The project deals with complex research of molecular mechanisms of actions of neurotrophic factors, neurotransmitters and cytokines and their overall interactions in different biological systems. a) Pharmacological modulation of synthesis and secretion of nerve growth factor (NGF) from neuronal and non-neuronal cells The research field includes mechanisms of actions of NGF, other trophic factors and cytokines that play a crucial role in development and normal function of neurons in PNS and CNS as well as immune system. NGF and brain-derived neurotrophic factor (BDNF) have been shown to provide neuroprotection to injured neurons in CNS and are responsible for impairment of specific populations of neurons during neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy). Our recent studies indicated that different pharmacological agents (cytokines, neurotransmitters, drugs, etc) via distinct molecular mechanisms effectively modulate (stimulate or inhibit) secretion of NGF from neuronal and non-neuronal cells (astrocytes). b) The influence of cytokines, neurotrophic factors and drugs on histamine and serotonin secretion from rat peritoneal mast cells Isolated mast cells from peritoneal of rat were shown to be a useful model system for studying the influence of a number of endogenous substances on the process of biogenic amines release. NGF is a potent stimulator of histamine and serotonin from rat mast cells. Since the mechanism of amines secretion influenced by NGF is different than the mechanism of secretion influenced by substance 48/80, we examined the effect of certain cytokines (GM-CSF, SCF, IL-3, IL-5). Some psychotropic substances are known to be involved in the inhibition of inflammation, therefore we also studied their influence on histamine and serotonin secretion from rat peritoneal mast cells. c) Histamine H1-, H2- and H3-receptors in the cardiovascular system and CNS Histamine causes its effect through stimulation of four known histamine receptor subtypes: H1, H2, H3 and H4. In our study we identified, characterized and compared molecular characteristics of central (astrocytes) and peripheral (vascular tissue) histamine receptor subtypes using newly synthesized histaminergic agonists/antagonists (in collaboration with the research group of dr. W. Schunack, Free University Berlin). Our project is a part of the overall international efforts on the field of biomedical sciences. The results of our study provided advances in our understanding the molecular mechanisms of action of NGF and other neurotrophic molecules in the CNS as well as interactions between immune and nervous system. Through the elucidation of the regulation of NTF's synthesis/secretion in the CNS, new possibilities in the treatment of brain injury and degenerative diseases are opened. Our knowledge about the molecular mechanisms of neurotransmitters, histamine and its receptors is particularly important for the therapy with histamine H1, H2, and H3 antagonists (see also the bibliography of principal investigator and coworkers). The project enables bringing up postgraduate young researches in the field of basic biomedical sciences (molecular pharmacology) as well as on studies of the clinicaly oriented level.