Cholinergic modulation of working memory activity in primate prefrontal cortex.

The prefrontal cortex, a cortical area essential for working memory and higher cognitive functions, is modulated by a number of neurotransmitter systems, including acetylcholine; however, the impact of cholinergic transmission on prefrontal activity is not well understood. We relied on systemic administration of a muscarinic receptor antagonist, scopolamine, to investigate the role of acetylcholine on primate prefrontal neuronal activity during execution of working memory tasks and recorded neuronal activity with chronic electrode arrays and single electrodes. Our results indicated a dose-dependent decrease in behavioral performance after scopolamine administration in all the working memory tasks we tested. The effect could not be accounted for by deficits in visual processing, eye movement responses, or attention, because the animals performed a visually guided saccade task virtually error free, and errors to distracting stimuli were not increased. Performance degradation under scopolamine was accompanied by decreased firing rate of the same cortical sites during the delay period of the task and decreased selectivity for the spatial location of the stimuli. These results demonstrate that muscarinic blockade impairs performance in working memory tasks and prefrontal activity mediating working memory.

The prototypical ranitidine analog JWS-USC-75-IX improves information processing and cognitive function in animal models.

This study was designed to evaluate further a prototypical ranitidine analog, JWS-USC-75-IX, [(3-[[[2-[[(5-dimethylaminomethyl)-2-furanyl]methyl]thio]ethyl]amino]-4-nitropyridazine, JWS], for neuropharmacologic properties that would theoretically be useful for treating cognitive and noncognitive behavioral symptoms of neuropsychiatric disorders. JWS was previously found to inhibit acetylcholinesterase (AChE) activity, serve as a potent ligand at muscarinic M2 acetylcholine receptors, and elicit positive effects on spatial learning, passive avoidance, and working memory in rodents. In the current study, JWS was evaluated for binding activity at more than 60 neurotransmitter receptors, transporters, and ion channels, as well as for inhibitory activity at AChE and butyrylcholinesterase (BChE). The results indicate that JWS inhibits AChE and BChE at low (micromolar) concentrations and that it is a functional antagonist at M2 receptors (K(B) = 320 nM). JWS was subsequently evaluated orally across additional behavioral assays in rodents (dose range, 0.03-10.0 mg/kg) as well as nonhuman primates (dose range, 0.05-2.0 mg/kg). In rats, JWS improved prepulse inhibition (PPI) of the acoustic startle response in nonimpaired rats and attenuated PPI deficits in three pharmacologic impairment models. JWS also attenuated scopolamine and (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801)-related impairments in a spontaneous novel object recognition task and a five-choice serial reaction time task, respectively. In monkeys, JWS elicited dose-dependent improvements of a delayed match-to-sample task as well as an attention-related version of the task where randomly presented (task-relevant) distractors were presented. Thus, JWS (potentially via effects at several drug targets) improves information processing, attention, and memory in animal models and could potentially treat the cognitive and behavioral symptoms of some neuropsychiatric illnesses.

In vivo pharmacological characterization of a novel selective alpha7 neuronal nicotinic acetylcholine receptor agonist ABT-107: preclinical considerations in Alzheimer's disease.

We previously reported that alpha7 nicotinic acetylcholine receptor (nAChR) agonism produces efficacy in preclinical cognition models correlating with activation of cognitive and neuroprotective signaling pathways associated with Alzheimer's disease (AD) pathology. In the present studies, the selective and potent alpha7 nAChR agonist 5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole (ABT-107) was evaluated in behavioral assays representing distinct cognitive domains. Studies were also conducted to address potential issues that may be associated with the clinical development of an alpha7 nAChR agonist. Specifically, ABT-107 improved cognition in monkey delayed matching to sample, rat social recognition, and mouse two-trial inhibitory avoidance, and continued to improve cognitive performance at injection times when exposure levels continued to decline. Rats concurrently infused with ABT-107 and donepezil at steady-state levels consistent with clinical exposure showed improved short-term recognition memory. Compared with nicotine, ABT-107 did not produce behavioral sensitization in rats or exhibit psychomotor stimulant activity in mice. Repeated (3 days) daily dosing of ABT-107 increased extracellular cortical acetylcholine in rats, whereas acute administration increased cortical extracellular signal-regulated kinase and cAMP response element-binding protein phosphorylation in mice, neurochemical and biochemical events germane to cognitive function. ABT-107 increased cortical phosphorylation of the inhibitory residue (Ser9) of glycogen synthase kinase-3, a primary tau kinase associated with AD pathology. In addition, continuous infusion of ABT-107 in tau/amyloid precursor protein transgenic AD mice reduced spinal tau hyperphosphorylation. These findings show that targeting alpha7 nAChRs may have potential utility for symptomatic alleviation and slowing of disease progression in the treatment AD, and expand the understanding of the potential therapeutic viability associated with the alpha7 nAChR approach in the treatment of AD.

The dopamine D3 receptor antagonist, S33138, counters cognitive impairment in a range of rodent and primate procedures.

Although dopamine D(3) receptor antagonists have been shown to enhance frontocortical cholinergic transmission and improve cognitive performance in rodents, data are limited and their effects have never been examined in primates. Accordingly, we characterized the actions of the D(3) receptor antagonist, S33138, in rats and rhesus monkeys using a suite of procedures in which cognitive performance was disrupted by several contrasting manipulations. S33138 dose-dependently (0.01-0.63 mg/kg s.c.) blocked a delay-induced impairment of novel object recognition in rats, a model of visual learning and memory. Further, S33138 (0.16-2.5 mg/kg s.c.) similarly reduced a delay-induced deficit in social novelty discrimination in rats, a procedure principally based on olfactory cues. Adult rhesus monkeys were trained to perform cognitive procedures, then chronically exposed to low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine which produced cognitive impairment without motor disruption. In an attentional set-shifting task of cognitive flexibility involving an extra-dimensional shift, deficits were reversed by S33138 (0.04 and 0.16 mg/kg p.o.). S33138 also significantly improved accuracy (0.04 and 0.16 mg/kg p.o.) at short (but not long) delays in a variable delayed-response task of attention and working memory. Finally, in a separate set of experiments performed in monkeys displaying age-related deficits, S33138 significantly (0.16 and 0.63 mg/kg p.o.) improved task accuracies for long delay intervals in a delayed matching-to-sample task of working memory. In conclusion, S33138 improved performance in several rat and primate procedures of cognitive impairment. These data underpin interest in D(3) receptor blockade as a strategy for improving cognitive performance in CNS disorders like schizophrenia and Parkinson's disease.

RAGE and Abeta immunoglobulins: relation to Alzheimer's disease-related cognitive function.

The immunoglobulins (IgGs) for beta amyloid (Abeta) and receptors for the advanced glycation end products (RAGE) have previously been shown to be related to memory and language measures in a mixed neurological sample of older adults. In this study, we examined group differences in Abeta and RAGE IgGs, as well as the relationship between both IgGs and cognitive performance in nondiabetic older adults with normal cognition, mild cognitive impairment (MCI), and probable Alzheimer's disease (AD). We found RAGE and Abeta levels to be elevated in some AD participants, leading to significant AD-control group differences. While there was an overall correlation between both IgG levels and global cognition across all three groups, this relationship was largely attributable to group differences in cognition, highlighted by considerable variability within groups in the relationship between IgG levels and cognition. While findings do not support a consistent relationship between cognition and either IgG, further research with larger samples is needed to better characterize cognitive differences between AD participants with high versus low Abeta and RAGE titers.

Desensitization of nicotinic acetylcholine receptors as a strategy for drug development.

The specific pharmacological response evoked by a nicotinic acetylcholine receptor (nAChR) agonist is governed by the anatomical distribution and expression of each receptor subtype and by the stoichiometry of subunits comprising each subtype. Contributing to this complexity is the ability of agonists that bind to the orthosteric site of the receptor to alter the affinity state of the receptor and induce desensitization and the observation that, at low doses, some nAChR antagonists evoke agonist-like nicotinic responses. Brain concentrations of nicotine rarely increase to the low-mid micromolar concentrations that have been reported to evoke direct agonist-like responses, such as calcium influx or neurotransmitter release. Low microgram per kilogram doses of nicotine administered to humans or to nonhuman primates to improve cognition and working memory probably result only in low nanomolar brain concentrations--more in line with the ability of nicotine to induce receptor desensitization. Here we review data illustrating that nicotine, its major metabolite cotinine, and two novel analogs of choline, JWB1-84-1 [2-(4-(pyridin-3-ylmethyl)piperazin-1-yl)ethanol] and JAY2-22-33, JWB1-84-1 [2-(methyl(pyridine-3-ylmethyl)amino)-ethanol], improve working memory in macaques. The effectiveness of these four compounds in the task was linearly related to their effectiveness in producing desensitization of the pressor response to ganglionic stimulation evoked by a nAChR agonist in rats. Only nicotine evoked an agonist-like action (increased resting blood pressure). Therefore, it is possible to develop new chemical entities that have the ability to desensitize nAChRs without an antecedent agonist action. Because these "silent desensitizers" are probably acting allosterically, an additional degree of subtype specificity could be attained.

Emerging cognitive enhancing drugs.

BACKGROUND: Advances in health sciences during the last century have increased the average age in industrialized nations. Despite this progress, neurodegenerative diseases that affect higher order thinking and memory continue to increase in prevalence as they take a devastating toll on human productivity in the later years. There is an acute need for new drugs and therapeutic approaches for treating these severe diseases, and also for improving the quality of cognitive function associated with normal aging and in many other disorders and syndromes that present with cognitive dysfunction. OBJECTIVE: The purpose of this review is to ascertain the pharmacological approaches being exploited to improve cognition and memory and to determine the most relevant and effective directions taken for new drug discovery. Limitations and difficulties encountered in this effort also are discussed. METHODS: This review focuses primarily on compounds already undergoing clinical trials for improving cognition and memory with some discussion of rising new drug targets. RESULTS/CONCLUSION: Compounds that act on allosteric sites on neurotransmitter receptors are expected to lead the field with new levels of specificity and reduced side effects. New multi-functional compounds can be designed that can both improve cognition and slow the process of disease.

Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways.

The alpha7 nicotinic acetylcholine receptor (nAChR) plays an important role in cognitive processes and may represent a drug target for treating cognitive deficits in neurodegenerative and psychiatric disorders. In the present study, we used a novel alpha7 nAChR-selective agonist, 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) to interrogate cognitive efficacy, as well as examine potential cellular mechanisms of cognition. Exhibiting high affinity to native rat (Ki = 10.8 nM) and human (Ki = 16.7 nM) alpha7 nAChRs, A-582941 enhanced cognitive performance in behavioral assays including the monkey delayed matching-to-sample, rat social recognition, and mouse inhibitory avoidance models that capture domains of working memory, short-term recognition memory, and long-term memory consolidation, respectively. In addition, A-582941 normalized sensory gating deficits induced by the alpha7 nAChR antagonist methyllycaconitine in rats, and in DBA/2 mice that exhibit a natural sensory gating deficit. Examination of signaling pathways known to be involved in cognitive function revealed that alpha7 nAChR agonism increased extracellular-signal regulated kinase 1/2 (ERK1/2) phosphorylation in PC12 cells. Furthermore, increases in ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation were observed in mouse cingulate cortex and/or hippocampus after acute A-582941 administration producing plasma concentrations in the range of alpha7 binding affinities and behavioral efficacious doses. The MEK inhibitor SL327 completely blocked alpha7 agonist-evoked ERK1/2 phosphorylation. Our results demonstrate that alpha7 nAChR agonism can lead to broad-spectrum efficacy in animal models at doses that enhance ERK1/2 and CREB phosphorylation/activation and may represent a mechanism that offers potential to improve cognitive deficits associated with neurodegenerative and psychiatric diseases, such as Alzheimer's disease and schizophrenia.

Estimation of working memory in macaques for studying drugs for the treatment of cognitive disorders.

Non-human primates have served as subjects for studies of the cognition-enhancing potential of novel pharmacological agents for over 25 years. Only recently has a greater appreciation of the translational applicability of this model been realized. Though most Old-World monkeys do not appear to acquire an Alzheimer's-like syndrome in old age, their value resides in the brain physiology they have in common with humans. Paradigms like the delayed matching-to-sample task engender behavior that models aspects of working memory that are substrates for the actions of cognition-enhancing drugs. Our studies have provided information relevant to factors that limit the effectiveness of clinical trial design for compounds that potentially improve cognition. For example, cognition-enhancing compounds from different pharmacological classes, when administered to monkeys, can exhibit remarkable pharmacodynamic effects that outlast the presence of the drug in the body. Studies with non-human primates also can provide information regarding dose ranges and individual subject sensitivity experienced in the clinic. Components of working memory are differentially sensitive to drug effects and may be characterized by different dose ranges for certain compounds, even within the same task. Examples are provided that underscore the possible idiosyncrasies of drug action in the pharmacology of cognition--which could be of critical importance in the design of clinical trials.

The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates.

RATIONALE: The scopolamine-reversal model is enjoying a resurgence of interest in clinical studies as a reversible pharmacological model for Alzheimer's disease (AD). The cognitive impairment associated with scopolamine is similar to that in AD. The scopolamine model is not simply a cholinergic model, as it can be reversed by drugs that are noncholinergic cognition-enhancing agents. OBJECTIVES: The objective of the study was to determine relevance of computer-assisted operant-conditioning tasks in the scopolamine-reversal model in rats and monkeys. MATERIALS AND METHODS: Rats were evaluated for their acquisition of a spatial reference memory task in the Morris water maze. A separate cohort was proficient in performance of an automated delayed stimulus discrimination task (DSDT). Rhesus monkeys were proficient in the performance of an automated delayed matching-to-sample task (DMTS). RESULTS: The AD drug donepezil was evaluated for its ability to reverse the decrements in accuracy induced by scopolamine administration in all three tasks. In the DSDT and DMTS tasks, the effects of donepezil were delay (retention interval)-dependent, affecting primarily short delay trials. Donepezil produced significant but partial reversals of the scopolamine-induced impairment in task accuracies after 2 mg/kg in the water maze, after 1 mg/kg in the DSDT, and after 50 microg/kg in the DMTS task. CONCLUSIONS: The two operant-conditioning tasks (DSDT and DMTS) provided data most in keeping with those reported in clinical studies with these drugs. The model applied to nonhuman primates provides an excellent transitional model for new cognition-enhancing drugs before clinical trials.

The effects of JWB1-84-1 on memory-related task performance by amyloid Abeta transgenic mice and by young and aged monkeys.

JWB1-84-1 is one of 50 tertiary amine analogs of choline synthesized with expectation that they would be high potency compounds for cytoprotection. As one of the more potent analogs in this regard, JWB1-84-1, a piperazine derivative, was selected for testing as a cognition-enhancing agent. The compound was evaluated for efficacy in Alzheimer's disease transgenic mice (B6C3-Tg(APPswe, PSEN1dE9)85Dbo/J). A separate cohort of mice (AD Tg) were first subjected to a behavioral test battery in which the transgenic strain was compared with the wild-type strain. AD Tg mice were shown to exhibit specific deficits in the acquisition of a working memory (5-trial/session radial arm water maze, RAWM) task at a time when the animals exhibited maximal cerebral amyloid burden. JWB1-84-1 produced a dose-dependent decrease in the number of errors made by well trained AD-Tg mice the RAWM task that was maximal after the 20 microg/kg dose. Aged macaques (20-32 y) were trained to proficiency in their performance of a computer-assisted delayed matching-to-sample task. Vehicle (normal saline) or JWB1-84-1 (5-150 microg/kg, i.m.) was administered 10 min before the initiating of testing. On average, JWB1-84-1 treatment significantly improved task accuracy after all but the lowest dose. The maximal degree of improvement was attained after animals received the 100 microg/kg dose. The drug's effects were restricted primarily to Medium and Long delay trials - the most difficult portions of the task, which were improved by up to 18% above control. In young macaques JWB1-84-1 treatment also significantly reversed the decrements in task accuracy associated with the random presentation of a task distractor. Thus JWB1-84-1exhibits the potential for treating the cognitive symptoms associated with neurodegenerative diseases and attention deficit disorders. Its cytoprotective action might also work to slow the progression of Alzheimer's disease.

Profile of nicotinic acetylcholine receptor agonists ABT-594 and A-582941, with differential subtype selectivity, on delayed matching accuracy by young monkeys.

ABT-594 and A-582941 are high affinity neuronal nicotinic acetylcholine receptor agonists with differential selectivity for the alpha4beta2 and the alpha7 subtypes, respectively. This study was designed to determine whether either compound, like nicotine also possesses cognitive-enhancing ability. The compounds were administered by intramuscular injection to young adult Rhesus monkeys trained to perform two versions of a computer-assisted delayed matching-to-sample (DMTS) task. ABT-594 (0.115-3.7 microg/kg) significantly improved DMTS accuracies, shifting the retention curve (accuracy-delay relationship) to the right in a parallel fashion. DMTS accuracy also was maintained during the sessions initiated 24h after compound administration. Because task accuracy was improved during short delay trials, a separate study was performed in which non-predictable distractors were inserted within the DMTS format to impair accuracy. The 0.115 microg/kg dose of ABT-594 almost completely reversed distractor-impaired performance associated with short delay trials. The alpha7 nAChR agonist, A-582941 (1.14-38 microg/kg) also significantly improved DMTS accuracies. The compound produced a significant improvement during long delay trials. The effect was twice as robust for long delay as compared with short delay trials and A-582941 was not as effective as ABT-594 in improving short delay trial accuracy. A-582941 also failed to sustain task improvement during sessions run 24h after dosing. These data are consistent with the ability of subtype-preferring nicotinic receptor agonists to enhance specific components of working memory and cognitive function, and they suggest that differential subtype selectivity could result in varied pharmacological response profiles.

Guidelines on nicotine dose selection for in vivo research.

RATIONALE: This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure. OBJECTIVES: This review capitalizes on the authors' collective decades of in vivo nicotine experimentation to clarify the issues and to identify the variables to be considered in choosing a dosaging regimen. Nicotine dose ranges tolerated by humans and their animal models provide guidelines for experiments intended to extrapolate to human tobacco exposure through cigarette smoking or nicotine replacement therapies. Just as important are the nicotine dosaging regimens used to provide a mechanistic framework for acquisition of drug-taking behavior, dependence, tolerance, or withdrawal in animal models. RESULTS: Seven species are addressed: humans, nonhuman primates, rats, mice, Drosophila, Caenorhabditis elegans, and zebrafish. After an overview on nicotine metabolism, each section focuses on an individual species, addressing issues related to genetic background, age, acute vs chronic exposure, route of administration, and behavioral responses. CONCLUSIONS: The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose-response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.

Disconnection between activation and desensitization of autonomic nicotinic receptors by nicotine and cotinine.

Cotinine is the major metabolite of nicotine in humans, and the substance greatly outlasts the presence of nicotine in the body. Recently, cotinine has been shown to exert pharmacological properties of its own that include potential cognition enhancement, anti-psychotic activity, and cytoprotection. Since the metabolite is generally less potent than nicotine in vivo, we considered whether part of cotinine's efficacy could be related to a reduced ability to desensitize nicotinic receptors as compared with nicotine. Rats freely moving in their home cages were instrumented to allow ongoing measurement of mean arterial blood pressure (MAP). The ganglionic stimulant dimethylphenylpiperazinium (DMPP) maximally increased MAP by 25mmHg. Slow (20min) i.v. infusion of nicotine (0.25-1micromol) produced no change in resting MAP, but the pressor response to subsequent injection of DMPP was significantly attenuated in a dose-dependent manner by up to 51%. Pre-infusion of equivalent doses of cotinine produced the same maximal degree of inhibition of the response to DMPP. Discrete i.v. injections of nicotine also produced a dose dependent increase in MAP of up to 43mmHg after the highest tolerated dose. In contrast, injection of cotinine produced no significant change in MAP up to 13 times the highest dose of nicotine. These results illustrate the disconnection between nicotinic receptor activation and receptor desensitization, and they suggest that cotinine's pharmacological actions are either mediated through partial desensitization, or through non-ganglionic subtypes of nicotinic receptors.

Hippocampal CA1 cell loss in a non-human primate model of transient global ischemia: a pilot study.

We exposed adult Rhesus (Macaca mulatta) to a transient global ischemia, which was induced by clipping the innominate and subclavian arteries that originated from the aortic arch. NHP1 received 20-min, while NHP2 and NHP3, were exposed to a 15-min transient global ischemia and were euthanized at day 1 (NHP1), day 5 (NHP2) or day 30 (NHP3) after ischemia, respectively. NHP1 displayed severe paralysis and rigidity, and intermittent convulsions over the next 24 h. Although histological examination of the brain revealed no detectable gross brain damage (i.e., swelling) and only minimal cell loss in the hippocampus, the acute survival time after surgery likely prevented the cerebral ischemia to fully develop and to be morphologically manifested. Nonetheless, the 20-min ischemia might have been too severe and caused a systemic multiple organ collapse that produced the abnormal behavioral symptoms. On the other hand, NHP2 and NHP3 which received 15-min ischemia only exhibited minor hindlimb paralysis. Indeed, by 48 h after ischemia, both animals appeared fully recovered with only fine motor deficits. Immunohistochemical examination revealed that NHP2 and 3, but not NHP1, had a marked neuronal cell loss in the hippocampal region, specifically the cornu Ammonis (CA1) region. The cell loss in these two ischemic NHP hippocampi was further confirmed by direct comparison with a normal Rhesus brain. These findings replicate the brain pathology seen in Japanese macaques exposed to the same ischemia model [T. Tsukada, M. Watanabe, T. Yamashima, Implications of CAD and DNase II in ischemic neuronal necrosis specific for the primate hippocampus, J. Neurochem. 79 (2001) 1196-1206; T. Yamashima, Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates, Prog. Neurobiol. 62 (2000) 273-295; T. Yamashima, Y. Kohda, K. Tsuchiya, T. Ueno, J. Yamashita, T. Yoshioka, E. Kominami, Inhibition of ischemic hippocampal neuronal death in primates with cathepsin B inhibitor CA-074: a novel strategy for neuroprotection based on calpain-cathepsin hypothesis, Eur. J. Neurosci. 10 (1998) 1723-1733; T. Yamashima, T.C. Saido, M. Takita, A. Miyazawa, J. Yamano, A. Miyakawa, H. Nishijyo, J. Yamashita, S. Kawashima, T. Ono, T. Yoshioka, Transient brain ischemia provokes Ca2+, PIP2 and calpain responses prior to delayed neuronal death in monkeys, Eur. J. Neurosci. 8 (1996) 1932-1944; T. Yamashima, A.B. Tonchey, T. Tsukada, T.C. Saido, S. Imajoh-Ohmi, T. Momoi, E. Kominami, Sustained calpain activation associated with lysosomal rupture executes necrosis of the postischemic CA1 neurons in primates, Hippocampus 13 (2003) 791-800]. The present minimally invasive transient global ischemia model using Rhesus shows many histopathological symptoms seen in human patients who experienced global ischemia, and should allow translational validation of experimental therapeutics for ischemic injury. Additional studies are warranted to reveal behavioral deficits associated with this ischemia model.

Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders.

Individuals with neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease are benefiting from drugs developed to act on a single molecular target. However, current pharmacological approaches are limited in their ability to modify significantly the course of the disease, and offer incomplete and transient benefit to patients. New therapeutic strategies comprise drug candidates designed specifically to act on multiple neural and biochemical targets for the treatment of cognition impairment, motor dysfunction, depression and neurodegeneration. Examples include the development of single molecular entities that combine two or more of the following properties: (i) cholinesterase inhibition; (ii) activation or inhibition of specific subtypes of acetylcholine receptors or alpha-adrenoceptors; (iii) anti-inflammatory activity; (iv) monoamine oxidase inhibition; (v) catechol-O-methyl transferase inhibition; (vi) nitric oxide production; (vii) neuroprotection; (viii) anti-apoptotic activity; and (ix) activation of mitochondrial-dependent cell-survival genes and proteins. These bi- or multi-functional compounds might provide greater symptomatic efficacy, and better utility as potential neuroprotective disease-modifying drugs.

Long-lasting cognitive improvement with nicotinic receptor agonists: mechanisms of pharmacokinetic-pharmacodynamic discordance.

Agonists of nicotinic acetylcholine receptors (nAChRs) produce long-lasting cognitive effects in animal models and humans. The duration of these cognitive effects can outlast the presence of the agonists in the system, and the persistence of cognitive enhancement is increased further by repeated exposure. The basis for this discrepancy appears be the cellular and systemic mechanisms of learning and memory. Agonists of nAChRs induce long-term potentiation (LTP), which is a strengthening of synaptic connections that is associated with learning and memory formation. Some of the cellular effects of nAChR agonists overlap with the known cellular mechanisms of LTP, including long-lasting increases in intracellular concentrations of Ca2+, activation of second-messenger systems and transcription factors, elevated levels of gene products and enhanced neurotransmitter release. A better understanding of this phenomenon might shed new light on the role of nAChR systems in memory formation and retrieval.

Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder.

1. The effectiveness of antimuscarinic agents in the treatment of the overactive bladder (OAB) syndrome is thought to arise through blockade of bladder muscarinic receptors located on detrusor smooth muscle cells, as well as on nondetrusor structures. 2. Muscarinic M3 receptors are primarily responsible for detrusor contraction. Limited evidence exists to suggest that M2 receptors may have a role in mediating indirect contractions and/or inhibition of detrusor relaxation. In addition, there is evidence that muscarinic receptors located in the urothelium/suburothelium and on afferent nerves may contribute to the pathophysiology of OAB. Blockade of these receptors may also contribute to the clinical efficacy of antimuscarinic agents. 3. Although the role of muscarinic receptors in the bladder, other than M3 receptors, remains unclear, their role in other body systems is becoming increasingly well established, with emerging evidence supporting a wide range of diverse functions. Blockade of these functions by muscarinic receptor antagonists can lead to similarly diverse adverse effects associated with antimuscarinic treatment, with the range of effects observed varying according to the different receptor subtypes affected. 4. This review explores the evolving understanding of muscarinic receptor functions throughout the body, with particular focus on the bladder, gastrointestinal tract, eye, heart, brain and salivary glands, and the implications for drugs used to treat OAB. The key factors that might determine the ideal antimuscarinic drug for treatment of OAB are also discussed. Further research is needed to show whether the M3 selective receptor antagonists have any advantage over less selective drugs, in leading to fewer adverse events.

Autoimmunity in Alzheimer's disease as evidenced by plasma immunoreactivity against RAGE and Abeta42: complication of diabetes.

Features of autoimmunity have been associated with both Alzheimer's disease (AD) and with diabetes. In both diseases high levels of advanced glycation end products (AGEs) and their receptor (RAGE) have been detected in tissues and in the circulation. In addition high titers of antibodies directed against a RAGE-like peptide occur in the circulation. In this study we report the presence of auto-antibodies directed against RAGE and the cytotoxic amyloid peptide Abeta42 in plasma samples derived from four study groups. Anti-RAGE IgG titers were greatest in the AD-diabetic cohort. They were followed in decreasing order by the AD-non-diabetic cohort, the elderly diabetic cohort, and lastly by the control non-diabetic elderly cohort. The same profile of IgG differences was evident for the anti-Abeta42 titers. When all of the data were combined, there was a strong linear correlation between the RAGE and Abeta42 titers suggesting that the two peptides exist as a tight complex in plasma. Plasma IgG titers were not correlated with cognitive status except that AD and AD-diabetic participants were significantly cognitively impaired relative to the two non-AD groups. There also was no significant correlation between IgG titers and subject age, except that there was a trend for a negative slope for the AD participants and a positive slope for the control participants. In keeping with the human data, we also report that chemically-induced diabetes in rats was associated with high levels of AGEs, anti-RAGE-like IgGs, and anti-Abeta42-like IgGs. For non-diabetic rats, there was a clear age-dependency regarding the magnitude of the IgG levels. These data support the concept of an interrelationship between diabetes and AD. For both diseases one underlying contributing factor to cytotoxicity could be the development of an autoimmune response triggered by the presence of AGEs and amyloid peptides.

Effect of amyloid peptides on the increase in TrkA receptor expression induced by nicotine in vitro and in vivo.

The ability of nicotine to induce a cytoprotective or neuroprotective action occurs through several downstream mechanisms. One possibility is that the drug increases the expression of tyrosine kinase A (TrkA) nerve growth factor (NGF) receptors. Certain beta-amyloid peptides (e.g., Abeta1-42) have been shown to bind with high affinity to alpha7 nicotinic receptors and thus interfere with a potentially neurotrophic influence. Treatment of differentiated PC-12 cells with nicotine produced a concentration-dependent increase in cell-surface TrkA receptors that occurred concomitantly with cytoprotection. The effect of nicotine was blocked by either of the alpha7 receptor antagonists alpha-bungarotoxin (alpha-BTX) or methyllycaconatine. The cytoprotective action of nicotine also was inhibited by pretreatment with 10-100 nM Abeta1-42. Nicotine also was administered (four injections of 30 microg, spaced evenly over 24 h) to rats by direct injection into a lateral cerebral ventricle. Brain TrkA expression was increased significantly in hippocampus and entorhinal cortex (up to 32% above control), with no changes found in cerebral cortex or hypothalamus. The nicotine-induced increases in TrKA expression in hippocampus and entorhinal cortex were significantly inhibited by 10 microg alpha-BTXor by 10 nmol Abeta1-42. Therefore, physiologically relevant concentrations of Abeta1-42 can prevent nicotine-induced TrkA receptor expression in brain regions containing cholinergic neurons susceptible to the neurotoxicity associated with Alzheimer's disease.