Treatment Of Cognitive Disorders Research Articles

Anti-amnesic potentials of a novel phytochemical formulation PZA-3 in animal models relevant to Alzheimer's disease

Event Abstract Back to Event Anti-amnesic potentials of a novel phytochemical formulation PZA-3 in animal models relevant to Alzheimer's disease Joshi Hanumanthachar1* and C. Disale1 1 SET’s College of Pharmacy, India Background: Dementia is one of the age related mental problems and a characteristic symptom of Alzheimer’s disease. There has been a steady rise in the number of patients suffering from Alzheimer’s disease (AD) all over the world. It is the most common form of onset of adult dementia and attention deficit disorders. Newer drugs are continually introduced into the market with little efficacy. Hence it is worthwhile to explore the utility of traditional medicines in treatment of cognitive disorders. The Indian system of medicine, Ayurveda has been in practice since 5000 years. Objective: The main goal of the studies reported here is to investigate the cerebro-protective and memory improving potentials of phytochemicals based formulation PZA-3. Methods: β-amyloid, scopolamine, ibotenic acid, CO2 and aging induced amnesia, KCN and Carotid artery ligation-induced hypoxia were the experimental models. Basal forebrain lesion induced decrease in cerebral Ach and ChAT activity were assessed, Concentrations of Norepinerphrine, Epinephrine, Dopamine, 5-HT in cerebral cortex, cerebellum, hypothalamus, hippocampus, and corpus striatum were measured by HPLC analysis. Neuromorphology, contents of MDA, NO, activities of SOA and CAT were also measured which indicated that PZA-3 protected the animals from stress, amnesia and neurodegeneration. Results and Discussion: They inhibited KCN and Carotid artery ligation induced hypoxia, reversed amnesia and neurodegeneration and produced normalizing action on discrete regions of brain and controlled alterations in neurotransmitter levels due to neurodegeneration. They also decreased ChAT activity in the parietal cortex and inhibited decrease in Ach levels in both parietal and frontal cortex in amnesic rats. Hence PZA-3 can be of enormous use in the treatment of dementia of Alzheimer’s type and other neurodegenerative disorders. Conference: 10th International Conference on Cognitive Neuroscience, Bodrum, Türkiye, 1 Sep - 5 Sep, 2008. Presentation Type: Poster Presentation Topic: Animal Models of Cognition Citation: Hanumanthachar J and Disale C (2008). Anti-amnesic potentials of a novel phytochemical formulation PZA-3 in animal models relevant to Alzheimer's disease. Conference Abstract: 10th International Conference on Cognitive Neuroscience. doi: 10.3389/conf.neuro.09.2009.01.077 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 01 Dec 2008; Published Online: 01 Dec 2008. * Correspondence: Joshi Hanumanthachar, SET’s College of Pharmacy, Karnataka, India, amanjoshi17@yahoo.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Joshi Hanumanthachar C. Disale Google Joshi Hanumanthachar C. Disale Google Scholar Joshi Hanumanthachar C. Disale PubMed Joshi Hanumanthachar C. Disale Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Novel dipyrazoles acting as glutamate modulators

Knowing the potential therapeutic interest of AMPA potentiation, patents have been published for 15 years relating the discovery of novel compounds able to allosterically bind to the AMPA receptors and leading to a potentiation of the AMPA signals. Besides this classical approach, a new target for the medicinal chemist has been defined due to the recent findings describing the modulation of AMPA receptors by neuronal proteins, and has led to the design of dipyrazole compounds by Aventis. These new dipyrazole derivatives may be considered as ‘indirect AMPApams’, constituting a new pharmacological class. Based on their in vitro activity, it is probable that these compounds could be of therapeutic value for the treatment of cognitive disorders, schizophrenia or depression.

‘I think therefore I am’: improving cognition

In the absence of a specific treatment for dementia, the effective management of cognitive symptoms is a clinical priority. Although some differences have been observed in the profile of cognitive complaints observed in subtypes of dementia, there is increasing recognition of common, interacting neurobiological causes suggesting the need to seek a common treatment applicable to all causes of cognitive deterioration. There also exists increasing interest in intervening at the level of minor cognitive dysfunction by reducing risk factors for subclinical states. Pharmacological treatment of cognitive disorder is beneficial but has only temporary benefit for a subgroup of patients. Pharmacogenetics may have an important future role to play in deciding which patients may best benefit from the treatment. Low side effect therapies such as cognitive therapy and acupuncture show some benefits but their utility in combination with pharmacotherapies remains to be demonstrated. Prevention of milder forms of cognitive disorder by controlling risk factors such as hypertension and diabetes may reduce rates of more severe cognitive degeneration. Persons with cognitive dysfunction are commonly excluded from making decisions about the implementation of cognition-enhancing treatments although they wish to do so.

Opposing effects of AMPA and 5-HT 1A receptor blockade on passive avoidance and object recognition performance: Correlation with AMPA receptor subunit expression in rat hippocampus

It has been suggested that antagonists at serotonin 5-HT 1A receptors may exert a procognitive effect by facilitating glutamatergic neurotransmission. Here we further explored this issue by looking for the ability of a 5-HT 1A antagonist to prevent the learning deficit induced by AMPA receptor blockade in two behavioural procedures in rats, and for concomitant molecular changes presumably involved in memory formation in the hippocampus. Pretraining administration of the competitive AMPA receptor antagonist, NBQX, produced a dose-related retention impairment in a passive avoidance task 24 h later, and also impaired retention in a novel object recognition test when an intertrial interval of 3 h was selected. Pretreatment with the selective 5-HT 1A receptor antagonist, WAY-100635, prevented the learning deficit induced by NBQX in the two behavioural procedures. In biochemical studies performed on rat hippocampus after the retention tests, we found that learning increased the membrane levels of AMPA receptor GluR1 and GluR2/3 subunits, as well as the phosphorylated forms of GluR1, effects that were abolished by NBQX administration before the training session. Pretreatment with WAY-100635 counteracted the NBQX effects and restored the initial learning-specific increase in Ca 2+/calmodulin-dependent protein kinase II (CaMKII) function and the later increase in GluR2/3 and phosphorylated GluR1 surface expression. Moreover, administration of WAY-100635 before object recognition training improved recognition memory 24 h later and potentiated the learning-associated increase in AMPA receptor subunits. The results support the proposed utility of 5-HT 1A antagonists in the treatment of cognitive disorders.

The use of herbal medicine in Alzheimer's disease-a systematic review.

The treatments of choice in Alzheimer's disease (AD) are cholinesterase inhibitors and NMDA-receptor antagonists, although doubts remain about the therapeutic effectiveness of these drugs. Herbal medicine products have been used in the treatment of Behavioral and Psychological Symptoms of Dementia (BPSD) but with various responses. The objective of this article was to review evidences from controlled studies in order to determine whether herbs can be useful in the treatment of cognitive disorders in the elderly. Randomized controlled studies assessing AD in individuals older than 65 years were identified through searches of MEDLINE, LILACS, Cochrane Library, dissertation (USA), ADEAR (Alzheimer's Disease Clinical Trials Database), National Research Register, Current Controlled trials, Centerwatch Trials Database and PsychINFO Journal Articles. The search combined the terms Alzheimer disease, dementia, cognition disorders, Herbal, Phytotherapy. The crossover results were evaluated by the Jadad's measurement scale. The systematic review identified two herbs and herbal formulations with therapeutic effects for the treatment of AD: Melissa officinalis, Salvia officinalis and Yi-Gan San and BDW (Ba Wei Di Huang Wan). Ginkgo biloba was identified in a meta-analysis study. All five herbs are useful for cognitive impairment of AD. M. officinalis and Yi-Gan San are also useful in agitation, for they have sedative effects. These herbs and formulations have demonstrated good therapeutic effectiveness but these results need to be compared with those of traditional drugs. Further large multicenter studies should be conducted in order to test the cost-effectiveness of these herbs for AD and the impact in the control of cognitive deterioration.

Low dose citalopram reverses memory impairment and electroconvulsive shock-induced immobilization

Citalopram, a selective serotonin reuptake inhibitor (SSRI), is one of the most widely used antidepressants. Recently, citalopram has been reported to improve working memory in patients with depression, and psychotic symptoms and behavioral disturbances in patients with dementia. However, the possibility of using citalopram in the treatment of cognitive disorders has not received much attention. The present study investigated the effects of citalopram on scopolamine- and Δ 9-tetrahydrocannabinol (THC)-induced impairment of spatial memory using an eight-arm radial maze and electroconvulsive shock (ECS)-induced immobilization (a behavioral model for the disturbance of consciousness). Low dose citalopram reversed both scopolamine- and THC-induced impairment of spatial memory, suppressed ECS-induced immobilization reversed the THC-induced decrease of acetylcholine (ACh) release in the dorsal hippocampus in vivo microdialysis, and enhanced tremors induced by oxotremorine, a muscarinic M 1 receptor agonist. Taken together these findings suggest that low dose citalopram is useful for the treatment of memory deficits and consciousness disturbance.

Gene targeting of presynaptic proteins in synaptic plasticity and memory: Across the great divide

The past few decades have seen an explosion in our understanding of the molecular basis of learning and memory. The majority of these studies in mammals focused on post-synaptic signal transduction cascades involved in post-synaptic long-lasting plasticity. Until recently, relatively little work examined the role of presynaptic proteins in learning and memory in complex systems. The synaptic cleft figuratively represents a “great divide” between our knowledge of post- versus presynaptic involvement in learning and memory. While great strides have been made in our understanding of presynaptic proteins, we know very little of how presynaptically expressed forms of short- and long-term plasticity participate in information processing and storage. The paucity of cognitive behavioral research in the area of presynaptic proteins, however, is in stark contrast to the plethora of information concerning presynaptic protein involvement in neurotransmitter release, in modulation of release, and in both short- and long-term forms of presynaptic plasticity. It is now of great interest to begin to link the extensive literature on presynaptic proteins and presynaptic plasticity to cognitive behavior. In the future there is great promise with these approaches for identifying new targets in the treatment of cognitive disorders. This review article briefly surveys current knowledge on the role of presynaptic proteins in learning and memory in mammals and suggests future directions in learning and memory research on the presynaptic rim of the “great divide.”

Serotonin 5‐HT1A receptor blockade enhances Ca2+/calmodulin‐dependent protein kinase II function and membrane expression of AMPA receptor subunits in the rat hippocampus: implications for memory formation

Stimulation of hippocampal 5-HT(1A) receptors impairs memory retention. The highly selective 5-HT(1A) antagonist, WAY-100635, prevents the cognitive deficits induced not only by 5-HT(1A) stimulation but also by cholinergic or NMDA receptor blockade. On this basis, the effects of WAY-100635 on molecular events associated with memory storage were explored. In rat hippocampus, WAY-100635 produced a rapid increase in phosphorylated Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and in Ca(2+)-independent CaMKII and protein kinase A (PKA) enzyme activity. This increase was followed a few hours later by an enhanced membrane expression of AMPA receptor subunits, especially of the GluR1 subunit phosphorylated at the CaMKII site, pGluR1(Ser831). The same qualitative effects were found with the weaker 5-HT(1A) antagonist NAN-190. The effects of both antagonists were no longer apparent in rats with a previous 5-HT depletion induced by the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA), suggesting that 5-HT(1A) receptor blockade removes the tonic inhibition of 5-HT through 5-HT(1A) receptor stimulation on excitatory hippocampal neurons, with the consequent increase in PKA activity. In addition, administration of WAY-100635 potentiated the learning-specific increase in the hippocampus of phospho-CaMKII, Ca(2+)-independent CaMKII activity, as well as the phosphorylation of either the CaMKII or the PKA site on the AMPA receptor GluR1 subunit. This study suggests that blockade of hippocampal 5-HT(1A) receptors favours molecular events critically involved in memory formation, and provides an in vivo molecular basis for the proposed utility of 5-HT(1A) receptor antagonists in the treatment of cognitive disorders.

Effort and cognition in schizophrenia patients

Objective The aim of this study was to determine whether low cognitive test scores in schizophrenia patients are due to insufficient effort and, if so, to what extent. Method Mental effort was measured with the Word Memory Test (WMT), an effort test that has been extensively validated. Schizophrenic patients ( n = 64), non-psychotic psychiatric patients ( n = 63), neurological controls ( n = 20), and normal controls ( n = 44) were tested with a neuropsychological test battery measuring memory, attention and executive functioning. Results The majority of the schizophrenia patients and a quarter of the psychiatric patients scored below the cut-offs for normal effort on the WMT. Scores on the effort test explained a significant amount of variance in the neuropsychological test performance of schizophrenic patients. This lends support to the notion that cognitive functioning in schizophrenia is compromised by insufficient effort. Furthermore, poor mental effort was related to negative symptoms. Conclusions Poor mental effort might be considered a core symptom of schizophrenia, representing an executive, monitoring or motivational problem. Mental effort should be taken into consideration in the neuropsychological assessment of schizophrenic patients and of psychiatric patients in general. Controlling for this variable may have a considerable impact on research, assessment and treatment of cognitive disorders in schizophrenic patients.

Magnitude of effect and special approach to Ginkgo biloba extract EGb 761 in cognitive disorders.

In the early 70's, improvements in methodical procedures of extraction and standardization of ginkgo preparation allowed the production of a highly concentrated and stable extract (EGb 761) (definition see editorial) by the company Dr. Willmar Schwabe, which could be systematically tested in scientific programs. Consequently, numerous studies have been undertaken and provided replicable outcomes to demonstrate its efficacy in human population. EGb 761 is currently registered as an ethical drug in more than 50 countries around the world, and is prescribed for a range of neurological and vascular disorders including dementia, arterial occlusive disease, retinal deficit, and tinnitus. The following chapter will focus on the relevant data that support EGb 761 efficacy in the treatment of cognitive disorders in general, and dementia in particular. Besides the published data, the author will provide original results unveiling different factors that could interfere with EGb 761 efficacy and may be the source of the variations observed among studies in the EGb 761 literature. In the author's opinion, such factors should be taken into consideration when implementing the design of future research and optimizing individual EGb 761 response in the clinical practice. Within the framework of this new approach, the author will not only answer the question as to whether EGb 761 works over placebo in cognitive disorders, but also attempt to estimate how well it works in particular conditions.

6,7-Dihydro-2-benzothiophen-4(5H)-ones: a novel class of GABA-A alpha5 receptor inverse agonists.

Nonselective inverse agonists at the benzodiazepine binding site on the GABA-A chloride ion channel enhance cognitive performance in animals but cannot be used in the treatment of cognitive disorders because of anxiogenic and convulsant side effects. We have identified a novel series of GABA-A alpha5 receptor ligands during our search for alpha5 receptor inverse agonists as potential cognition enhancers. In particular, 6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (26) has been identified as a functionally selective GABA-A alpha5 inverse agonist.

Effect of the calcium channel blockers nifedipine and diltiazem on pentylenetetrazole kindling-provoked amnesia in rats

A large body of research supports the view that memory disturbance is an integral part of epilepsy. Deficit in various behaviour tasks has been found in rats subjected to experimental epilepsy–pentylenetetrazole (PTZ) kindling. In the present study we examined the effect of post-training administered calcium channel blockers nifedipine (10 and 40 mg/kg) and diltiazem (10 and 30 mg/kg) on amnesia induced by PTZ kindling in shuttle-box- and step-down-trained rats. Retention in nifedipine- or diltiazem-treated kindled animals was significantly improved compared to the kindled controls. The mechanisms of action of calcium antagonists studied is considered. Taken together with the data about calcium channel blocker anticonvulsive activity, the results of this study further suggest that nifedipine and diltiazem might be useful in the treatment of cognitive disorders in epileptic patients.

Future trends in the treatment of cognitive disorders.

This review provides an overview of the different types of cognitive disorders, with special emphasis on the description on Alzheimer's disease, as statistical data indicate that it is the major cause of dementia or cognitive decline. The factors responsible for biochemical changes at the cellular level and the different therapies available for the treatment of cognitive disorders are described. Recent advances, including the elucidation of biochemical changes at the molecular level and different approaches to treat the disease, are also briefly reviewed. (c) 2001 Prous Science. All rights reserved.

Effect of the neurotoxin MPTP on behavior and cerebral content of neurotransmitters in mice

We compared the effects of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) on exploratory behavior and conditioning in C57B1 and outbred animals. Two intraperitoneal injections of MPTP suppressed the orienting and exploratory behavior in C57B1 (reductions of both horizontal and vertical motor activity), but not in outbred mice, and impaired conditioning. The data indicate the dopaminergic nature of learning disturbances and suggest that the MPTP model may hold a lot of promise for the search for new drugs for the treatment of cognitive disorders in Parkinsonism.

Emerging Drugs: The Prospect for Improved Medicines (Vol. 3)

The third Annual Executive Briefing on emerging drugs offers an elaborative overview of drugs currently emerging from pharmaceutical pipelines. It consists of 25 reviews that cover the development of future drugs within a wide range of therapeutic areas. They are written by a variety of scientists who are all actively engaged in selected areas of interest within R&D departments of pharmaceutical industries. These areas, among others, include pain, stroke, cardiovascular disease, cancers, incontinence, thromboses and atheroscleroses. All reviews adhere to one unitary format which covers short background information, existing treatments, the scientific rationale for new drugs, medical need for new drugs, current research goals and a highlight of compounds currently in development. Furthermore, each review concludes with an editorial analysis of the prospects for improved medicines in the particular areas of interest.One drawback of this exploratory book is inherently related to its purpose, that is to reflect innovative drug research within a very broad range of scientific disciplines. The individual reader might therefore find only a few of the reviews directly relevant to their everyday professional activities. However, the book also contains several chapters that will appeal to most people's interests. For example, the review of cannabinoid pharmacology provides an exiting update on the anatomical distribution of the two subtypes of cannabinoid receptors CB1 and CB2 in both central and peripheral nervous systems, and their involvement in physiological functions such as analgesia, cognition, memory, locomotor activity, control of appetite and vomiting, and regulation of the inflammatory and immune responses. Existing cannabinoid receptor agonists and antagonists already appear to have promising therapeutic effects, many of which will lead undoubtedly to the emergence of new useful drugs. Today, cannabinoid pharmacology is one of the most promising examples of innovative research in the pharmaceutical industry that could lead to improved medicines for the treatment of a range of psychiatric, neurological and immune-related disorders.Other examples of new interesting chemical entities with novel specific actions in animals or man or both are being reviewed. The single element that seems to underpin them all is the search for therapeutic superiority. The reason is, of course, that the R&D-based industry will not be able to market its new products unless they provide worthwhile advantages over existing treatments. Yet that same goal might also be attained by the development of medicines with an improved safety profile. Though less practised, such an approach might certainly result in promising drugs as well. For example, the therapeutic utility of either activating or antagonizing muscarinic receptors has long been recognized, but the clinical use of existing compounds is limited by their central and peripheral side-effects, e.g. drowsiness, amnesia, confusion, mydriasis, dry mouth and cycloplegia. Because these effects usually emanate from a lack of subtype discrimination, a concerted effort is underway to identify selective muscarinic acetylcholine receptor agonists and antagonists. One review describes how this has led to the development of functionally selective M1 receptor agonists for the treatment of cognitive disorders, and to some challenging selective M2 and M3 receptor antagonists for the treatment of smooth muscle function.Generally, this is an informative book which achieves its objectives. It is a thorough, open and fair account of current trends in drug development, which, in addition to researchers and marketing people from pharmaceutical industries, should also appeal to academic researchers in their particular fields of interest.

Physiological, Pathophysiological and Therapeutic Roles of 5-HT Systems in Learning and Memory

Multiple 5-hydroxytryptamine (5-HT) receptors have been identified (5-HT1A/1B/1D/1E/1F, 5-HT2A/2B/2C, 5-HT3A/3B, 5-HT4A/4B, 5-HT5A/5B, 5-HT6 and 5-HT7A/7B/7C/7D) and extensive evidence suggests that 5-HT receptors have a role in learning and memory. Indeed, available evidence strongly supports physiological, pathophysiological and therapeutic roles of 5-HT systems in cognitive processes, although the evidence seems incomplete. Indeed, there has been a clear tendency to use pre-learning administration most frequently, whereas post-learning and pre-retention administration protocols have been utilized in only a few studies, and probably this trend has led to missed relevant information. For instance, when pre- vs post-training administration of 5-HT1A agonist, 5-HT2 antagonists and 5-HT4 agonists have been compared contrasting findings were reported in aversive and appetitive learning tasks. Emerging evidence also indicates that 5-HT1A and 5-HT4 receptor agonists, as well as, 5-HT1A antagonists, 5-HT2 antagonists, 5-HT3 antagonists and 5-HT uptake inhibitors may have therapeutic utility in the treatment of Alzheimer's disease and amnesia. Inasmuch as the activation or blockade of diverse 5-HT receptors is able to modulate cognitive processes, and 5-HT uptake inhibition could have therapeutic applications in the treatment of cognitive disorders, it seems evident that the role of 5-HT in learning and memory is more complex than a simple imbalance. Consequently, the notion that activation of the 5-HT systems impairs performance, whereas reduced serotonergic function may facilitate learning, must be reconsidered.

Effects of F lunarizine and Nitrendipine on Electroconvulsive Shock- and Clonidine-Induced Amnesia

This study was designed to examine the calcium channel blockers flunarizine and nitrendipine for their ability to prevent electroconvulsive shock (ECS)- or clonidine-induced deterioration of the inhibitory avoidance performance (step-down) in rats. Flunarizine (10 mg/kg) and nitrendipine (40 mg/kg) were found to prevent the ECS- or clonidine-provoked amnesia after oral administration for 12 days. The mechanisms of action of the two drugs are considered. The results of this study further suggest that calcium antagonists might be useful in the treatment of cognitive disorders.

Protein kinase C in synaptic plasticity: a molecular target in the treatment of cognitive disorders.

Protein kinase C in synaptic plasticity: a molecular target in the treatment of cognitive disorders.

Structure-activity studies on 2-methyl-3-(2(S)-pyrrolidinylmethoxy) pyridine (ABT-089): an orally bioavailable 3-pyridyl ether nicotinic acetylcholine receptor ligand with cognition-enhancing properties.

2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAChR) ligands, shows positive effects in rodent and primate models of cognitive enhancement and a rodent model of anxiolytic activity and possesses a reduced propensity to activate peripheral ganglionic type receptors. The profiles of S-4, its N-methyl analogue, and the corresponding enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro metabolism and in vivo bioavailability data. On the basis of its biological activities and favorable oral bioavailability, S-4 is an attractive candidate for further evaluation as a treatment for cognitive disorders.

Applications of Dynamic Susceptibility Contrast Magnetic Resonance Imaging in Neuropsychiatry

Functional neuroimaging has assumed an important role in the cognitive and clinical neurosciences. Recently, substantial progress has been made toward developing functional magnetic resonance imaging techniques for the examination of cerebral hemodynamic changes that accompany brain function and toward earlier and better diagnosis of brain disease. Dynamic susceptibility contrast (DSC) MRI offers unique information about cerebral hemodynamics both at rest and in response to brain activation. We review the clinical applications of DSC MRI and present our experience with this modality in the evaluation of patients with neuropsychiatric disorders. Our experience suggests that DSC MRI may afford new insights into the diagnosis and treatment of cognitive disorders.