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Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are widely distributed both pre- and post-synaptically in the mammalian brain. By modulating cation flux across cell membranes, neuronal nAChRs regulate neuronal excitability and the release of a variety of neurotransmitters to influence multiple physiologic and behavioral processes including synaptic plasticity, motor function, attention, learning and memory. Abnormalities of neuronal nAChRs have been implicated in the pathophysiology of neurologic disorders including Alzheimer’s disease, Parkinson’s disease, epilepsy, and Tourette´s syndrome, as well as psychiatric disorders including schizophrenia, depression, and anxiety. The potential role of nAChRs in a particular illness may be indicated by alterations in the expression of nAChRs in relevant brain regions, genetic variability in the genes encoding for nAChR subunit proteins, and/or clinical or preclinical observations where specific ligands showed a therapeutic effect. Over the past 25 years, extensive preclinical and some early clinical evidence suggested that ligands at nAChRs might have therapeutic potential for neurologic and psychiatric disorders. However, to date the only approved indications for nAChR ligands are smoking cessation and the treatment of dry eye disease. It has been argued that progress in nAChR drug discovery has been limited by translational gaps between the preclinical models and the human disease as well as unresolved questions regarding the pharmacological goal (i.e., agonism, antagonism or receptor desensitization) depending on the disease.

Tubulocystic renal cell carcinoma is a rare cancer that was not defined as a distinct entity until the early 2000s. Due to the recency of its classification, it remains poorly understood and leaves much room for future research. This report looks at a unique case of this rare subtype of renal cancer. This specific case is unique due to both the demographics of the affected patient and the finding of bone metaplasia within the tumor. We believe this is the first ever reported incidence of this phenomenon.

Stress and stress-induced glucocorticoids have been implicated in many neuropsychiatric disorders including schizophrenia. In addition, the neurotrophin, brain derived neurotrophic factor (BDNF) has been shown to play an important role in stress-mediated changes in neuroplasticity, however, the exact relationship between glucocorticoid and BDNF levels in schizophrenia is unclear. Here, we measured the levels of cortisol (a major glucocorticoid hormone in humans) and BDNF in prefrontal cortex and CSF samples of postmortem schizophrenia subjects. We also assessed the levels of cortisol and BDNF in the frontal cortex and plasma from an animal model (the offspring of prenatally stressed rats), which demonstrates several behavioral and neuroendocrine abnormalities similar to schizophrenia. A significant increase in cortisol levels was found in prefrontal cortex and CSF samples from subjects with schizophrenia. The BDNF levels were significantly lower in prefrontal cortex and CSF samples of subjects with schizophrenia (compared to age-matched controls). Data from animal studies indicated that prenatally stressed offspring have significantly higher plasma and prefrontal cortex cortisol, whereas BDNF levels were significantly lower when compared to control, non-stressed offspring. Moreover, olanzapine treatment for 45 days starting at postnatal day 60 significantly attenuated prenatal stress-induced increase in cortisol levels in prefrontal cortex, but no change in BDNF levels was observed after olanzapine treatment. A significant negative correlation between BDNF and cortisol was observed in both human and animal studies. The above data from human and animal studies suggest that a negative association between stress hormone, cortisol and neuroprotective molecule, BDNF plays an important role in the pathophysiology of schizophrenia.

Background: Brain network analysis is an emerging field of research that could lead to the development, testing and validation of novel biomarkers for epilepsy. This could shorten the diagnostic uncertainty period, improve treatment, decrease seizure risk and lead to better management. This scoping review summarises the current state of electroencephalogram (EEG)-based network abnormalities for childhood epilepsies. The review assesses the overall robustness, potential generalisability, strengths, and limitations of the methodological frameworks of the identified research studies., Reporting Methods: PRISMA guidelines for Scoping Reviews and the PICO framework was used to guide this review. Studies that evaluated candidate network-based features from EEG in children were retrieved from four international indexing databases (Cochrane Central / Embase / MEDLINE/ PsycINFO). Each selected study design, intervention characteristics, methodological design, potential limitations, and key findings were analysed., Results: Of 2,959 studies retrieved, nine were included. Studies used a group-level based comparison (e.g. based on a statistical test) or a classification-based method (e.g. based on a statistical model, such as a decision tree). A common limitation was the small sample-sizes (limiting further subgroup or confounder analysis) and the overall heterogeneity in epilepsy syndromes and age groups., Conclusion: The heterogeneity of included studies (e.g. study design, statistical framework, outcome metrics) highlights the need for future studies to adhere to standardised frameworks (e.g. STARD) in order to develop standardised and robust methodologies. This would enable rigorous comparisons between studies, which is critical in assessing the potential of network-based approaches in developing novel biomarkers for childhood epilepsies., Competing Interests: Declaration of competing interest KM is an employee of Neuronostics; WW and JT are co-founders, directors and share-holders of Neuronostics. RS holds joint grants with the co-founders of Neuronostics and is a member of the Neuronostics advisory board. Further, RS has received Honoria, institutional and research support from LivaNova, UCB, Eisai, Veriton Pharma, Bial, Angelini, UnEEG and Jazz/GW pharma outside the submitted work. He holds grants from NIHR AI, SBRI and other funding bodies all outside this work. LJ and AW declare no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The United States Chronic Thromboembolic Pulmonary Hypertension Registry (US-CTEPH-R) was designed to characterize the demographic characteristics, evaluation, clinical course, and outcomes of surgical and nonsurgical therapies for patients with chronic thromboembolic pulmonary hypertension., Research Question: What are the differences in baseline characteristics and 1-year outcomes between operated and nonoperated subjects?, Study Design and Methods: This study describes a multicenter, prospective, longitudinal, observational registry of patients newly diagnosed (< 6 months) with CTEPH. Inclusion criteria required a mean pulmonary artery pressure ≥ 25 mm Hg documented by right heart catheterization and radiologic confirmation of CTEPH. Between 2015 and 2018, a total of 750 patients were enrolled and followed up biannually until 2019., Results: Most patients with CTEPH (87.9%) reported a history of acute pulmonary embolism. CTEPH diagnosis delays were frequent (median, 10 months), and most patients reported World Health Organization functional class 3 status at enrollment with a median mean pulmonary artery pressure of 44 mm Hg. The registry cohort was subdivided into Operable patients undergoing pulmonary thromboendarterectomy (PTE) surgery (n = 566), Operable patients who did not undergo surgery (n = 88), and those who were Inoperable (n = 96). Inoperable patients were older than Operated patients; less likely to be obese; have a DVT history, non-type O blood group, or thrombophilia; and more likely to have COPD or a history of cancer. PTE resulted in a median pulmonary vascular resistance decline from 6.9 to 2.6 Wood units (P < .001) with a 3.9% in-hospital mortality. At 1-year follow-up, Operated patients were less likely treated with oxygen, diuretics, or pulmonary hypertension-targeted therapy compared with Inoperable patients. A larger percentage of Operated patients were World Health Organization functional class 1 or 2 at 1 year (82.9%) compared with the Inoperable (48.2%) and Operable/No Surgery (56%) groups (P < .001)., Interpretation: Differences exist in the clinical characteristics between patients who exhibited operable CTEPH and those who were inoperable, with the most favorable 1-year outcomes in those who underwent PTE surgery., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT02429284; URL: www.clinicaltrials.gov., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The enhanced heat resistance of Salmonella developed at low water activity makes it a serious challenge to eliminate them during thermal processing. The objectives of this research are to (i) investigate the effect of water activity on thermal inactivation of Salmonella cocktail (Agona, Tennessee, Mbandaka, Montevideo, and Reading) in dried basil leaves, and (ii) evaluate Enterococcus faecium NRRL B-2354 as an appropriate surrogate for Salmonella in dried basil leaves. Dried basil leaves, inoculated with a Salmonella cocktail and E. faecium separately, were equilibrated to different water activities (a w : 0.40, 0.55, and 0.70) in a humidity-controlled chamber. The basil samples were packed (1.6 ± 0.1 g) in aluminum pouches and thermally treated at 70, 75, and 80 °C using a dry heating method for 0-180 min to obtain the thermal death curve. The microbial survival data was fit using two primary models (Log-linear and Weibull model). Results from AIC c showed that the log-linear model fits well for thermal inactivation of both microorganisms. As the a w decreases from 0.70 to 0.40 at 75 °C, the D-value increases from 3.30 to 9.14 min for Salmonella and 6.53 to 14.07 min for E. faecium. Based on the AIC c values, the modified Bigelow model fits the D-values better than the response surface model for both the microorganisms. The kill ratio of surrogate to pathogen ranged from 1.4 to 2.8, indicating that it is a conservative surrogate for Salmonella for performing validation of the thermal pasteurization process. The identification of suitable surrogate and development of modified Bigelow model will help the spice industry in developing the thermal processes for improving the safety of basil leaves., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: For people with idiopathic generalized epilepsy, functional networks derived from their resting-state scalp electrophysiological recordings have shown an inherent higher propensity to generate seizures than those from healthy controls when assessed using the concept of brain network ictogenicity (BNI). Herein we tested whether the BNI framework is applicable to resting-state magnetoencephalography (MEG) from people with juvenile myoclonic epilepsy (JME)., Methods: The BNI framework consists in deriving a functional network from apparently normal brain activity, placing a mathematical model of ictogenicity into the network and then computing how often such network generates seizures in silico. We considered data from 26 people with JME and 26 healthy controls., Results: We found that resting-state MEG functional networks from people with JME are characterized by a higher propensity to generate seizures (i.e., higher BNI) than those from healthy controls. We found a classification accuracy of 73%., Conclusions: The BNI framework is applicable to MEG and was capable of differentiating people with epilepsy from healthy controls., Significance: The BNI framework may be applied to resting-state MEG to aid in epilepsy diagnosis., Competing Interests: Declaration of Competing Interest JT is co-founder and Director of Neuronostics., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Antipsychotic drugs (APDs) have a variety of important therapeutic applications for neuropsychiatric disorders. However, they are routinely prescribed off-label across all age categories, a controversial practice given their potential for producing metabolic and extrapyramidal side effects. Evidence also suggests that chronic treatment with some APDs may lead to impairments in cognition and decreases in brain volume, although these findings are controversial. The purpose of the studies described here was to evaluate one of the most commonly prescribed APDs, quetiapine, for chronic effects on recognition memory, brain-derived neurotrophic factor (BDNF), its precursor proBDNF, as well as relevant downstream signaling molecules that are known to influence neuronal plasticity and cognition. Multiple cohorts of adult rats were treated with quetiapine (25.0 mg/kg/day) for 30 or 90 days in their drinking water then evaluated for drug effects on motor function in a catalepsy assessment, recognition memory in a spontaneous novel object recognition (NOR) task, and BDNF-related signaling molecules in the post mortem hippocampus via Western Blot. The results indicated that oral quetiapine at a dose that did not induce catalepsy, led to time-dependent impairments in NOR performance, increases in the proBDNF/BDNF ratio, and decreases in Akt and CREB phosphorylation in the hippocampus. These results indicate that chronic treatment with quetiapine has the potential to adversely affect recognition memory and neurotrophin-related signaling molecules that support synaptic plasticity and cognitive function. Given the widespread use this APD across multiple conditions and patient populations, such long-term effects observed in animals should be considered., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Organophosphates (OPs) are valuable as pesticides in agriculture and for controlling deadly vector-borne illnesses; however, they are highly toxic and associated with many deleterious health effects in humans including long-term neurological impairments. Antidotal treatment regimens are available to combat the symptoms of acute OP toxicity, which result from the irreversible inhibition of acetylcholinesterase (AChE). However, there are no established treatments for the long-term neurological consequences of OP exposure. In addition to AChE, OPs can negatively affect multiple protein targets as well as biological processes such as axonal transport. Given the fundamental nature of axonal transport to neuronal health, we rationalized that this process might serve as a general focus area for novel therapeutic strategies against OP toxicity. In the studies described here, we employed a multi-target, phenotypic screening, and drug repurposing strategy for the evaluations of potential novel OP-treatments using a primary neuronal culture model and time-lapse live imaging microscopy. Two multi-target compounds, lithium chloride (LiCl) and methylene blue (MB), which are FDA-approved for other indications, were evaluated for their ability to prevent the negative effects of the OP, diisopropylfluorophosphate (DFP) on axonal transport. The results indicated that both LiCl and MB prevented DFP-induced impairments in anterograde and retrograde axonal transport velocities in a concentration dependent manner. While in vivo studies will be required to confirm our in vitro findings, these experiments support the potential of LiCl and MB as repurposed drugs for the treatment of the long-term neurological deficits associated with OP exposure (currently an unmet medical need)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Antipsychotic drugs (APDs) are essential for the treatment of schizophrenia and other neuropsychiatric illnesses such as bipolar disease. However, they are also extensively prescribed off-label for many other conditions, a practice that is controversial given their potential for long-term side effects. There is clinical and preclinical evidence that chronic treatment with some APDs may lead to impairments in cognition and decreases in brain volume, although the molecular mechanisms of these effects are unknown. The purpose of the rodent studies described here was to evaluate a commonly prescribed APD, risperidone, for chronic effects on recognition memory, brain-derived neurotrophic factor (BDNF), its precursor proBDNF, as well as relevant downstream signaling molecules that are known to influence neuronal plasticity and cognition. Multiple cohorts of adult rats were treated with risperidone (2.5 mg/kg/day) or vehicle (dilute acetic acid solution) in their drinking water for 30 or 90 days. Subjects were then evaluated for drug effects on recognition memory in a spontaneous novel object recognition task and protein levels of BDNF-related signaling molecules in the hippocampus and prefrontal cortex. The results indicated that depending on the treatment period, a therapeutically relevant daily dose of risperidone impaired recognition memory and increased the proBDNF/BDNF ratio in the hippocampus and prefrontal cortex. Risperidone treatment also led to a decrease in Akt and CREB phosphorylation in the prefrontal cortex. These results indicate that chronic treatment with a commonly prescribed APD, risperidone, has the potential to adversely affect recognition memory and neurotrophin-related signaling molecules that support synaptic plasticity and cognitive function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The effectiveness of intracranial electroencephalography (iEEG) to inform epilepsy surgery depends on where iEEG electrodes are implanted. This decision is informed by noninvasive recording modalities such as scalp EEG. Herein we propose a framework to interrogate scalp EEG and determine epilepsy lateralization to aid in electrode implantation., Methods: We use eLORETA to map source activities from seizure epochs recorded from scalp EEG and consider 15 regions of interest (ROIs). Functional networks are then constructed using the phase-locking value and studied using a mathematical model. By removing different ROIs from the network and simulating their impact on the network's ability to generate seizures in silico, the framework provides predictions of epilepsy lateralization. We consider 15 individuals from the EPILEPSIAE database and study a total of 62 seizures. Results were assessed by taking into account actual intracranial implantations and surgical outcome., Results: The framework provided potentially useful information regarding epilepsy lateralization in 12 out of the 15 individuals (p=0.02, binomial test)., Conclusions: Our results show promise for the use of this framework to better interrogate scalp EEG to determine epilepsy lateralization., Significance: The framework may aid clinicians in the decision process to define where to implant electrodes for intracranial monitoring., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The term organophosphate (OP) refers to a diverse group of chemicals that are found in hundreds of products worldwide. As pesticides, their most common use, OPs are clearly beneficial for agricultural productivity and the control of deadly vector-borne illnesses. However, as a consequence of their widespread use, OPs are now among the most common synthetic chemicals detected in the environment as well as in animal and human tissues. This is an increasing environmental concern because many OPs are highly toxic and both accidental and intentional exposures to OPs resulting in deleterious health effects have been documented for decades. Some of these deleterious health effects include a variety of long-term neurological and psychiatric disturbances including impairments in attention, memory, and other domains of cognition. Moreover, some chronic illnesses that manifest these symptoms such as Gulf War Illness and Aerotoxic Syndrome have (at least in part) been attributed to OP exposure. In addition to acute acetylcholinesterase inhibition, OPs may affect a number of additional targets that lead to oxidative stress, axonal transport deficits, neuroinflammation, and autoimmunity. Some of these targets could be exploited for therapeutic purposes. The purpose of this review is thus to: 1) describe the important uses of organophosphate (OP)-based compounds worldwide, 2) provide an overview of the various risks and toxicology associated with OP exposure, particularly long-term neurologic and psychiatric symptoms, 3) discuss mechanisms of OP toxicity beyond cholinesterase inhibition, 4) review potential therapeutic strategies to reverse the acute toxicity and long term deleterious effects of OPs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Organophosphates (OPs) are found in hundreds of valuable agricultural, industrial, and commercial compounds; however, they have also been associated with a variety of harmful effects in humans. The acute toxicity of OPs is attributed to the inhibition of the enzyme acetylcholinesterase (AChE); however, this mechanism may not account for all of the deleterious neurologic effects of OPs, especially at doses that produce no overt signs of acute toxicity. In this study, the effects of two weeks of daily subcutaneous exposure to the OP-nerve agent diisopropylfluorophosphate (DFP) in doses ranging from 0.125-0.500 mg/kg on whole brain volume, white matter, and gray matter integrity were evaluated in post mortem tissues using histology and magnetic resonance imaging (MRI) methods. The effects of DFP on axonal transport in the brains of living rats were evaluated using a manganese-enhanced MRI (MEMRI) method. DFP was associated with dose-dependent impairments in red blood cell and brain AChE (down to 29 and 18% of control, respectively at the highest dose), 24 h after the last injection. However, there were no visible signs of cholinergic toxicity noted in any portion of the study. Moreover, histological and MRI analysis of post mortem brains did not reveal any pronounced alterations of whole brain, white matter, or gray matter volumes associated with DFP. Electron microscopy did reveal a DFP-related increase in structural disruptions of myelinated axons (i.e., decompactions) in the fimbria region on the corpus callosum. MEMRI indicated that DFP was also associated with dose-dependent decreases in axonal transport in the brains of living rats, an effect that was also present after a 30-day (DFP-free) washout period, when AChE was not significantly inhibited. These results indicate that repeated exposures to the nerve agent, DFP at doses that are below the threshold for acute toxicity, can result in alterations in myelin structure and persistent decreases in axonal transport in the rodent brain. These observations could explain some of the long-term neurological deficits that have been observed in humans who have been repeatedly exposed to OPs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A sensitive method to simultaneously quantitate quetiapine and norquetiapine in rat plasma and brain tissue was developed using a one-step liquid-liquid extraction for sample preparation and LC-MS/MS for detection. The method provided a linear range of 1.0-500.0ng/mL for each analyte in plasma and 3.0-1500.0ng/g in brain tissue. The method was validated with precision within 15% relative standard deviation (RSD), accuracy within 15% relative error (RE), matrix effects within 10% and a consistent recovery. This method has been successfully applied in a preclinical study of quetiapine and norquetiapine to simultaneously determine their concentrations in rat plasma and brain tissue., (Copyright © 2015 Elsevier B.V. All rights reserved.)

There is considerable evidence that centrally acting α2A adrenergic receptor agonists can attenuate impairments in executive function that result from dysfunction of the prefrontal cortex. Such positive effects resulted in the recent approval by the United States Food and Drug Administration (FDA) of the α2A agonists clonidine and guanfacine for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), but also suggest that they could have beneficial effects in substance abuse disorders and other neuropsychiatric conditions. The purpose of this study was to evaluate guanfacine for its ability to attenuate behavioral alterations associated with acute cocaine exposure in rats trained to perform a task of sustained attention, the five choice serial reaction time task (5C-SRTT) and monkeys trained to perform a task of working/short term memory, the delayed match to sample (DMTS) task. In the rodent 5C-SRTT acute intraperitoneal (i.p.) administration of cocaine (3.5-15.0mg/kg) did not affect accuracy, but was associated with dose-dependent increases in premature responses and timeout responses. Guanfacine (0.1-1.0mg/kgi.p.) dose-dependently decreased premature responses and timeout responses associated with cocaine and it attenuated similar deficits in inhibitory response control observed in a variable ITI version of the 5C-SRTT. In the DMTS task in monkeys, acute intramuscular (i.m.) administration of cocaine (4.0mg/kg) was associated with impairments in accuracy at long delay intervals, an effect that was attenuated by guanfacine (0.4mg/kg). These animal studies suggest that guanfacine may have therapeutic potential for treating impairments of executive function that are associated with the abuse of cocaine., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Rats repeatedly exposed to variable prenatal stress (PNS) exhibit behavioral signs that are similar to those manifested in several neuropsychiatric disorders such as deficits in attention and inhibitory control, and impairments in memory-related task performance. The purpose of the study described here was to conduct a comprehensive battery of tests to further characterize the behavioral phenotype of PNS rats as well as to evaluate the sensitivity of the model to therapeutic interventions (i.e., to compounds previously shown to have therapeutic potential in neuropsychiatric disorders). The results of this study indicated that PNS in rats is associated with: 1) increased locomotor activity and stereotypic behaviors, 2) elevated sensitivity to the psychostimulant amphetamine, 3) increased aggressive behaviors toward both adult and juvenile rats and 4) delay-dependent deficits in recognition memory. There was no evidence that PNS rats exhibited deficits in other areas of motor function/learning, sensorimotor gating, spatial learning and memory, social withdrawal, or anhedonia. In addition, the results revealed that the second generation antipsychotic risperidone attenuated amphetamine-related increases in locomotor activity in PNS rats; however, the effect was not sustained over time. Furthermore, deficits in recognition memory in PNS rats were attenuated by the norepinephrine reuptake inhibitor, atomoxetine, but not by the α7 nicotinic acetylcholine receptor partial agonist, GTS-21. This study supports the supposition that important phenomenological similarities exist between rats exposed to PNS and patients afflicted with neuropsychiatric disorders thus further establishing the face validity of the model for evaluating potential therapeutic interventions., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In this work, we developed a sensitive method to quantify cotinine (COT), norcotinine (NCOT), trans-3'-hydroxycotinine (OHCOT) and cotinine-N-oxide (COTNO) in rat plasma and brain tissue, using solid phase extraction (SPE), hydrophilic interaction liquid chromatography (HILIC) and tandem mass spectrometry (MS/MS). The linear range was 1-100 ng/mL for each analyte in rat plasma and brain homogenate (3-300 ng/g brain tissue). The method was validated with precision within 15% relative standard deviation (RSD) and accuracy within 15% relative error (RE). Stable isotope-labeled internal standards (IS) were used for all the analytes to achieve good reproducibility, minimizing the influence of recovery and matrix effects. This method can be used in future studies to simultaneously determine the concentrations of COT and three major metabolites in rat plasma and brain tissue., (Copyright © 2012 Elsevier B.V. All rights reserved.)

An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as "Mild Cognitive Impairment" (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD and MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy and adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory function., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive impairment and congenital heart defects in the human population. To date, the contribution of microRNAs (miRNAs) in DS has not been investigated. Bioinformatic analyses demonstrate that human chromosome 21 (Hsa21) harbors five miRNA genes; miR-99a, let-7c, miR-125b-2, miR-155, and miR-802. MiRNA expression profiling, miRNA RT-PCR, and miRNA in situ hybridization experiments demonstrate that these miRNAs are overexpressed in fetal brain and heart specimens from individuals with DS when compared with age- and sex-matched controls. We hypothesize that trisomic 21 gene dosage overexpression of Hsa21-derived miRNAs results in the decreased expression of specific target proteins and contribute, in part, to features of the neuronal and cardiac DS phenotype. Importantly, Hsa21-derived miRNAs may provide novel therapeutic targets in the treatment of individuals with DS.

One prerequisite for therapeutic effects of psychiatric drugs is the ability to pass the blood brain barrier. Hence, it is important to know the concentration of antipsychotic drugs in brain tissue. In general, determinations of lipophilic compounds from lipophilic matricies such as the brain are a challenge. Here we have adapted a plasma assay for antipsychotics for the target organ the brain. Using modified sample preparation and chromatographic strategies, the analytes were extracted from rat brain homogenate and analyzed by LC-MS/MS. The method used a Waters Atlantis dC-18 (30 mm x 2.1 mm i.d., 3 microm) column with a mobile phase of acetonitrile/5 mM ammonium formate (pH 6.1 adjusted with formic acid) and gradient elution. All analytes were detected in positive ion mode using multiple-reaction monitoring. The method was validated and the linearity, lower limit of quantitation, precision, accuracy, recoveries, specificity and stability were determined. This method was then successfully used to quantify the rat brain tissue concentration of the analytes after chronic treatment with these antipsychotic drugs.

A significant percentage of psychiatric patients who are treated with antipsychotics are treated with more than one antipsychotic drug in the clinic. Thus, it is advantageous to use a rapid and reliable assay that is suitable for determination of multiple antipsychotic drugs in plasma in a single run. A simple and sensitive HPLC-UV method was developed and validated for simultaneous quantification of olanzapine, haloperidol, chlorpromazine, ziprasidone, risperidone and its active metabolite 9-hydroxyrisperidone in rat plasma using imipramine as an internal standard (I.S.). The analytes were extracted from rat plasma using a single step liquid-liquid acid solution back extraction technique with wash procedure, which provided the very clear baseline for blank plasma extraction. The compounds were separated on an Agilent Eclipse XDB C8 (150 mm x 4.6 mm i.d., 5 microm) column using a mobile phase of acetonitrile/30 mM ammonium acetate including 0.05% triethylamine (pH 5.86 adjusted with acetic acid) with gradient elution. All of the analytes were monitored using UV detection. The method was validated and the linearity, lower limit of quantitation (LLOQ), precision, accuracy, recoveries, selectivity and stability were determined. The LLOQ was 2.0 ng/ml and correlation coefficient (R(2)) values for the linear range of 2.0-500.0 ng/ml were 0.998 or greater for all the analytes. The precision and accuracy for intra-day and inter-day were better than 7.44%. The recovery was above 74.8% for all of the analytes. This validated method has been successfully used to quantify the plasma concentration of the analytes for pharmacological and toxicological studies following chronic treatment with antipsychotic drugs in the rat.

A simple, sensitive and robust liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for quantification of chlorpromazine in rat plasma and brain tissue. Chlorpromazine was extracted from rat plasma and brain homogenate using liquid-liquid extraction. The compounds were separated on a Waters Atlantis dC-18 (30 mm x 2.1 mm i.d., 3 microm) column using a mobile phase of acetonitrile/20 mM ammonium formate (pH 4.25 adjusted with formic acid) with gradient elution. Chlorpromazine was detected in positive ion mode using multiple reaction monitoring (MRM). The method was validated and the specificity, linearity, lower limit of quantitation (LLOQ), precision, accuracy, recoveries and stability were determined. The LLOQ was 0.2 ng/ml for plasma and 0.833 ng/g for brain tissue. The method was linear over the concentration range from 0.2 to 200.0 ng/ml for plasma and from 0.833 to 833.3 ng/g for brain tissue. The correlation coefficient (R(2)) values were more than 0.998 for both plasma and brain homogenate. The precision and accuracy for intra-day and inter-day were better than 7.54%. The relative and absolute recovery was above 84.9% and matrix effects were lower than 5.6%. This validated method has been successfully used to quantify the rat plasma and brain tissue concentration of chlorpromazine after chronic treatment.

Cotinine is a primary metabolite of nicotine that has been suggested in many studies in animals and in humans to exert measurable effects on aspects of on-going behavior or on cognitive function. Much of the interest in cotinine derives from its long pharmacological half-life (15-19 hours) relative to nicotine (2-3 hours). Despite decades of study focusing on nicotine as the predominant behaviorally active component of tobacco, there continue to be aspects of the pharmacology of the drug that have yet to be explained. For example, nicotine can evoke a protracted behavioral response, i.e., in great excess of the presence of the drug in the plasma. Also, there is often a striking differential between the potency for nicotine-induced behavioral responses in humans and animals, and its potency as a cholinergic agonist, neurochemically. One possibility that may explain one or more of these properties of nicotine is the presence of a long-lived bioactive metabolite or breakdown product of nicotine such as cotinine. Preliminary data in support of this hypothesis are consistent with the ability of cotinine to improve performance accuracy on delayed matching task by macaque monkeys, and in reversing apomorphine-induced deficits in prepulse inhibition of acoustic startle in rats. The drug also was shown to be as potent as nicotine in the ability to act as a cytoprotective agent in cells that express a neuronal cholinergic phenotype. This new appreciation for the role of cotinine in nicotine's actions, and as a pharmacological agent in its own right, particularly in aspects of cognitive function and for neuroprotection, ultimately may be applied towards the treatment of Alzheimer's disease and related disorders, and for various psychiatric syndromes.

Objective: The purpose of this study was to evaluate the accuracy of algorithms for the assignment of gestational age with the use of the last menstrual period and early ultrasound information., Study Design: Gestational age estimates that are based on last menstrual period, ultrasound scanning, or their combination were compared among women who attended prenatal care clinics in central North Carolina (n = 3655) by an evaluation of digit preference in the last menstrual period dates and a comparison of mean gestational age, preterm and postterm categories with the use of kappa statistics, difference between actual and expected delivery date, and birth weight among subgroups with discrepant assignments., Results: Last menstrual period reports show digit preference, assign gestation 2.8 days longer on average than ultrasound scanning, yield substantially more postterm births (12.1% vs 3.4%), and predict delivery among term births less accurately. Misclassification of births as postterm was more common in younger women, those of nonoptimal prepregnancy body weight, cigarette smokers, and women who reported last menstrual period using preferred dates of the month., Conclusion: Last menstrual period estimates of the duration of gestation are subject to both random error and a systematic tendency to overstate the duration of gestation, most likely because of delayed ovulation.

Objectives: This study examines human scalp electroencephalographic (EEG) data for evidence of non-linear interdependence between posterior channels. The spectral and phase properties of those epochs of EEG exhibiting non-linear interdependence are studied., Methods: Scalp EEG data was collected from 40 healthy subjects. A technique for the detection of non-linear interdependence was applied to 2.048 s segments of posterior bipolar electrode data. Amplitude-adjusted phase-randomized surrogate data was used to statistically determine which EEG epochs exhibited non-linear interdependence., Results: Statistically significant evidence of non-linear interactions were evident in 2.9% (eyes open) to 4.8% (eyes closed) of the epochs. In the eyes-open recordings, these epochs exhibited a peak in the spectral and cross-spectral density functions at about 10 Hz. Two types of EEG epochs are evident in the eyes-closed recordings; one type exhibits a peak in the spectral density and cross-spectrum at 8 Hz. The other type has increased spectral and cross-spectral power across faster frequencies. Epochs identified as exhibiting non-linear interdependence display a tendency towards phase interdependencies across and between a broad range of frequencies., Conclusions: Non-linear interdependence is detectable in a small number of multichannel EEG epochs, and makes a contribution to the alpha rhythm. Non-linear interdependence produces spatially distributed activity that exhibits phase synchronization between oscillations present at different frequencies. The possible physiological significance of these findings are discussed with reference to the dynamical properties of neural systems and the role of synchronous activity in the neocortex.

Impairment in nerve growth factor (NGF)-mediated support to basal forebrain cholinergic neurons may represent an initial insult to certain neural cells in Alzheimer's disease (AD). High affinity NGF receptor (TrkA) levels are decreased in AD brains as compared to age-matched control brains. One of the approaches suggested for the treatment of AD exploits the ability of small molecular substances to enhance the expression of endogenous growth factors and/or their receptors. The purpose of this study was to determine whether treatment with nicotine in both in vitro and in vivo settings would increase the neural expression of TrkA receptors. Using a differentiated PC12 neuronal-like system, chronic nicotine treatment increased cell surface TrkA receptor expression. Nicotine's action was blocked by co-treatment with either the non-competitive nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine or with the alpha7 nAChR-selective antagonist methyllycaconitine. Surprisingly, certain low doses of mecamylamine alone also increased TrkA receptor levels. Rats prepared with chronic indwelling intravenous catheters were continuously infused with nicotine to deliver a total dose of 12 mg/kg over 24 hr. This treatment resulted in a significant 44% increase in TrkA receptor expression in the hippocampus. As in the cell experiments, mecamylamine also increased hippocampal TrkA receptor expression. In fact, the ratio of the maximal mecamylamine response to the maximal nicotine response that was measured in vitro, i.e., 0.43 was remarkably similar to that for the in vivo experiment, i.e., 0.47. Since in our previous studies the increase in TrkA expression produced by nicotine was shown to be related to its cytoprotective actions, these results suggest that nicotine's neuroprotective actions might also be mediated through the drug's interaction with central alpha7 nAChRs and subsequent increase in TrkA receptor expression.

Celastrus paniculatus (CP), a medicinal plant from India has been reputed to be useful as a pharmaceutical aid for learning and memory. We investigated the effects of the seed oil of CP on the 6 day performance of young adult rats in a navigational memory task-the Morris water maze. Chronic oral (gavage) daily treatment with CP. (50, 200, or 400 mg/kg) for 14 days completely reversed the scopolamine (0.5 mg/kg)-induced task performance deficit. On the other hand, acute treatment (single injection prior to scopolamine treatment) with CP (200 mg/kg) did not significantly reverse the scopolamine-induced impairment in maze performance. Alone, CP produced a slight, but significant improvement in maze performance on the first day of testing. Acute treatment or chronic 14 day treatment with CP resulted in no significant alteration in normal locomotor activity in an open field. Moreover, CP did not alter the scopolamine-induced increases in locomotor activity. Chronic treatment with CP did not alter brain acetylcholinesterase levels and no signs of cholinergic overstimulation were ever noted during or after treatment. Thus, the seed oil of CP, when administered chronically, selectively reversed the impairment in spatial memory produced by acute central muscarinic receptor blockade, supporting the possibility that one or more constituents of the oil may offer cognitive enhancing properties. The neural mechanism underlying the reversal of scopolamine's mnemonic effects by CP is not yet known, but it is not related to an anticholinesterase-like action.

The free radical gas nitric oxide (NO) is formed from the amino acid precursor L-arginine in brain regions which are associated with learning and the formation of memory. We have previously reported that administration of the nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-Name) impairs delayed recall in non-human primates but that, at higher doses, impairment is associated with aversive gastrointestinal side effects. The purpose of the present study was to examine the effects of L-Name on learning in a rat spatial navigation task and to assess the ability of L-Name to induce a conditioned taste aversion (CTA) to a novel sucrose solution in a two-bottle choice paradigm. In the Morris water maze. L-Name (5, 20, and 50 mg/kg) markedly impaired cued spatial learning required to locate a hidden platform on three consecutive days of testing, but did not affect general activity levels. These data also demonstrated the ability of L-Name to induce a potent CTA, though only with the 20 and 50 mg/kg doses. Both the impairment of learning and CTA were blocked by administration of a mole equivalent dose of L-arginine, indicating that attenuated NO activity was associated with both behavioral effects. These data demonstrate that inhibition of NO activity by L-Name induces significant and selective impairment of cognitive performance at low pharmacologic doses (< 20 mg/kg). However, with higher doses of NOS inhibitors, impairment may be a secondary effect of drug-induced malaise, possibly related to peristaltic dysregulation of gastrointestinal musculature. Therefore, conclusions as to the mediation of learning and memory processes by CNS NO may be difficult to interpret without the use of selective, centrally-acting compounds.

The gaseous neuromodulator nitric oxide (NO) is formed in brain regions known to mediate learning and memory processes. In rodent models, pharmacologic inhibition of NO synthesis impairs such processes. In the present study, N omega-nitro-L-arginine methyl ester (L-Name), an inhibitor of the constitutive form of the NO synthetic enzyme, was administered to seven non-aged, mature monkeys (Macaca Fascicularis, Macaca Mulatta, and Macaca Nemestrima) trained to perform a delayed matching-to-sample task (DMTS). L-Name (1.5, 25, and 50 mg/kg) produced marked decrements in task performance, as well as a reduction in the number of trials completed at the highest dose. This impairment of DMTS accuracy by the 50 mg/kg doses of L-Name appears to be associated with an aversive state marked by gastrointestinal disturbance and lethargy. The detrimental effects of the 25 mg/kg dose of L-Name on DMTS accuracy were completely blocked by concurrent administration of a mole-equivalent dose of the NO amino acid precursor L-arginine. As a whole, these data suggest that L-Name impairs processes involved in delayed recall in monkeys and that this impairment is associated with attenuated synthesis of NO. However, at higher doses (> or = 25 mg/kg) this impairment is associated with aversive effects of L-Name, possibly at both central and peripheral sites.

Previous studies have suggested that nicotine may have beneficial actions in neurodegenerative disease models. The purpose of the experiments described in this study was to determine whether the long lasting and beneficial effects of nicotine observed previously could be expressed through actions upon nerve growth factor (NGF) receptors. Using a differentiated PC-12 neuronal cell model, we have detected an increase in expression of cell surface NGF receptor protein after acute exposure to nicotine in the micromolar range. In addition, we have also observed a persistent effect upon NGF receptor expression which lasted even after nicotine (nanomolar range) was removed from the tissue culture medium. This increase in cell surface NGF receptor protein was blocked in the presence of mecamylamine, indicating that this effect is likely nicotinic receptor mediated. These results are consistent with the hypothesis that the lasting and beneficial actions of nicotine previously observed in vivo may involve an indirect effect upon the level of neuronal cell surface NGF receptor expression. Our observations offer one possible mechanism for a potential neurotrophic effect of nicotine.

The basis for the memory enhancing action of nicotine was evaluated in five adult monkeys (Macaca fascicularis) well trained in the performance of a delayed matching-to-sample (DMTS) paradigm. Nicotine (1.25-20 micrograms/kg, IM) produced a dose-dependent improvement in performance of the task. The optimal dose of nicotine for each monkey also improved performance when the animals were tested 24 h later in the no-drug situation. In the same animals, low doses of scopolamine produced a dose-dependent decrement in DMTS performance. A subthreshold dose (defined by DMTS performance decrement) of scopolamine was administered 20 min prior to the optimal dose of nicotine. Scopolamine pretreatment completely blocked the enhanced performance observed earlier with nicotine. The results of this study are consistent with the hypothesis that the enhanced cognitive performance associated with nicotine is due to central acetylcholine release and subsequent muscarinic receptor stimulation.

Physostigmine and other centrally-acting acetylcholinesterase inhibitors are currently being examined for their potential in the treatment of Alzheimer's Disease. The ability to employ this class of agents is limited by the potential for debilitating and dangerous side effects. Clonidine and related drugs have recently been demonstrated to enhance memory performance in monkeys. Clonidine also inhibits the function of cholinergic neurons in specific brain regions and reduces certain side effects of physostigmine. Seven adult macaque monkeys performing a delayed matching-to-sample (DMTS) task received regimens of increasing doses of clonidine and physostigmine on separate occasions to determine the 'best dose' of each agent in terms of enhanced memory performance. The best doses were combined as a single administration and performance compared to that using the two drugs alone. The combination regimen of clonidine and physostigmine was more effective than either drug alone in enhancing memory performance. Part of the benefit may have been due to the ability to employ significantly higher doses of physostigmine in the combination regimen. A single injection of the combination resulted in enhanced performance both on the day of administration as well as on the following day. These results are consistent with the ability of clonidine to limit the expression or intensity of certain physostigmine-induced autonomic side effects, while allowing the cognitive beneficial effects of the cholinesterase inhibitor.