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Lithium-Containing Peptides

#A-1734


The Synthesis and Study of New Lithium-Containing Peptides on Experimental Model of Bipolar Disorder

Tech Area / Field

  • BIO-CHM/Biochemistry/Biotechnology

Status
3 Approved without Funding

Registration date
31.03.2009

Leading Institute
Institute of Biochemistry, Armenia, Yerevan

Collaborators

  • Pacific Northwest National Laboratory, USA, WA, Richland\nUniversitätsklinikum Tübingen / Abteilung Klinische Pharmakologie, Germany, Tübingen\nUniversite de Nantes / Laboratoire de Biotechnologie, France, Nantes

Project summary

Bipolar disorder (BD) is a serious pathology of infringement of the brain function under chronic condition inducing development of various mental displays dangerous to life. Over one percent of the world population suffers of that disorder. The treatment of this pathology is connected with application of various preparations, among which in the past 15 years univalent cation lithium is included. Studies of biological action of lithium at a molecular-cellular level showed its inhibiting action on enzymes of signal transduction system as glycogen synthase kinase-3 and neurotrophic signaling cascades, inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3, fructose 1,6-bisphosphatase, bisphosphate nucleotides, and phosphoglucomutase enzymes. It has been shown lithium’s intracellular downstream targets including adenylate cyclase, the phosphoinositol cascade (and its effect on protein kinase C), arachidonic acid metabolism, and effects on neurotrophic cascades. Many of the new insights of lithium actions may lead to the strategic development of improved therapeutics for the treatment of BD. A number of studies show that the outcome for a high percentage of patients is poor, with a high rate of chronic, residual symptoms, relapse, cognitive and functional impairment, and psychosocial disability. In addition to the tremendous economic cost, suicide is estimated to be the cause of death in 10–20% of the inpiduals with BD, and increasingly, mood disorders are associated with many other health-related consequences. The discovery of lithium efficacy as an antimanic agent over fifty years ago revolutionized the treatment of patients with BD. The remarkable efficacy of lithium has served to spark a revolution that has, over time, reshaped not only medical and scientific but also popular concepts of severe mental illnesses. Indeed, the efforts to understand how a simple monovalent cation like lithium can exert such profound beneficial effects has led the investigators to examine the signal transduction pathways involved in BD. After nearly fifty years, lithium continues to be one of the mainstays of treatment for this disorder, both for the acute manic phase and as prophylaxis for recurrent manic and depressive episodes. Adequate lithium treatment, particularly in the context of a lithium clinic (an outpatient clinic dedicated to the treatment of bipolar patients and psychopharmacological management of lithium), also reportedly reduces the excessive mortality observed in the illness. In the last decade, there has been an explosion in the number of options available for the treatment of recurrent mood disorders with a parallel and unprecedented increase in the interest in the treatment of BD by pharmaceutical companies, clinicians, researchers, and indeed the general public. Despite the introduction of a number of new anticonvulsants and antipsychotic into the pharmacopeias, the last three years appeared to be of a resurgence of interest not only in lithium utility in the long-term treatment of BD, but possibly also for neurodegenerative disorders. Consistent evidence shows that lithium is effective for reducing the risk of suicide. This renewed interest in lithium has come about largely due to converging evidence from biochemical studies that have identified critical signaling and neurotrophic molecules as targets for lithium actions.

This proposal is focused on studying the influence of Li+-content peptides on innate immune response and neutrophils and mononuclear phagocytes activation in vitro. These processes are known to be connected with apoptosis and chemotaxis, oxidative burst induction and NO synthesis, as well as the synthesis of different cytokines and receptors.

The dendrite cells show mild aberrancies in BD that are fully restored to even activation after in vivo lithium treatment. Macrophages, lymphocytes and their products may be involved in the pathophysiology of psychiatric disorders. Cell-mediated immune response has shown to be activated in patients with BD during the pre-medication, medication, and the remission stages.

To accomplish the goal of the presented project there will be carried out immunological, pharmacological and morphological studies; researches referring phospholipids, as well as NOS and ADPRT A systems in brain and blood formed elements in psychopathology to develop the new approaches for prevention, evaluation of the efficiency of therapy and rehabilitation of mental illness; there will be fulfilled a quantitative estimation of neurotransmitters and biogenic amines; the observed changes of adenosine deaminase activity and problems connected with the bioenergetics and mitochondrial dysfunction will be investigated.

The main object for experiments in this project will be rats and rabbits. The research tactics and strategy in experiments with animals will be performed in the frames of the ethics and Animal Protection Laws of the Republic of Armenia approved by the National Academy of Sciences of the Republic of Armenia and Ethical Committee of the Institute of Physiology (according to the Guide for the Care and Use of Laboratory Animals).

It should be noted, that the new Li+-content synthetic peptides for examination on the experimental BD models is possible to obtain from the Institute of Fine Organic Chemistry of NAS RA according to the agreement between the Institutes. Totally we need 7 peptides (in a whole 210 mg) for the first year, and 6 peptides for the second year (in a whole 180 mg) by 45 USD per mg/amino acids residues.

The scientific stuff of this project under the leadership of Dr.Gevorg Gevorgyan is going to carry out studies in a wide scale to address these findings and find a way to decrease human sufferings. He is a well-known biochemist-radiologist. He is also experienced in studies of brain and cardiac pathologies, in use of nuclear energy and radioisotopes in industry, clinics and scientific investigations. He is Vice-President of the Armenian Association of Biochemists, member of International Society for Neurochemistry, European Society for Neurochemistry, IBRO, and FEBS. Member of Scientific Board of USA for Scientific expert of CRDF. It is for several years he is the reviewer of INTAS applications. At present he is proposed by NAS RA to serve as an Associate member on the NATO SPS Advisory Panel.

Thus, the realization of the present project is directed to the creation of the effective new Li+-content peptide preparation for the treatment of several diseases of pathogenesis of BD, probably, other immune disorders of the brain.


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