Cognitive-enhancing Drugs Research Articles

Reduction of motoric agitation and restlessness by AF102B and tacrine in the macaque.

The cholinesterase inhibitor tacrine (THA) and the M1 muscarinic agonist AF102B (cevimeline), both reported to enhance cognition in animals and humans, were tested in 5 macaques for reduction of spontaneous, random movements. Monkeys were videotaped 1 hour after administration of normal saline vehicle, after low- and high-dose intramuscular AF102B, and after low- and high-dose oral THA. Two independent blind judges counted numbers of spontaneous movements made by each monkey over 12 consecutive 15-second segments for each drug condition. Both THA and AF102B reduced movement significantly at high doses without overt side effects, warranting further research on the agitation-reducing potential of cognition-enhancing cholinomimetic drugs.

Memory assessment in studies of cognition-enhancing drugs for Alzheimer's disease.

There is an increasing number of cognition-enhancing drugs for Alzheimer's Disease (AD) and, consequently, drug trials represent a growing field of interest in research. As memory dysfunction is generally the first and most severe cognitive impairment in AD, the choice of memory testing to be used in these studies is of great importance. It should reflect an understanding of memory systems being assessed with neuropsychological tests and the fact that some tests can be more appropriate than others to show benefit with certain classes of cognition-enhancing drugs. Severe deterioration of episodic and semantic memory occurs very early in the AD process while working memory shows a gradual deterioration over time. Some aspects of working and implicit memory can be spared in the mild to moderate stages of AD. Tests of working, episodic, semantic and implicit memory are used as outcomes in trials with acetylcholinesterase inhibitors, drugs with other neurotransmitter strategies, metabolic enhancers and drugs which may impact upon a variety of CNS processes. The clinical scales and observational measures are largely used in trials of cognition-enhancing drugs for AD (46.66% of all the studies reviewed). The Digit Span test, the Rey Auditory Verbal Learning Test, the Buschke Selective Reminding Test and the verbal fluency tasks are the most sensitive memory tests, whereas the most sensitive scales are the Sandoz Clinical Assessment-Geriatric, the Gottfried-Bräne-Steel scale and the Blessed Dementia Scale. Finally, we suggest that future investigations should use sensitive memory tests, together with behavioural and psychiatric scales, rather than general observational evaluations.

Drugs that increase intelligence?: Application for childhood cognitive impairment

Due in part to the favorable demographics of Alzheimer's disease in the general population, pharmaceutical companies worldwide are aggressively pursuing the research and development of cognitive-enhancing drugs. There have been two rather noteworthy successes in recent years as both tacrine and donepezil have received FDA approval as useful pharmacologic treatment for Alzheimer's disease. Given what is now known regarding the critical periods for synaptic development and the organization of large-scale neuronal circuits in the developing cerebral cortex, it appears that there may exist a window of opportunity during which specifically targeted, pharmacologic intervention could exert a significantly favorable biologic effect during development. Pharmacologic agents that increase the brain's responsiveness to activity-dependent plasticity may be of particular therapeutic benefit to children with some forms of mental retardation. Currently available medications designed for use in adults with dementia have targeted cholinergic neurotransmission and to a lesser degree glutamatergic neurotransmission, both of which play important roles in learning, memory, and developmental organization of the brain. The “cholinergic hypothesis” of memory dysfunction has done much to focus research efforts on cholinergic strategies for the enhancement of learning and memory. Medications that affect cholinergic neurotransmission include acetylcholine precursors, acetylcholinesterase inhibitors, and muscarinic agonists. Drugs targeting the glutamatergic system are among the most novel modalities in treating disorders of memory and learning. These drugs have grown in proportion to advancements in our understanding of the physiologic and pathologic effects of this important excitatory amino acid neurotransmitter. The most important class of medications that affect glutamatergic neurotransmission include nootropics (ampakines) and glycinergic compounds. The rationale for using drugs that act on the glutamatergic system during critical periods for neuronal organization depends, in part, on the degree to which abnormal dendritic spine morphology and/or function associated with some forms of mental retardation is mediated by dysfunctional glutamatergic neurotransmission. It also depends to what degree spine morphology and/or function can be modified in these conditions. MRDD Research Reviews 1998;4:36–49. © 1998 Wiley-Liss, Inc.

Drugs that increase intelligence?: Application for childhood cognitive impairment

Due in part to the favorable demographics of Alzheimer's disease in the general population, pharmaceutical companies worldwide are aggressively pursuing the research and development of cognitive-enhancing drugs. There have been two rather noteworthy successes in recent years as both tacrine and donepezil have received FDA approval as useful pharmacologic treatment for Alzheimer's disease. Given what is now known regarding the critical periods for synaptic development and the organization of large-scale neuronal circuits in the developing cerebral cortex, it appears that there may exist a window of opportunity during which specifically targeted, pharmacologic intervention could exert a significantly favorable biologic effect during development. Pharmacologic agents that increase the brain's responsiveness to activity-dependent plasticity may be of particular therapeutic benefit to children with some forms of mental retardation. Currently available medications designed for use in adults with dementia have targeted cholinergic neurotransmission and to a lesser degree glutamatergic neurotransmission, both of which play important roles in learning, memory, and developmental organization of the brain. The “cholinergic hypothesis” of memory dysfunction has done much to focus research efforts on cholinergic strategies for the enhancement of learning and memory. Medications that affect cholinergic neurotransmission include acetylcholine precursors, acetylcholinesterase inhibitors, and muscarinic agonists. Drugs targeting the glutamatergic system are among the most novel modalities in treating disorders of memory and learning. These drugs have grown in proportion to advancements in our understanding of the physiologic and pathologic effects of this important excitatory amino acid neurotransmitter. The most important class of medications that affect glutamatergic neurotransmission include nootropics (ampakines) and glycinergic compounds. The rationale for using drugs that act on the glutamatergic system during critical periods for neuronal organization depends, in part, on the degree to which abnormal dendritic spine morphology and/or function associated with some forms of mental retardation is mediated by dysfunctional glutamatergic neurotransmission. It also depends to what degree spine morphology and/or function can be modified in these conditions. MRDD Research Reviews 1998;4:36–49. © 1998 Wiley-Liss, Inc.

7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide: a partial modulator of AMPA receptor desensitization devoid of neurotoxicity.

In cerebellar granule neurons of neonatal rats micromolar concentrations of 7-chloro-3-methyl-3,4-dihydro-2H-1,2, 4-benzothiadiazine S,S-dioxide (IDRA-21) and cyclothiazide, two negative modulators of the spontaneous agonist-dependent rapid desensitization of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA)-gated ion channels, facilitate AMPA receptor function by increasing the content of free cytosolic Ca2+ as measured by single-cell fura-2 acetoxymethyl ester (Fura-2) Ca2+-dependent fluorescence and intracellular Na+ measured with the sodium-binding bezofuran isophthalate acetoxymethyl ester fluorescence indicator. IDRA-21 increases intracellular Na+ transient with a threshold (5 microM) that is approximately 10 times higher and has an intrinsic activity significantly lower than that of cyclothiazide. By virtue of its low intrinsic activity, IDRA-21 elicits a free cytosolic Ca2+ transient increase that is shorter lasting than that elicited by cyclothiazide even when the drug is left in contact with cultured granule cells for several minutes. Additionally, while dose dependently, 5-25 microM cyclothiazide in the presence of AMPA is highly neurotoxic, IDRA-21 (up to 100 microM) is devoid of neurotoxicity. The neurotoxicity elicited by cyclothiazide persists in the presence of dizocilpine (an antagonist of N-methyl-D-aspartate-selective glutamate receptors) but is blocked by 2,3-dihydroxy-6-nitrosulfamoylbenzo[f]quinoxaline (a competitive AMPA receptor antagonist) and the 1-(aminophenyl)-4-methyl-7, 8-methylendioxy-5H-2,3-benzodiazepine (GYKI 52466; a noncompetitive AMPA receptor antagonist). Since the doses of IDRA-21 that enhance cognitive processes in rats and monkeys are several orders of magnitude lower than those required to elicit marginal neurotoxicity in cultured neurons, it can be surmised that IDRA-21 is a potent cognition-enhancing drug virtually devoid of neurotoxic liability because it acts as a partial negative allosteric modulator of AMPA receptor desensitization.

TrkB expression in dentate granule cells is associated with a late phase of long-term potentiation.

Recent studies have demonstrated that the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are induced in hippocampal neurons following the induction of long-term potentiation (LTP), a model of memory, and that BDNF and NT-3 (but not NGF) can induce LTP-like increases in synaptic efficacy. Receptors for these neurotrophins have been cloned and characterized and we investigated whether LTP alters the expression of two neurotrophin receptors, trkB (BDNF receptor) and trkC (NT-3 receptor) in dentate granule neurons of the hippocampus using in situ hybridization analysis. Results show that trkB is strongly induced in these neurons in an N-methyl-D-aspartate (NMDA) receptor-dependent manner. Moreover, the induction of trkB and trkC mRNAs was attenuated by sodium pentobarbital, which interferes with the durability of LTP. Low-frequency stimulation of the perforant path had no effect on trkB mRNA levels but significantly reduced trkC mRNA in dentate granule cells. Thus, both BDNF and its receptor trkB are induced in granule cells by stimulation that produces durable LTP, suggesting that this neurotrophin and its receptor play an important role in memory formation and may be suitable targets for the development of cognitive-enhancing drugs in the treatment of diseases, such as Alzheimer's.

Mecamylamine- or scopolamine-induced learning impairment: ameliorated by nefiracetam.

Nefiracetam is undergoing preclinical and clinical tests as a cognition-enhancing drug in Alzheimer's disease (AD). Nicotinic cholinergic receptors are lost in AD, and nicotinic as well as muscarinic cholinergic receptors are involved in the modulation of eyeblink conditioning. Experiments were carried out using young rabbits to examine the effect of nefiracetam on cholinergic antagonists to nicotinic (mecamylamine) and muscarinic (scopolamine) receptors. Rabbits were tested for 15 days in the 750 ms delay eyeblink classical conditioning paradigm in paired and explicitly unpaired conditions. Nefiracetam at a dose of 15 mg/kg significantly ameliorated the effects of 0.5 mg/kg mecamylamine, and nefiracetam at a dose of 10 mg/kg significantly ameliorated the effect of 1.5 mg/kg scopolamine. The vehicle alone and nefiracetam alone groups performed similarly to the groups treated with mecamylamine or scopolamine and nefiracetam. Reversal by nefiracetam of a nicotinic as well as a muscarinic cholinergic antagonist indicates that the drug may affect deficits specific to AD.

Pharmacotherapy of Alzheimer dementia: therapy of cognitive symptoms--new results of clinical studies

Recent investigations have given new insights into pathogenetical determinants of Alzheimer's disease. Amyloid deposition and neurofibrillary tangles are no longer considered to be primary pathological changes. Neurobiological research tries to work out the etiopathogenital cascade that finally causes Alzheimer's disease. So far, several relevant pathogenetical factors have been detected, e.g. pertubated control of glucose breakdown, impairment of oxidative metabolism, impaired neuroprotection due to increased oxidative stress and non-enzymatic protein glycation as well as immunological disturbances. Thus, new strategies for the development of cognition-enhancing drugs are emerging. The authors review reports on agents, that are under investigation for the treatment of cognitive symptomatology in Alzheimer's disease. Some of these agents have already been used for treatment of other medical conditions, e.g. nimodipine, memantine as well as selegiline. Many of them are still experimental. Promising strategies include antioxidative agents (e.g. vitamin E, vitamin C, beta-carotin), acetylcholinesterase-inhibitors with central selectivity (e.g. ENA 713), M1- and M4-muscarinic receptor agonists (milameline) as well as sabeluzole, a benzothazide derivative that shows neurotrophic activities and anti-inflammatory substances like indomethacin.

Hippocampus in delay eyeblink classical conditioning: essential for nefiracetam amelioration of learning in older rabbits

Rabbits acquire conditioned responses (CRs) normally with bilateral removal of the hippocampus, but alterations of the intact hippocampus can affect the rate of acquisition. The cognition-enhancing drug, nefiracetam ameliorated the acquisition of CRs in older rabbits, protected membrane dysfunction in hippocampal CA1 neurons following oxygen and glucose deprivation, and promoted the release of diverse neurotransmitters, including acetylcholine. Because the septo-hippocampal cholinergic system is demonstrated to be involved in eyeblink conditioning, this experiment was undertaken to explore whether nefiracetam ameliorates conditioning via the hippocampus. Data from 53 rabbits of a mean age of 28 months were tested under two drug conditions (10 or 0 mg/kg nefiracetam) and 4 lesion conditions (bilateral hippocampectomy, bilateral neocortical removal, sham surgery, no surgery). The three groups of nefiracetam-treated rabbits with intact hippocampus acquired CRs more rapidly than the vehicle-treated groups, but rabbits with bilateral hippocampectomy treated with nefiracetam learned like vehicle-treated rabbits. Results suggest that nefiracetam ameliorates learning via the hippocampus. Because of the parallels between conditioning in rabbits with disrupted hippocampal cholinergic systems and conditioning in Alzheimer's disease (AD), these results suggest that nefiracetam may ameliorate conditioning in AD as it ameliorates conditioning in older rabbits.

The older rabbit as an animal model: Implications for Alzheimer's disease

Eyeblink classical conditioning (EBCC) is impaired in rabbits and humans during normal aging and severely disrupted in Alzheimer's disease (AD) and older Down's Syndrome patients (called DS/AD). To determine if older rabbit brains developed neuropathological evidence of Alzheimer-like pathology to account for impaired EBCC, the cerebellum and hippocampus of behaviorally tested rabbits aged 3 months to 7 years were probed using immunohistochemical techniques. Significant cell loss and gliosis were observed in some brain regions, but there was little or no deposition of β-amyloid (Aβ) or abnormal tau accumulations in telencephalic neurons, even in rabbits over 7 years of age. Our aims here are to: 1) report the results of our search for Alzheimer-like neuropathology in aged rabbit brains; and 2) highlight similarities in the brain mechanisms for EBCC between rabbits and humans and, hence, the utility of studies of EBCC in rabbits as a model system for testing cognition-enhancing drugs.

Synthesis and enantioselectivity of the enantiomers of PG9 and SM21, new potent analgesic and cognition-enhancing drugs.

The enantiomers of two alpha-tropanyl esters, SM21 (1) and PG9 (2), derived from (+)-R-hyoscyamine, that act by increasing the central cholinergic tone, were obtained by esterification after resolution of the corresponding racemic acids [(-)-S-1, (-)-R-2 and (+)-S-2] and by stereospecific synthesis [(+)-R-1]. Their analgesic and cognition-enhancing activities were tested in mice and their ACh-releasing properties determined on rat parietal cortex. These compounds show enantioselectivity in analgesic and cognition-enhancing tests on mice, the eutomers being the isomers which possess the same spatial arrangement of the groups on the chiral atom as (+)-R hyoscyamine [(+)-R-SM21, (+)-S-PG9]. The ACh-releasing effect of the enantiomers of SM21 in rats is in agreement with the results in mice, while PG9 enantiomers do not show any appreciable enantioselectivity in this test. On the basis of the different effects of the 5-HT4 antagonist SDZ 205557 on analgesia induced by the enantiomers of 1 and 2 and by (+)-R-hyoscyamine and the alpha-tropanyl ester of 2-phenylpropionic acid 3, a mechanism of action is proposed for this class of compounds.

Effects of β-cyclodextrins on skin: implications for the transdermal delivery of piribedil and a novel cognition enhancing-drug, S-9977

The effects of β-cyclodextrin (β-CD), randomly methylated β-cyclodextrin (RAMEB) and 2-hydroxypropyl β-cyclodextrin (HPβ-CD) on skin were investigated. The three cyclodextrins (CDs) were able to destabilize model liposomes and to extract significant amounts of cholesterol from isolated stratum corneum (SC). However, only RAMEB extracted all the major lipid classes from isolated SC, as shown by thin layer chromatography. Both RAMEB and HPβ-CD could release 5–10% of the extractable cholesterol as well as proteins from hairless rat skin. Nevertheless, CDs did not induce any major modification of the differential scanning calorimetry (DSC) profile or the Fourier-transformed infrared (FTIR) spectrum of SC. This was explained by the low percutaneous penetration of CDs. Furthermore, the influence of RAMEB on the transdermal diffusion through hairless rat skin of piribedil, a central dopaminergic agonist and of S-9977, a novel cognition enhancing drug, was studied. RAMEB was found to decrease the transdermal flux of piribedil, with which it forms an inclusion complex, as shown by NMR. Conversely, RAMEB increased by 2-fold the percutaneous absorption of the S-9977 hydrochloride, which does not interact with CD. Finally, a combination of oleic acid and RAMEB greatly increased by about 30-fold the flux of S-9977 hydrochloride.

Linopirdine (DUP 996; AVIVA): Its effects in the morris water escape task and on retention of an incompletely acquired bar-press response in rodents

The present study assessed the effects of linopirdine, a putative cognition-enhancing drug, on the acquisition and retention of a bar-press response [continous reinforcement schedule (CRF)] in young Wistar rats. It was also investigated whether this substance influenced the acquisition and retention of a standard Morris water escape task by young NMRI mice and by young and old Wistar rats. Linopirdine was given subcutaneously (0.03, 0.1, 0.3, 1.0, or 3.0 mg/kg body wt.), 30 min before the first trial of a session and in one experiment immediately after the last trial of each session. A probe trial was given after the last acquisition session. In the CRF task, linopirdine did not affect the response latency and the 24-h retention of young rats. None of the parameters investigated in the Morris maze, including the escape latency (the time the animals need to find the platform), was affected by linopirdine in the rat and mouse experiments. This was also true for performance in the probe trial: linopirdine treatment did not affect the bias of the animals for the quadrant in which the platform had been positioned during acquisition. Thus, we found no experimental evidence for the hypothesized action of linopirdine as a cognition enhancer.

Pharmacotherapy of cognitive impairment in Alzheimer's disease: a review.

Experimental pharmacotherapy of cognitive impairment in Alzheimer's disease has seen a recent proliferation of drug trials involving a wide variety of drugs. Many of the earlier studies focused on cholinergic agents. However, subsequent advances in basic and biological sciences have broadened the scope of therapeutic strategies beyond the neurotransmitter approaches to include neurotrophic, metabolic-enhancing, membrane-modifying, and antitoxic agents, and have also provided rationale for developing antiamyloid and anti-infective therapies. For the clinician, it has not been easy to keep abreast of these developments. In this article, I present an overview of the cognition-enhancing drugs that have been used in the past, of those currently under investigation, and of new drugs and strategies that are likely to receive attention in the next few years.

The cognition-enhancing drug tenilsetam is an inhibitor of protein crosslinking by advanced glycosylation.

Non-enzymatic glycosylation of proteins, also called Maillard reaction, which occurs at an accelerated rate in diabetes, can lead to the formation of advanced glycosylation endproducts (AGEs). Tenilsetam (CAS 997: (+/-)-3-(2-thienyl)-2-piperazinone), a cognition-enhancing drug successfully used for treatment of patients suffering from Alzheimer's disease, when included in the Maillard reaction apparently inhibits protein crosslinking by AGEs in vitro. According to the mechanism proposed, Tenilsetam acts via covalent attachment to glycated proteins, thus blocking the reactive sites for further polymerisation reactions. A beneficial effect of Tenilsetam in Alzheimer's disease could come from the interference with AGE-derived crosslinking of amyloid plaques and a decreased inflammatory response by diminished activation of phagocytosing microglia.

Developing drugs for cognitive enhancement

Cognition-enhancing drugs are receiving a great deal of attention, and considerable research resources are being poured into their development. Based on presentations from the Collegium Internationale Neuro-Psychopharmacologicum (CINP) Congress [ Washington, US; June 1994 ], Inpharma® reports on the latest progress in this area.

PKC translocation in rat brain cortex is promoted in vivo and in vitro by alpha-glycerylphosphorylcholine, a cognition-enhancing drug.

Protein kinase C (PKC) activity was measured in soluble and particulate fractions of rat individual brain areas after treatment with alpha-glycerylphosphorylcholine (GPC), a cognition-enhancing drug which promotes acetylcholine synthesis and release. The drug induced both in vivo and in vitro PKC translocation. In vivo, an increase of particulate PKC activity was observed 1 hour following the acute oral administration of a behaviorally active dose (600 mg/kg); the effect was transient. In vitro, GPC promoted PKC translocation in cortical slices at concentrations as low as 50 nM; the concentration-response curve was bell shaped. The increased PKC activity may be related to the cortical effects of GPC.

Molecular mechanisms mediating the effects of l-α-glycerylphosphorylcholine, a new cognition-enhancing drug, on behavioral and biochemical parameters in young and aged rats

The behavioral effects of the acute and subchhronic adminstrationof L-α-glycerylphosphorylcholine (α-GPC) on passive and active avoidance behavioral tasks were investigated. When administered IP after training together with scopolamine 2 h before retest, α-GPC reverses the scopolamine-induced amnesia in the passive avoidance conditioning in young and old rats. Furthermore, the subchronic treatment with α-GPC positively and significantly influences the performance of both young and old animals in the active avoidance test. Moreover, in in vitro/ex vivo experiments α-GPC potentiates receptor-stimulated phosphatidylinositol hydrolysis in cortical synaptoneurosomes derived from young and old animals. In young but not old animals, α-GPC significantly potentiates potassium (40 mM)-stimulated intrasynaptosomal calcium oscillations in purified synaptosomes derived from the hippocampus. These results show that α-GPC improves the performance of animals in both active and passive conditioning tasks. Furthermore, subchronic treatment with the compound enhances in young and restores in aged animals the transduction of the signal, namely, the receptor-mediated production of inositol phosphate and the potassium-induced calcium mobilization. These modifications may represent at least part of the molecular mechanism of action of the compound.

Pharmacology of long-term potentiation

Long-term potentiation is widely used as a model for memory formation. Recently, much information concerning this topic like the involvement of protein kinase C, arachidonic acid and N-methyl-D-aspartate receptors has been reported. In this review recent discoveries concerning long-term potentiation and the pharmacological implications for the development of cognition-enhancing drugs are discussed.

Nasal administration of a cognition enhancer provides improved bioavailability but not enhanced brain delivery

Compound 1 [3,3-bis(4-pyridylmethyl)-1-phenylindolin-2-one] is an experimental cognition-enhancing drug now being developed for cognitive disorders. Oral bioavailability of 1 in rats was <10% of the dose. Nasal dosing improved bioavailability to >50%. Brain levels of total radioactivity were measured after iv and nasal doses of radiolabeled 1. The ratio of AUCbrain:AUCplasma was the same by both routes, so nasal dosing did not enhance brain delivery. This is in contrast to other reports of large molecular weight substances and metals gaining direct access to the brain through the nasal epithelium.