Completed research grants
Title: „Protective role of astrocytes in the process of neurodegeneration of dopaminergic cells and during functional compensation of this process. Analysis of function and architecture of mitochondrial oxphos complexes and supercomplexes in animal models of early Morbus Parkinson.”
Performed during three 6 month visits at Technische Universität Darmstadt, Darmstadt, Germany in group of Prof. Norbert A. Dencher.
α7 nicotinic acetylcholine receptors (α7-nAChRs) play important role in the regulation of complex cognitive functions which may be impaired in a number of psychiatric disorders. Moreover, it has been suggested that the α7-nAChRs may be implicated in the pathogenesis of schizophrenia. Therefore, in recent years, α7-nAChRs arouse a great interest as a target for the development of pharmacological treatment of cognitive dysfunctions in schizophrenia. The activity of α7-nAChR can be modulated be either orthosteric agonists or positive allosteric modulators (PAMs). Despite numerous preclinical evidences, the procognitive action of direct α7-nAChR agonist has not been conclusively confirmed in patients with schizophrenia. Allosteric modulation is thought to be associated with more favourable and more specific action. Hence, α7-nAChR PAMs may represent more promising tool. While several α7-nAChR PAMs have been recently developed, their behavioural effects, including their potential impact on cognitive processes, have not been yet extensively characterised. Our research hypothesis is based on the presumption that the action of PAMs may differ from the effects induced by orthosteric receptor activation. It is suggested by PAM-induced retardation of rapid desensitization, a fundamental feature of α7-nAchR. Therefore, the aim of the proposed project is to examine the effects of α7-nAChR PAM in comparison to orthosteric agonists in animal tasks assessing cognitive domains that are important from the perspective of cognitive deficits encountered in schizophrenia (e.g., executive functions, attention, and working memory).
OPUS 3 grant nr 2012/05/B/NZ4/02599 financed by
National Science Centre (NCN).
Title: „The role of astrocytes and cellular metabolism in functional compensation of degeneration of dopaminergic system in threats brain. Analysis of expression of AMPK and energy sensing proteins in aspect of Parkinson's disease.”
Performed in the Institute of Pharmacology, Polish Academy of Sciences – project leader.
Glucocorticoids can produce either protective or neurodegenerative effects, depending on the concentration and duration of action. Experimental data have indicated that long-lastingly increased glucocorticoid level can contribute to neurodegenerative changes observed in depression and after cerebral stroke. However, in opposite to in vivo studies, in a majority of in vitro experiments, neurotoxic action of glucocorticoids was observed only after application of their very high doses. Since in vivo investigations have demonstrated that glucocorticoids influence many types of nervous system cells (neurons, astrocytes, microglia), it appears that the lack of junctions between different cells can be one of causes of their weak cytotoxic effect in in vitro studies, conducted most often in neuronal cultures. Moreover, in a few studies on organotypic cultures carried out so far, the cultures were initiated from tissues collected from control animals while HPA axis activity and strength of glucocorticoid action in adults largely depends on factors acting in perinatal period. The aim of the proposed experiments is to examine a potential, cytotoxic action of corticosterone and its interaction with glutamate in organptypic cultures of the hippocampus obtained from the prenatally stress-exposed animals.
We assume that prenatal stress which changes expression of many factors affecting the function of glucocorticoid and NMDA receptors and glutamate level will alter also the effect of corticosterone on neurodegenerative/neuroprotective processes in the hippocampus. Determination of the effect and mechanism of action of corticosterone added to culture medium on markers of cell damage in organotypic cultures of hippocampi from control and prenatally stressed animals (an animal model of depression) will allow for answering the question whether the changes triggered by prenatally elevated glucocorticoids will sensitize the tissue to damaging factors acting in adulthood.