215: Nootropyl), which is a cyclic, disubstituted GABA derivative.
Piracetam never induced any sedation but, for reasons described elsewhere [Giurgea, 1972, 1976], we have tested and found it active to inhibit the central nystagmus in the rabbit, and also a vestibular nystagmus |Giurgea el al., 1967], Despite all our extensive studies, and with the exception of a particular anticonvulsant potency [Moyersoons et al., 1969], piracetam was found to be nontoxic and devoid of any common psychopharmacological, cardiovascular, respiratory, or other activities [Giurgea, 1972, 1973, 1976].
As for the GABA-related hypothesis to explain nystagmus inhibition, and particularly antiepileptic activities, we soon found out that it was also wrong. Indeed, piracetam, which is almost entirely eliminated as such, nonmetabolized [Gobert, 1972], does not interfere with GABA metabolism or receptors [Gobert, 1972; Beart and Johnston, 1973].
The first human studies, performed by Oosterveld in 1965, showed that piracetam inhibited torsion-swing nystagmus. Internal UCB reports shortly afterward claimed some activity against motion-sickness and especially vertigo of various origins. Very recently Oosterveld  showed, in a controlled study, the efficacy of the drug in vertigo of cerebral vascular origin.
Those were expected results, confirming animal data. New clinical feedbacks of practically unexpected findings came to our attention, almost in one year’s time (1966-1967): Professor Hillbom and Dr. Jahro [personal communications] (Finland) reported that memory seemed somewhat improved in postconcussion patients, that they seemed to “think” better; Professor Sorel [personal communications] (Brussels) tried piracetam in epileptic children and reported cases in which patients, or their parents, claimed some kind of improvement in the overall mental efficiency. By that time we already knew that piracetam selectively facilitated transcallosal, corticocortical evoked potentials [for references, see Giurgea, 1972; Giurgea and Moyersoons, 1979], We therefore suspected that the compound might preferentially facilitate cortically integrated mental functions. However, the new clinical claims were practically unexpected; they changed both our clinical and experimental program and generated studies related to a potential beneficial effect of piracetam on mental activity. That is how we found out that in several animal species— and of course within certain limitations—piracetam facilitated learning and memory in normal and in deficient animals (old, isolated, etc.) and protected the learned material against amnesic agents [for review, see Giurgea, 1972, 1981]. Piracetam also enhances survival probability and speeds up recovery of normal EEG after aggressions such as hypoxia or chemical toxics [Giurgea, 1972, 1981],
On the other hand, new animal data became available that were used as some sort of “feedforward” to human pharmacoclinics, for instance those concerning the interhemispheric communications.
We have found, as said above, that piracetam in the cat selectively facilitates transcallosal evoked responses [see for references Giurgea and Moyersoons, 1979] whereas Buresova and Bures in behavioral experiments [1973, 1976] obtained with the drug a selective enhanced efficacy of the callosal “writing-in” function. This incited Dimond  and Dimond and Brouwers  to give piracetam to young, healthy volunteers in whom they described an improvement of verbal memory and, with dichotic listening, of callosal-dependent transfer of information. Finally this led Wilsher  and Wilsher et al.  to anticipate and to produce the first clinical data showing a potential indication of piracetam in dyslexic children.
Nowadays, clinical correlations have been found in reliable, controlled trials with all major pharmacological features of piracetam [Giurgea and Salama, 1977]. Furthermore, reliable clinical studies are now available which advocate therapeutic usefulness of piracetam in postconcussional syndrome, posttraumatic coma, acute alcohol withdrawal as well as in the general field of ger-opsychiatry [Giurgea and Salama, 1977]. Theoretical ground for the use of piracetam is given elsewhere [Giurgea et al., 1981; Giurgea, 1981].
One should particularly insist upon the data of Bartus  that showed the efficacy of piracetam as well as that of centrophenoxine and several other drugs to significantly compensate the specific age-related short-term memory impairment in monkeys. Also related to this problem are the findings of Valzelli et ai. [1980a,b] showing (1) that piracetam enhances the brain tryptophan levels and (2) that this effect is particularly important in aged mice.
Although, even nowadays, we do not dispose of a comprehensive, causal, neurochemical interpretation of the therapeutic efficacy of piracetam, new and important data are by now accumulating that will eventually lead to such an interpretation. Nickolson and Wolthuis [1976a,b] for instance, claimed that piracetam rather selectively activates brain adenylatekinase and inhibits cortical release of proline, a putative inhibitory neurotransmitter. More recently, from extensive work of Woelk and his colleagues [1978, 1979], one may conclude that piracetam (1) enhances the formation in the rat’s brain of ethanolamine plasmalogen via an increased synthesis and/or turnover of cytochrome b5; (2) enhances both the neuronal and synaptosomal phospholipase A2 activity, and thus contributes in some manner to the synaptic transmission; and (3) increases the incorporation of 32P into phosphatidylinositol and phosphatidylcholine of both glia and neuronal cells. We have already mentioned the Valzelli findings concerning brain tryptophan levels and we may add that preliminary data of our own [Giurgea, 1979] show furthermore, in a particular model of learning [Greindl and Preat, 1971], that piracetam and ACTH 4-10 mutually potentiate each other to enhance learning efficiency.
THE TELENCEPHALIC HYPOTHESIS
We now reach the final topic of this contribution, i.e., the problems of terminology and classification [see also Giurgea, 1972, 1976, 1981].
Obviously piracetam does not fit into any known categories of psychotropic drugs. The positive effect on brain integrative mechanisms in normal and deficient animals as well as in human patients may then express a direct impact upon mental functions. The ineffectiveness of the compound on limbic and reticular excitability allowed us to assume that piracetam shows a functional, telencephalic selectivity and, by way of consequence, that it opens up a new class of psychoanaleptic drugs (in the Delay-Deniker classification). Because drugs along this line “aim” selectively at the noetic functions, we suggest that they should be called nootropics (noos = mind; tropic = toward).
In contradistinction to usual psychotropics that act essentially indirectly upon higher telencephalic structures, piracetam’s main functional impact is the telencephalic. higher brain integrative activity: it enhances its efficacy and compensates, at least partially, for its deficits.
Our point of view as to how to classify nootropic agents, even though it is not shared by all psychopharmacologists, including our distinguished chairman. Professor Itil, is clearly shown in Figure 1.
A final point is the possible enlargement of the nootropic concept to drugs other than piracetam, especially in dealing with gerontopsychiatric patients. Obviously such a complex therapeutic problem as geriatric psychopathology cannot be handled by one single drug.
Clinically it is common practice to speak of primary and secondary dementia (mild or severe) and of at least two sorts of primary ones: Alzheimer-like and multiinfarction dependent. Consequently, careful differential pharmacotherapy should be considered for individual cases as well as the psychodynamic view of Dolce et al.  about the interaction of drugs with rehabilitation techniques. Figure 2 gives a digest of the main pharmacological tools in this field. Nootropics, in my opinion, should be accepted as a distinct category inasmuch as they enhance primarily, directly the noetic, cognitive brain functions.
This is the main, potential achievement of the nootropic research although nootropics do share with other drugs several activities—for instance, in Figure 2, discrete microcirculation activation [Reuse-Blom, 1979J.
Agreement has, however, not yet been reached on all aspects of divergences and similitudes between those various drugs. This is due mainly, I think, to the fact that up to now none of them is as harmless or as potent as the ideal, future nootropic drug actually should be.
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