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Sara Xapelli
Institute of Pharmacology and Neuroscience, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
Chronic stress poses a significant risk for neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target for alleviating stress-related disorders. Recent research highlights the interplay between cannabinoids and neurotrophic factors in regulating AHN, influencing cognitive plasticity and emotional flexibility. This study explores the synergistic effects of modulating cannabinoid type 2 receptors (CB2R), devoid of psychotropic effects, and physical exercise (PE) in chronically stressed animals. Contrary to CB2R activation, CB2R inhibition combined with PE improves stress-induced emotional and cognitive changes. This combined approach enhances AHN dynamics, and induces an overall reduction in neuroinflammation. The findings underscore CB2Rs as critical regulators, revealing a potential therapeutic framework for countering chronic stress effects through lifestyle interventions coupled with endocannabinoid pharmacomodulation.
Angelika Jagielska1,2, Aleksandra Koszałka1,2, Klaudia Lustyk1, Marcin Kołaczkowski2, Adrian Newman-Tancredi3, Karolina Pytka1
1Jagiellonian University Medical College, Department of Pharmacodynamics, Faculty of Pharmacy, Kraków, Poland,
2Jagiellonian University Medical College, Doctoral School of Medical and Health Sciences, Kraków, Poland,
3Jagiellonian University Medical College, Department of Medicinal Chemistry, Faculty of Pharmacy, Kraków, Poland,
4Neurolixis SAS, Castres, France
Cognitive flexibility, a key executive function, is compromised in individuals with depression, hindering therapeutic goals. This study aimed to investigate the potential of NLX-101, cortical 5-HT1A receptor biased agonist known for antidepressant-like and procognitive effects, in mitigating the impairment of cognitive flexibility induced by the administration of MK-801, an NMDA receptor antagonist. Using a two-choice pairwise visual discrimination and reversal task in male BALB/c mice, we demonstrated that NLX-101 did not affect the percentage of correct responses. However, at a lower dose, the compound decreased the number of correction trials on the fifth day of the reversal phase compared to the group receiving MK-801. The study suggests while the activation of the ERK 1/2-related signal transduction pathway following 5-HT1A receptor stimulation may be beneficial, it might be insufficient to completely reverse cognitive flexibility impairments caused by NMDA receptor blockade.
Nicolas Singewald
Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, LFU, Innsbruck, Austria
There is accumulating evidence that epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs, play a contributing role in dysregulated gene expression patterns and brain circuitry dysfunction associated with various neuropsychiatric disorders. One idea is therefore to explore novel pharmacological interventions (“Epipsychopharmacology”) that can modulate epigenetic modifications to restore normal gene expression and circuitry function in these conditions. This involves drugs that target enzymes regulating epigenetic modifications, such as histone deacetylases (HDACs), DNA methyltransferases or utilizing non-coding RNA molecules. In the talk I will discuss the potential of targeting epigenetic mechanisms in anxiety-and trauma-related disorders and will use therapeutic improvement of impaired fear-inhibitory extinction learning as an example. This phenotype is common in PTSD and specific anxiety disorders and is considered an important contributor to treatment resistance in exposure-based therapies. We show that deficits in the formation of fear extinction memories in mice can indeed be normalized by modifying different epigenetic mechanisms. Enhancing histone acetylation via HDAC inhibitors was critical to stabilize the newly built extinction memory in the long-term. Neurons in brain areas known to mediate extinction showed particular increases in histone acetylation and modified activity patterns. Recently, first human exposure therapy trials using repurposed drugs with HDAC inhibitor action have started. Although this research field is still evolving and important challenges including safety, drug specificity and efficacy remain to be further investigated, these findings indicate new ways for the development of improved treatment strategies to overcome treatment-resistance in extinction-driven therapies.
Judith Schweimer
Boehringer Ingelheim Pharma GmbH & Co. KG, CNS DR, Biberach, Germany
At Boehringer Ingelheim, we are embracing a patient-centric approach which includes improved patient stratification, identifying innovative targets within the brain and advancing novel chemical, biological and digital approaches in order to find new treatment options for neuropsychiatric conditions.
We are offering several possibilities to collaborate and accelerate drug discovery through our Open Science programmes. This includes sponsoring research groups through initiatives like BioMed X, but also our opnMe platform. Via this platform, we offer free Molecules to Order (M2O), as well as Molecules for Collaborations (M4C), these are research grants related to specific compounds and broader grants for scientific questions that we are interested in (opn2EXPERTS).
In CNS DR, our research focuses on the patient aiming to better understand and target the maladaptive brain circuitry that underlies the major untreated symptom domains. This is aiming to bring increasing precision to the treatment of psychiatric disorders both pharmacologically and digitally. Precision psychiatry is a novel approach to identify the right patient for the right treatment by connecting symptoms to specific brain-circuit dysfunctions, therefore enabling treatment to target the underlying neurobiological processes.
