The idea is that of a selective ATM Kinase Inhibitor in vitro marker because in the elderly particular nootropic drugs are able to significantly restore P300.28 Figure 5. Age-related modifications in P300. Top left: Average curves for elderly (aged >55 years; blue lines) and young volunteers (gray lines) for several scalp positions. Top right: Statistical comparison between elderly and young subjects.

Bottom left: … Due to the lack of clinical efficacy of AchE inhibitors,29 more and more alternative mechanisms of action on central receptors or enzymes are being explored. Inhibitors,research,lifescience,medical An example of the effect of a noncholinergic drug is given in Figure 5 (bottom).30 Indeed, a clear-cut indication of recovery can be observed, even though the increase in absolute terms is modest. The concept of a pharmacological model in young Inhibitors,research,lifescience,medical volunteers The established approach in behavioral neuropsychopharmacology is the use of a pharmacological challenge to reversibly provoke symptoms. As an example, we refer to the model that makes use of the comparison of performance in a battery of psychometric tests (eg, digit vigilance speed) and recording of continuous electrical cerebral activity.31 Inhibitors,research,lifescience,medical Both types of examination undergo changes with scopolamine and some of these effects have been shown to be reversed by AchE inhibitors. Hence P300 responses constitute

a useful tool in neuropsychopharmacology in exactly the same way as continuous electrical Inhibitors,research,lifescience,medical cerebral activity, for the reasons shown in Figure 4. Interestingly, manipulation with benzodiazepines in order to provoke – like scopolamine – symptoms of cognitive impairment at the clinical level in, for example, free word recall,32 induces similar collapses in P300 in auditory33-36 (eg, lorazepam, Figure 6) and visually37 evoked cognitive responses. Inhibitors,research,lifescience,medical Figure 6. Superimposed average P300 responses for baseline conditions (light-blue lines) and after a drug challenge (dark-blue lines). The

effect of an acetylcholinesterase (AchE) inhibitor (gray lines) restores the deteriorated signal in the direction of baseline … In our experience, the effects on neurophysiological parameters are often much more sensitive than the effects seen in performance Chlormezanone changes. Schematically, the procedure can be summarized as follows: Drug 1 induces a simulation of the acute state of “nontreated” patient (symptom provocation). Drug 2 is used to verify its potency to (partially) reverse the deterioration (validation for pharmacotherapy). An example of the reversal of the challenge-induced deterioration (drug 1) with an AchE inhibitor (drug 2) is shown in Figure 6 (for study design see reference 38). The interesting aspect of such a model is the possibility of preventing the induction of symptoms by compounds with out, direct, cholinergic effects39 and using a neurophysiological readout, as surrogate marker at the same time.