Two tandem projects between NRU and Univ. CPH funded by the Novo Nordisk Foundation
- Published: Monday, 08 May 2023 15:42
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The first project is titled "Neuroplastic effects of psychedelics" and is led by Prof. Gitte Moos Knudsen (NRU) and with Assoc. Prof. Matthias Herth (Department of Drug Design and Pharmacology, Univ. CPH) as co-applicant. This project has been supported by 10 mio DKK.
Abstract: Psychedelic drugs are widely known for their perceptual effects but lately, a surge of interest in the therapeutic potential of psychedelics has emerged and a rapidly increasing number of clinical trials in depression, eating disorders, and cluster headache report on a rapid onset of sustained therapeutic effects after a single psychedelic dose which is believed to induce long-lasting neuroplastic effects. Widespread therapeutic use is, however, hampered by the need to screen patients for psychosis liability, as well as preparation and support during the psychedelic session. The psychedelic drugs LSD and psilocybin stimulate the brain’s serotonin 2A receptor (5-HT2AR) by involving the G protein-coupled receptor and the β-arrestin pathways. Intriguingly, since not all 5-HT2AR agonists induce psychedelic effects, it is questioned if these are required for the therapeutic benefits. Novel evidence suggests that 5-HT2AR pathway-selectivity is key to separate these effects. To compare the behavioral and perceptual outcome of different 5-HT2AR agonists at a similar level of 5-HT2AR occupancy, we propose to synthesize and radiolabel a range of pathway-selective 5-HT2AR agonist Positron Emission Tomography (PET) tracers, and to establish relationships between dose of different 5-HT2AR agonists, intensity of the psychedelic experience, and brain 5-HT2AR occupancy. To investigate the neuroplastic effects of different 5-HT2AR agonists, we will image brain functional connectivity in humans, and analyze brain-derived neurotrophic factor (BDNF), synaptic and inflammatory markers in postmortem pig brain. Finally, building on our recent advances in neuroimaging of monoclonal antibodies, we will develop a PET radioligand for in vivo imaging of BDNF. The results of our project will catalyze improved treatment strategies of patients with a range of brain disorders and enable brain imaging of BDNF, but also pave the way for future neuroimaging studies of other peptides, such as GLP-1.
The other project is titled "Synaptogenesis and Neuroinflammation in Epilepsy" and is led by Prof. Jens Mikkelsen (Faculty of Health and Medical Sciences, Univ. CPH) and with Assoc. Prof. Lars Pinborg (NRU and the Epilepsy Clinic). This project has been supported by 8 mio DKK.
Abstract: Epilepsy a neurological disease of numerous etiologies characterized by abnormal neuronal excitation and recurring seizures. Epilepsy can develop into a severe form and become treatment resistant which is the main challenging situation in the clinic. We know little about what mechanisms that occur when neuronal excitability in networks become high enough to generate unprovoked repetitive seizures (epileptogenesis), and why the disease develops to the worse and become treatment resistant. Coming from experimental and clinical neuroscience, the two teams and applicants have worked together on these issues over the last years and have generated the first results, established procedures in the laboratory, phenotyped complex epilepsy patients in the clinic, and have co-authored publications in 2022. The objective of the present research proposal is to determine changes in neuronal circuits in brains from patients and animal models, and with this information and experience to better diagnose and treat patients with severe epilepsy. We have ex vivo validated a novel radioligand, UCB-J, that bind to a presynaptic vesicular protein (SV2A), and is believed to be a marker of synapses. We have shown changes in synapse numbers in animal models and in brain resections from epilepsy patients. Using this binding technology, we will now examine (a) changes in neuronal connections in patients with treatment resistance, and (b) conduct a prospective study to determine synapses in patients with epilepsy over a 2-year observation period. Further, tissues resected from these patients and animals will be used to analyze structural changes, including neuroinflammation, at the cellular level. Finally, we intend to use animal models to explore the effect of novel pharmacological interventions. This research is aimed to define new standards for diagnosing patients with epilepsy, to a better prediction of disease progression, and to propose new treatments.