Microglia-Neuron interactions in neurodegenerative processes: the role of hormonal micro-environment. Inflammation and microglial activation is a common component of the pathogenesis for multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease (PD), or Multiple sclerosis. For instance, degeneration of the nigrostriatal dopaminergic neurons in PD is caused by programmed cell death (apoptosis) due to increased levels of cytokines and/or decreased production of neurotrophins. Microglia, the resident innate immune cells in the brain, actively monitor their environment and can become over-activated in response to diverse cues to produce neurotoxic pro-inflammatory cytokines, or to decrease neuroprotective neurotrophins. In chronic neurodegenerative diseases, microglial activation is an early sign that often precedes apoptotic neuronal death At this time, the mechanisms initiating deleterious neuroinflammation in neurodegenerative diseases are poorly understood. Recent evidence indicates that neuroendocrine factors, such as stress neuropeptides and neurosteroids play a significant role in Microglia activation and the paracrine link between glia and neurons.

Our team is studying the paracrine role of hormonal micro-environment in Microglia-neuron interactions, using in vitro models (microglial cells challenged with lipopolysaccharide and co-cultured with neuronal cells) and experimental animals models of neurodegenerative diseases (MPTP mice for Parkinson’s, NGF+/- mice for Alzheimer’s and EAE mice for Multiple Sclerosis).  The interplay between locally produced stress neuropeptides, cytokines and Neurotrophins and their effects on gene expression is evaluated, in order to identify the factors involved in these processes that would serve as potential targets for new therapeutic approaches for neurodegeneration.

Molecular mechanisms of apoptotic cell death in neurodegenerative diseases: Neuroprotective compounds with antiapoptotic and neurogenic activity:  Neuronal cell death by apoptosis is the ‘end-point’ of many human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, stroke/trauma, multiple and amyotrophic lateral sclerosis. Indeed, apoptotic death of hippocampal and cortical neurons is responsible for the symptoms of Alzheimer's disease; death of midbrain neurons that use the neurotransmitter dopamine underlies Parkinson's disease; Huntington's disease involves the death of neurons in the striatum, which control body movements; and death of lower motor neurons manifests as amyotrophic lateral sclerosis. Additionally, brain ischemia and trauma induce necrosis of a small brain area, which then propagates neuronal cell loss by apoptosis to a larger brain area, due to the neurotoxic material released by the necrotic cells. Apoptotic neuronal cell loss is also observed in the ageing brain, as a physiological process. With the identification of molecular mechanisms that prevent neuronal apoptosis come new approaches for preventing and treating neurodegenerative disorders. Our team works in collaboration with Dr Theodora Calogeropoulou at the Institute of Organic and Pharmaceutical Chemistry, (http://www.eie.gr/nhrf/institutes/iopc/index-en.html), National Research Foundation Athens, to develop synthetic neurosteroid analogs with anti-apoptotic and neuroprotective, neurogenic properties. We are currently screening a large chemical library of our in house made synthetic compounds for their anti-apoptotic, neuroprotective effects using various in vitro cell culture models. A number of highly effective compounds were selected, which protect neuronal cells against neurotrophin deprivation induced apoptosis, with EC50 in the range of 0,1-1 nM. These synthetic compounds are tested in vivo in animal models of neurodegenative diseases. The effects of the compounds are tested on cell dysfunction and death and on gene activity, using cell, molecular biology and functional genomic approaches. In collaboration with Dr Eumorphia Remboutsika at the Fleming Institute, Athens (http://www.fleming.gr/en/investigators/Remboutsika/index.html) we are also testing the neurogenic properties of these compounds on neural progenitor and neural stem cell cultures.

The role of Stress neuropeptides (Corticotropin Releasing Hormone-CRH, Urocortins) in the cross-talk between neural and immune systems. Neural and immune systems interact at multiple levels. Both neuroendocrine (the primary hormonal pathway is hypothalamic-pituitary-adrenal axis) and neuronal (direct sympathetic innervation of the lymphoid organs) pathways are involved in the control of the humoral and cellular immune responses. The immune system, in turn, influences the central nervous system primarily through cytokines. At the molecular level, neuro- and immune signal molecules (hormones, neurotransmitters, neuropeptides, and cytokines) or their receptors are members of the same superfamily which enable the mutual neuroimmune communication. Our team, in collaboration with Drs Andreas Margioris and Christos Tsatsanis, at the Dept of Clinical Chemistry, studies the cytokine-neuropeptide/neurotransmitter interactions and the subcellular and molecular mechanisms of these interactions. Our interest is focused on neuropeptide Corticotropin-releasing hormone (CRH) which coordinates the systemic stress response via hypothalamic-pituitary-adrenal (HPA) axis activation. Stress is known to affect expression of immune-mediated inflammatory diseases, many of which are associated with HPA axis abnormalities. HPA axis components including CRH, urocortins and their receptors (CRHR) are expressed in the many neuroendocrine cells, found scattered in different organs, including the GI, the gonads and the immune cells. Peripheral CRH and urocortins are strong paracrine modulators of inflammatory phenomena. Methods to control the inflammatory diseases via the pharmacological manipulation of the endogenous Corticotrophin-Releasing Hormone (CRH) and Urocortin (UCN) systems, through regulation of the Monocyte/ Macrophage function are under investigation. The new therapeutic approaches include the use of synthetic CRHR1 receptor antagonists and synthetic CRFR2 receptor agonists aiming in modifying the response of monocyte/ macrophage monocyte/ macrophage cell activation, proliferation, differentiation, apoptosis and cytokine production and, thus, control of the magnitude of the inflammatory response.

Stress neuropeptide Urocortin, expressed in neuroendocrine Kupffer cells