Tanya L. Wallace

Targeting the nicotinic alpha7 acetylcholine receptor to enhance cognition in disease.

A promising drug target currently under investigation to improve cognitive deficits in neuropsychiatric and neurological disorders is the neuronal nicotinic alpha7 acetylcholine receptor (α7nAChR). Improving cognitive impairments in diseases such as Alzheimers (AD) and schizophrenia remains a large unmet medical need, and the α7nAChR has many properties that make it an attractive therapeutic target. The α7nAChR is a ligand gated ion channel that has particularly high permeability to Ca(2+) and is expressed in key brain regions involved in cognitive processes (e.g., hippocampus). The α7nAChRs are localized both pre-synaptically, where they can regulate neurotransmitter release, and post-synaptically where they can activate intracellular signaling cascades and influence downstream processes involved in learning and memory. In particular, activation of the α7nAChR with small molecule agonists enhances long-term potentiation, an in vitro model of synaptic plasticity, and improves performance across multiple cognitive domains in rodents, monkeys, and humans. Positive allosteric modulation of the α7nAChR offers an alternate approach to direct agonism that could prove to be particularly beneficial in certain disease populations where smoking nicotine is prevalent (e.g., schizophrenia) and could interfere with an orthosteric agonist approach. The current review focuses on the neurobiology of the α7nAChR, its role in cognition and the development status of some of the most promising molecules advancing for the treatment of cognitive dysfunction in disease.

Effect of Bitopertin, a Glycine Reuptake Inhibitor, on Negative Symptoms of Schizophrenia: A Randomized, Double-Blind, Proof-of-Concept Study

IMPORTANCE In schizophrenia, the severity of negative symptoms is a key predictor of long-term disability. Deficient signaling through the N-methyl-D-aspartate receptor is hypothesized to underlie many signs and symptoms associated with schizophrenia in particular negative symptoms. Glycine acts as an N-methyl-D-aspartate receptor coagonist. Blockade of the glycine transporter type 1 to inhibit glycine reuptake and elevate synaptic glycine concentrations represents an effective strategy to enhance N-methyl-D-aspartate receptor transmission. OBJECTIVE To determine the efficacy and safety of bitopertin (RG1678), a glycine reuptake inhibitor, in patients with schizophrenia and predominant negative symptoms who were stable while taking an antipsychotic treatment. DESIGN, SETTING, AND PARTICIPANTS This randomized, double-blind, placebo-controlled, phase 2 proof-of-concept trial involved 323 patients with schizophrenia and predominant negative symptoms across 66 sites worldwide. INTERVENTIONS Bitopertin (10, 30, or 60 mg/d) or placebo added to standard antipsychotic therapy for a treatment duration of 8 weeks. MAIN OUTCOMES AND MEASURES Change from baseline in the Positive and Negative Syndrome Scale negative factor score. RESULTS In the per-protocol population, 8 weeks of treatment with bitopertin was associated with a significant reduction of negative symptoms in the 10-mg/d (mean [SE] reduction in negative symptoms score, -25% [2%]; P = .049) and 30-mg/d (mean [SE], -25% [2%]; P = .03) bitopertin groups, a significantly higher response rate and a trend toward improved functioning in the 10-mg/d group when compared with placebo (mean [SE], -19% [2%]). Results reached trend-level significance in the intent-to-treat population. Estimates of bitopertin binding to glycine transporter type 1 showed that low to medium levels of occupancy yielded optimal efficacy in patients, consistent with findings in preclinical assays. CONCLUSIONS AND RELEVANCE Bitopertin-mediated glycine reuptake inhibition may represent a novel treatment option for schizophrenia, with the potential to address negative symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00616798.

Drug targets for cognitive enhancement in neuropsychiatric disorders

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimers disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA(A) α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.

Importance of the nicotinic acetylcholine receptor system in the prefrontal cortex.

The prefrontal cortex (PFC) is responsible for integrating cortical and subcortical inputs to execute essential cognitive functions such as attention, working memory planning and decision-making. The importance of this brain region in regulating complex cognitive processes is underscored by a decline in PFC-mediated ability observed in aging and disease. The cholinergic system plays a vital role in cognitive function and treatments (e.g., cholinesterase inhibitors) to improve cholinergic neurotransmission provide the standard-of-care for diseases such as Alzheimers. Nicotinic receptors (nAChRs) are a primary site of action for acetylcholine (ACh), and the resulting pro-cognitive effects observed by stimulating nAChRs with nicotine has long been appreciated by tobacco users, prompting investigation of therapeutic development for diseases (e.g., schizophrenia, Alzheimer or attention-deficit-hyperactivity disorder) by targeting the neuronal nAChR system. Noteworthy, improvements in attention, working memory and executive processes mediated by the PFC have been reported following nicotinic agonist exposure. Relevance of these ligand gated channels in higher brain function is further supported by the association of cognitive deficits reported in humans with mutations in CHRNB2 or CHRNA7 the genes encoding for the nicotinic receptor β2 and α7 subunits, respectively. In this work we review, in light of the latest findings, how nicotinic agonists may be acting in the PFC to influence cognitive function.

Alpha7 neuronal nicotinic receptors as a drug target in schizophrenia.

Introduction: Schizophrenia is a profoundly debilitating disease that represents not only an individual, but a societal problem. Once characterized solely by the hyperactivity of the dopaminergic system, therapies directed to dampen dopaminergic neurotransmission were developed. However, these drugs do not address the significant impairments in cognition and the negative symptoms of the disease, and it is now apparent that disequilibrium of many neurotransmitter systems is involved. Despite enormous efforts, minimal progress has been made toward the development of safer, more effective therapies to date. Areas covered: The high preponderance of smoking in schizophrenics suggests that nicotine may provide symptomatic improvement, which has led to investigation for selective molecules targeted to individual nicotinic receptor (nAChR) subtypes. Of special interest is activation of the homomeric α7nAChR, which is widely distributed in the brain and has been implicated in the pathophysiology of schizophrenia through numerous approaches. Expert opinion: Preclinical and clinical data suggest that neuronal α7nAChRs play an important role in cognitive functions. Moreover, some, but not all, early clinical trials conducted with α7nAChR agonists show cognitive benefits in schizophrenics. These encouraging results suggest that development of compounds targeting α7nAChRs will represent a valuable tool to mitigate symptoms associated with schizophrenia, and open new strategies for better pharmacological treatment of these patients.

Consideration of species differences in developing novel molecules as cognition enhancers.

The NIH-funded CNTRICS initiative has coordinated efforts to promote the vertical translation of novel procognitive molecules from testing in mice, rats and non-human primates, to clinical efficacy in patients with schizophrenia. CNTRICS highlighted improving construct validation of tasks across species to increase the likelihood that the translation of a candidate molecule to humans will be successful. Other aspects of cross-species behaviors remain important however. This review describes cognitive tasks utilized across species, providing examples of differences and similarities of innate behavior between species, as well as convergent construct and predictive validity. Tests of attention, olfactory discrimination, reversal learning, and paired associate learning are discussed. Moreover, information on the practical implication of species differences in drug development research is also provided. The issues covered here will aid in task development and utilization across species as well as reinforcing the positive role preclinical research can have in developing procognitive treatments for psychiatric disorders.

Neuronal α7 Nicotinic Receptors as a Target for the Treatment of Schizophrenia.

Schizophrenia is a lifelong disease, the burden of which is often underestimated. Characterized by positive (e.g., hallucinations) and negative (e.g., avolition, amotivation) symptoms, schizophrenia is also accompanied with profound impairments in cognitive function that progress throughout the development of the disease. Although treatment with antipsychotic medications can effectively dampen some of the positive symptoms, these medications largely fail to reverse cognitive deficits or to mitigate negative symptoms. With a worldwide prevalence of approximately 1%, schizophrenia remains a large unmet medical need that stands to benefit greatly from (1) continued research to better understand the biological underpinnings of the disease and (2) the targeted development of novel therapeutics to improve the lives of those affected individuals. Improvements in our understanding of the neuronal networks associated with schizophrenia as well as progress in identifying genetic risk factors and environmental conditions that may predispose individuals to developing the disease are advancing new strategies to study and treat it. Herein, we review the evidence that supports the role of α7 nicotinic acetylcholine receptors in the central nervous system and why these receptors constitute a promising target to treat some of the prominent symptoms of schizophrenia.

Characterization of RO5126946, a novel α7 nicotinic acetylcholine receptor positive allosteric modulator

Both preclinical evidence and clinical evidence suggest that α7 nicotinic acetylcholine receptor activation (α7nAChR) improves cognitive function, the decline of which is associated with conditions such as Alzheimer’s disease and schizophrenia. Moreover, allosteric modulation of α7nAChR is an emerging therapeutic strategy in an attempt to avoid the rapid desensitization properties associated with the α7nAChR after orthosteric activation. We used a calcium assay to screen for positive allosteric modulators (PAMs) of α7nAChR and report on the pharmacologic characterization of the novel compound RO5126946 (5-chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide), which allosterically modulates α7nAChR activity. RO5126946 increased acetylcholine-evoked peak current and delayed current decay but did not affect the recovery of α7nAChRs from desensitization. In addition, RO5126946’s effects were absent when nicotine-evoked currents were completely blocked by coapplication of the α7nAChR-selective antagonist methyl-lycaconitine. RO5126946 enhanced α7nAChR synaptic transmission and positively modulated GABAergic responses. The absence of RO5126946 effects at human α4β2nAChR and 5-hydroxytryptamine 3 receptors, among others, indicated selectivity for α7nAChRs. In vivo, RO5126946 is orally bioavailable and brain-penetrant and improves associative learning in a scopolamine-induced deficit model of fear conditioning in rats. In addition, procognitive effects of RO5126946 were investigated in the presence of nicotine to address potential pharmacologic interactions on behavior. RO5126946 potentiated nicotine’s effects on fear memory when both compounds were administered at subthreshold doses and did not interfere with procognitive effects observed when both compounds were administered at effective doses. Overall, RO5126946 is a novel α7nAChR PAM with cognitive-enhancing properties.

Peripheral complement interactions with amyloid β peptide: Erythrocyte clearance mechanisms

Although amyloid β peptide (Aβ) is cleared from the brain to cerebrospinal fluid and the peripheral circulation, mechanisms for its removal from blood remain unresolved. Primates have uniquely evolved a highly effective peripheral clearance mechanism for pathogens, immune adherence, in which erythrocyte complement receptor 1 (CR1) plays a major role.

Animal paradigms to assess cognition with translation to humans.

Cognition is a complex brain function that represents processes such as learning and memory, attention, working memory, and executive functions amongst others. Impairments in cognition are prevalent in many neuropsychiatric and neurological disorders with few viable treatment options. The development of new therapies is challenging, and poor efficacy in clinical development continues to be one of the most consistent reasons compounds fail to advance, suggesting that traditional animal models are not predictive of human conditions and behavior. An effort to improve the construct validity of neuropsychological testing across species with the intent of facilitating therapeutic development has been strengthening over recent years. With an emphasis on understanding the underlying biology, optimizing the use of appropriate systems (e.g., transgenic animals) to model targeted disease states, and incorporating non-rodent species (e.g., non-human primates) that may enable a closer comparison to humans, an improvement in the translatability of the results will be possible. This chapter focuses on some promising translational cognitive paradigms for use in rodents, non-human primates, and humans.