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Central Research Aims
Structural brain abnormalities are well known in patients with neuropsychiatric disorders, including patients with affective disorders. These structural changes are in agreement with an impaired homeostasis of neurotrophic factors, that may be a cause or a consequence of the resepective neuropsychiatric disorder.
Also in primary neurological disorders such as Parkinson's disease, ischemic stroke, multiple sclerosis or dementia, depressive syndromes are frequently observed as a complication of the underlying disease. Also in this context a link is discussed between a structural alteration, a neuropsychiatric syndrome and a pathologically altered homeostasis of neurotrophic factors.
A promising target in this context is retinoic acid (RA), a highly active metabolite of vitamin A, with impressive neuroprotective and anti (neuro-)inflammatory effects, which may play a pivotal role in m.
Retinoic acid homeostasis in the adult CNS
In the brain, retinoic acid is locally synthesized and metabolized via a tightly coordinated process, resulting in a specific temporal and spatial pattern of RA concentrations throughout the (adult) central nervous system. The resulting RA concentration gradients will likely represent an important basis for the various effects of RA, also in the adult CNS.
While the properties of RA as an intimate morphogen during embryonic development, and as a phototransducer in the retina are already well understood, rather little is known about the role of RA in the adult CNS, despite being detected at relatively high concentrations under physiological conditions.
Several preclinical findings suggest an essential role of RA in processes such as neuronal differentiation (neurogenesis), synaptic plasticity (synaptic scaling) and the modulation of inflammatory processes in the immune system (eg, inhibition of macrophage activation and differentiation of regulatory T-cells). Furthermore, clinical findings support evidence for a general neuroprotective action of retinoids and suggest a possible link between the emergence of depressive syndromes and a pathologically altered homeostasis of retinoid acid (Bremner, Shearer and McCaffery, 2012).
In summary, RA may be considered a promising target in neuropsychiatric research, potentially acting as an "endogenous neuroprotective factor".
Our team focuses on the characterization of the local brain RA-homeostasis under physiological and pathological conditions. In this context, we are interested in elucidating potential environmental influences (light and other electromagnetic radiation, nutrition, microbiota) as well as pharmacological modulation of RA-homeostasis in the adult CNS.
In vitro models for neurostimulatory treatments
We are also interested in understanding the basic mechanisms potentially underlying non-pharmacological neurostimulatory techniques such as rTMS and tDCS and ECT. For this purpose, various human, predominantly neuronal cell culture models were developed. They combine easy accessibility for examining basic mechanisms of signal transduction in a homogenous system and the concept of personalized medicine, when derived from patients directly.
Metabolism of psychotropic drugs in the brain
Most psychopharmacological substances are considered to be mainly degraded by the cytochrome P450 system of the liver. Interestingly enough, it is well recognized that certain regions of the CNS express a significant level of specific, functional and not least highly active CYP450 isozymes. In this context, we are interested in the quantitative and qualitative distribution of such enzymes in the CNS, and their potential contribution to a differential regulation of local tissue levels of the various psychopharmacological substances. We are currently developing various pharmacological in-vitro approaches that are mainly based on organotypic slice cultures and synaptosomal preparations of different brain regions.
Basic biochemical methodology: Western Blotting, ELISA, histology, immunohistochemistry
Cell- and tissue culture: human neuronal cell lines, including human ESC-derived neuronal stem cells
Molecular biology: PCR, cloning, modulation of gene expression
HPLC: Quantification of endogenous catecholamine and amino acid neurotransmitters
Quantification of endogenous retinoids and -metabolites Cell- and tissue-culture based in vitro assays for determining tissue-specific retinoic acid homeostasis
- Regina Hill (CTA)
- Rita Benz (MTA)
- Meike Terborg (MTA)
- Angela Zepp (MTA)
- Lisa Otto (naturwiss. Doktorandin)
- Berk Üsekes (naturwiss. Doktorand)
- Janine Gellrich (med. Doktorandin)
- Lana Sakasone (med. Doktorandin)
- Franziska Gawron (med. Doktorandin)
- Nicoleta Cosma (med. Doktorandin)
- Dr. Thi Minh Tam Ta (Clinician Scientist)
- Dr. Vera Clemens (Ärztin, Wiss. MA)
- Dr. Francesca Regen (Ärztin, Wiss. MA)
- Dr. Julian Hellmann-Regen (Arzt, Arbeitsgruppenleitung)
- Experimental Neurology, Charité Berlin
- Centrum für Schlaganfallforschung Berlin (CSB)
- Dept. of Dermatology, Charité Berlin
- Dept. of Urology, Charité Berlin
- Zelluläre Neurowissenschaften, Max-Delbrück-Centrum für Molekulare Medizin
- Physikalische Biochemie, TU Darmstadt
- Authors:Clemens, V., Regen, F., Le Bret, N., Heuser, I., & Hellmann-Regen
Journal:J Alzheimers Dis Year:2018; Volume:61Issue:(4):Pages:1295-1300.
Title:Retinoic Acid Enhances Apolipoprotein E Synthesis in Human Macrophages
- Authors:Hellmann-Regen, J., Gertz, K., Uhlemann, R., Colla, M., Endres, M., & Kronenberg, G
Title:Retinoic acid as target for local pharmacokinetic interaction with modafinil in neural cells
- Authors:Hellmann-Regen, J., Herzog, I., Fischer, N., Heuser, I., & Regen, F
Title:Do tetracyclines and erythromycin exert anti-acne effects by inhibition of P450-mediated degradation of retinoic acid?
- Authors:Hellmann J, Jüttner R, Roth C, Bajbouj M, Kirste I, Heuser I, Gertz K, Endres M, Kronenberg G
Journal:Eur Arch Psychiatry Clin Neurosci Year:2012; Volume:262Issue:(1):Pages:87-91.
Title:UV-A emission from fluorescent energy-saving light bulbs alters local retinoic acid homeostasis
- Authors:Hellmann-Regen, J., Kronenberg, G., Uhlemann, R., Freyer, D., Endres, M., & Gertz, K
Journal:J Neuroimmunol Year:2013; Volume:265Issue:(1-2):Pages:1-6.
Title:Accelerated degradation of retinoic acid by activated microglia
- Authors:Hellmann-Regen, J., Uhlemann, R., Regen, F., Heuser, I., Otte, C., Endres, M, ..., Kronenberg, G
Title:Direct inhibition of retinoic acid catabolism by fluoxetine