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New Approaches and Agents for Old Memory Reconsolidation

#2368


Study of Memory Consolidation and Reconsolidation Mechanisms and Focused Search for Novel Agents that Can Stimulate these Processes in Normal Aging and in Neurodegenerative Disorders

Tech Area / Field

  • MED-DRG/Drug Discovery/Medicine
  • MED-OTH/Other/Medicine

Status
8 Project completed

Registration date
03.12.2001

Completion date
20.06.2008

Senior Project Manager
Endrullat B

Leading Institute
Institute of Physiologically Active Substances, Russia, Moscow reg., Chernogolovka

Supporting institutes

  • Anokhin Institute of Normal Physiology, Russia, Moscow

Collaborators

  • Open University, UK, Walton Hall\nUniversity of Illinois, USA, IL, Chicago\nGerontology Research Center, USA, MD, Baltimore\nUtrecht University, The Netherlands, Utrecht\nForschungsinstitut Angewandte Neurowissenschaften gGmbH, Germany, Magdeburg\nSt Elizabeth's Medical Center / Department of Psychiatry, USA, MA, Boston

Project summary

Memory impairments and decrease of cognitive functions are common features of aging and various age-related neurodegenerative disorders, in particular, Alzheimer’s disease (AD). All existing cognitive enhancers, i.e., compounds that improve memory, have a significant limitation. They can act on memory only at the time of its acquisition. These drugs cannot restore old memory, which is impared due to aging or neurodegenerative disorders.

The studies within a framework of the present project are based on the discovery of new neurochemical properties of reactivated old memory that make it sensitive to pharmacological regulation found recently by a group of the project authors [Anokhin et al., 2001]. In particular, it was found that modulators of glutamate receptors and drugs, affecting protein synthesis in CNS, can be considered among such compounds [Litvin and Anokhin, 1998; Litvin and Anokhin, 2000]. In relation the development of drugs affecting the glutamate receptors, in particular agonists and positive modulators of NMDA and AMPA receptors (in particular, so-called “ampakines”), can be considered to be one of the most important strategies.

The goals of the current project are: (1) to investigate mechanisms and conditions that allow to transform old memory into the labile form in which it becomes sensitive to pharmacological regulation and (2) to search for novel synthetic compounds that can affect this process. Accomplishment of these goals will result in identification of memory forms sensitive to pharmacological modulation at their retrieval and will eventually lead to development of a new generation of cognitive enhancers based on cellular mechanisms of long-term memory consolidation and reconsolidation. These compounds should be able to improve new and old memories weakened due to natural aging and neurodegenerative disorders, in particular, AD.

The project will be based on complementary experience and previous results obtained by two main participants of the project – Institute of Physiologically Active Compounds of the Russian Academy of Sciences (IPAC) and Anokhin Institute of Normal Physiology of the Russian Academy of Medical Sciences (AINP).

The AINP group, as mentioned before, has made the initial finding on the sensitivity of reactivated memory to protein synthesis and NMDA receptor modulation, which establishes the background for the present project. Large experience of this group in studies of molecular mechanisms of long-term memory consolidation, experimental animal models of learning and memory used in the group and techniques of long-term memory reactivation developed by this group, will be exploited in the current project. In addition, the system for 3-D analysys of gene expression patterns in the brain, developed by this group will be used for the study of molecular bases of long-term memory modulation by the synthetized compounds in a current project.

The IPAC research team was actively engaged during the last ten years in the pursuit and investigation of novel cognitive enhancers synthesized on the basis of ligands of the glutamatergic system. This search was performed within different classes of compounds. In particular, a novel group of compounds that potentiate activity of AMPA receptors and thus exhibit ampakines-like properties were synthesized by this group. These compounds were found to have pronounced cognition-enhancing properties. Quantitative structure-activity relationships that determine interaction of these compounds with NMDA receptors were analyzed [Bachurin S. et al., 2001]. Original approaches of primary screening for directed selection and properties of the novel compounds were developed, based on estimation of the glutamate-induced 45Ca2+ uptake along with the detailed analysis of their cognition-enhancing properties in neurotoxicological models of AD-type dementia. A new image analysis system with original software was developed for the latter studies [Mukhina T. V., Bachurin S. O. Automated computerized system Behavioral Vision (BVision). Russian certificate for registration of the software for PC, No. 2000610678; Mukhina T. et al., Behav Res. Methods Instrum. Comput., 2001, v. 33, №3, P:371-80.].

The project will be carried out according to the following scheme:

1. Synthesis of potential agonists and positive modulators of the glutamate (NMDA, AMPA and metabotropic) receptors based on the structural analogs of already established activators of the glutamatergic synaptic transmission.

2. Screening, selection and investigation of the most plausible positive modulators of glutamate receptors in in vitro systems.

3. Establishment of conditions for effective pharmacological regulation of reactivated old memory.

4. Study of the effects of novel compounds on long-term memory and molecular mechanisms of its consolidation and reconsolidation.

5. Investigation of cognition-enhancing properties of the selected compounds in in vivo neurotoxicological models of dementia and amnesia.

The following results are expected to be obtained in the current project:

Stage I (1st year, 12 months). The goal of this stage will be to determine a duration of pharmacological sensitivity of old reactivated memory to the drugs affecting glutamate (AMPA or NMDA) receptors and protein synthesis in brain after learning. Comparison of this duration with the overall duration of memory storage will result in an estimation of a time interval for effective pharmacological modulation of stable consolidated memory. Synthesis of a series of potential positive modulators of AMPA receptors (i.e., ampakines) will be also carried out during this stage, followed by characterization of their effect on CNS ionotropic glutamate receptors in in vitro models. These experiments will result in selection of 2 or 3 prospective compounds. The effects of these compounds on both new and reactivated old memory (i.e., processes of memory consolidation and reconsolidation) as well as their cognition-enhancing properties in the neurotoxicological AD model will be tested.

Stage II (2nd year, 12 months). Directed search for potential ampakines followed by synthesis of about 30 new compounds will be performed, using the results obtained at the first stage. Novel potential activators of NMDA receptors in a series of modulators of their redox site will be synthesized as well. Effect of all the synthesized compounds (about 50 structures) on the ionotropic glutamate receptors will be estimated in different in vitro models. These phase will result in selection of 4 or 5 prospective compounds which will be studied to establish their possible effect on both new and reactivated old memories (i.e., on memory consolidation and reconsolidation) along with cognition-enhancing properties in the neurotoxicological AD model.

Stage III (3rd year, 12 months). The results obtained during two previous stages of the project will be analyzed using QSAR approaches to optimize active structures in the series of ampakines and redox modulators of NMDA receptors. This analysis will result in synthesis of 3-5 prospective compounds followed by their examination in in vitro and in vivo models. The newly synthesized and model compounds having the highest potential in enhancing old and new memory will be characterized in terms of the neural sites of their effects on memory formation by studying their influence on learning-induced expression of transcription factors (c-fos, egr-1, pCREB) that serve as molecular markers of long-term neuronal plasticity. These experiments will allow to select the compounds producing the highest memory potentiation effects at a cellular level and will reveal their neuroanathomic targets in the CNS. Memory-enhancing properties of these compounds will be examined in models of several forms of learning and memory in order to make primary estimation of their potential therapeutical spectrum.

The most promising compounds developed during the project will be patented as novel drugs for improvement and recovery of weakened or impaired memory.

According to the ISTC's objectives, accomplishment of this project will promote integration of the Russian weapons scientists into international scientific community to solve important problem of international medicine, namely - treatment of age pathologies and improvement of the quality of life.


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