Biology subjects

De Bundel, D.

Publications and source records attributed to De Bundel, D..

6 recordsLinked to original sources

bioRxiv2026

A photoswitchable cannabinoid for precision treatment of refractory seizures in a mouse epilepsy model

Temporal lobe epilepsy (TLE) has an unmet need for precision treatments targeting the seizure focus while avoiding effects on other body parts to minimise side effects. Photopharmacology could enable precision treatment by combining systemic administration of a photoswitchable drug with implantation of an optic fibre in the epileptic focus to induce light-dependent drug conversion from an inactive to an active configuration that interacts with its target receptor to suppress seizures. The photoswitchable {Delta}9-tetrahydrocannabinol ({Delta}9-THC) derivative, azo-THC-3, transitions from an inactive trans to an active cis configuration upon UV irradiation. We demonstrate that local or systemic administration of azo-THC-3 and local UV irradiation in the hippocampus supresses difficult-to-treat seizures in the intrahippocampal kainic acid mouse model of TLE. Furthermore, our findings illustrate that the photoswitch strategy avoids hypolocomotion, a common side effect of systemic {Delta}9-THC administration. As such, we provide the first demonstration of seizure suppression with the systemic administration of a photoswitchable compound and its local photoactivation in the seizure focus. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/720358v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1e42794org.highwire.dtl.DTLVardef@1e26891org.highwire.dtl.DTLVardef@13f2b6forg.highwire.dtl.DTLVardef@3c8e48_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Molecular dynamics study of differential effects of serotonin-2A-receptor (5-HT2AR) modulators

The serotonin-2A receptor (5-HT2AR) is an interesting target for drug design in the context of antidepressants that might have a rapid onset of action and/or be effective in treatment-resistant cases. The main challenge, however, is that the activation of this receptor can provoke hallucinations. Recent studies have shown that activating the receptor with certain (partial) agonists could potentially give rise to antidepressant effect without hallucinogenic side effects. Although substantial research has been done in this area, the atomistic details of this differential activation of the serotonin-2A receptor are not fully understood. In the present study we performed multiple atomistic molecular dynamics (MD) simulations on 5-HT2AR bound with an antipsychotic, two different potential non-hallucinogenic antidepressants and a hallucinogen to identify the receptors ligand dependent conformations. Overall, our findings suggest that modest 5-HT2AR activation would only yield antidepressant effects and hallucinations result from excessive activation. While modest activation through microdosing may be problematic on account of abuse potential as well as possibly narrow and patient-dependent therapeutic windows, modest activation through administration of a sufficiently weak partial agonist may offer a viable drug development pathway. Author SummaryActivating the serotonin-2A receptor (5-HT2AR) with specific agonists is a promising strategy for the development of a new class of antidepressants. However, potent agonists such as LSD, DMT or psylocibin generally cause hallucinations. To aid the development of 5-HT2AR-targeted antidepressants that do not cause this side effect, we seek to gain a better understanding of the receptor by studying its activation mechanism. Specifically, we performed molecular dynamics simulations to explore how different drugs interact with 5-HT2AR, both in the absence and presence of an intracellular binding partner. This led to the identification of tentative intermediate states along the activation pathway, which could be linked to the ligands pharmacological properties. Our findings suggest that hallucinogens cause an excessive build-up of activated receptors, whereas carefully designed mild activators could lead to a new generation of antidepressants that do not induce hallucinations.

biochemistry↗

bioRxiv2024

Photopharmacological activation of adenosine A1receptor signaling suppresses seizures in a mousemodel for temporal lobe epilepsy

Up to 30% of epilepsy patients suffer from drug-resistant epilepsy (DRE). The search for innovative therapies is therefore important to close the existing treatment gap in these patients. The adenosinergic system possesses potent anticonvulsive effects, mainly through the adenosine A1 receptor (A1R). However, clinical application of A1R agonists is hindered by severe systemic side effects. To achieve local modulation of A1Rs, we employed a photopharmacological approach using a caged version of the A1R agonist N6-cyclopentyladenosine, termed cCPA. We performed the first in vivo study with intracerebroventricularly (ICV) administered cCPA to investigate the potential to uncage sufficient amounts of cCPA in the hippocampus by local illumination in order to suppress hippocampal excitability and seizures in mice. Using hippocampal evoked potential recordings, we showed a reduction in hippocampal neurotransmission after photo-uncaging of cCPA, similar to that obtained with ICV injection of CPA. Furthermore, in the intrahippocampal kainic acid mouse model for DRE, photo-uncaging of CPA in the epileptic hippocampus resulted in a strong suppression of seizures. Finally, we demonstrated that intrahippocampal photo-uncaging of CPA resulted in less impairment of motor performance in the rotarod test compared to ICV administration of CPA. These results provide a proof of concept for photopharmacological A1R modulation as an effective precision treatment for DRE.

neuroscience↗

bioRxiv2023

Neuroanatomical characterization of the Nmu-Cre knock-in mice reveals an interconnected network of unique neuropeptidergic cells

Neuromedin U (NMU) is an evolutionary conserved neuropeptide that has been implicated in multiple processes, such as circadian regulation, energy homeostasis, reward processing and stress coping. Although central expression of NMU has been addressed previously, the lack of specific and sensitive tools has prevented a comprehensive characterization of NMU-expressing neurons in the brain. We have generated a knock-in mouse model constitutively expressing Cre recombinase under the Nmu promoter. We have validated the model using a multi-level approach based on quantitative reverse-transcription polymerase chain reactions, in situ hybridization, a reporter mouse line and an adenoviral vector driving Cre-dependent expression of a fluorescent protein. Using the Nmu-Cre mouse, we performed a complete mapping of NMU expression in adult mouse brain, unveiling a potential midline NMU modulatory circuit with the ventromedial hypothalamic nucleus (VMH) as a key node. Moreover, immunohistochemical analysis suggested that NMU neurons in the VMH mainly constitute a unique population of hypothalamic cells. Taken together, our results suggest that Cre expression in the Nmu-Cre mouse model largely reflects NMU expression in the adult mouse brain, without altering endogenous NMU expression. Thus, the Nmu-Cre mouse model is a powerful and sensitive tool to explore the role of NMU neurons in mice.

neuroscience↗

bioRxiv2022

No evidence that post-training D2R dopaminergic drug administration affects differential fear responding in rats

The neurotransmitter dopamine plays an important role in the processing of emotional memories, and prior research suggests that dopaminergic manipulations immediately after fear learning can affect the retention and generalization of acquired fear. The current study focuses specifically on the role of dopamine D2 receptors (D2Rs) in adult, male Wistar rats. In a series of five experiments, D2R (ant)agonists were injected systemically immediately after differential cued fear conditioning (CS+ followed by shock, CS- without shock). All five experiments involved the administration of the D2R agonist quinpirole at different doses versus saline (n = 12, 16 or 44 rats/group). Additionally, one of the studies administered the D2R antagonist raclopride (n = 12). One day later, freezing during the CS+ and CS- was assessed. We found no indications for an effect of quinpirole or raclopride on fear generalization during this drug-free test. Importantly, and contradicting prior research in mice, the evidence for the absence of an effect of quinpirole (1 mg/kg) on fear generalization was substantial according to Bayesian analyses and was observed in a highly powered experiment (N = 87). We did find acute behavioral effects in line with the literature, for both quinpirole and raclopride in a locomotor activity test.

neuroscience↗

bioRxiv2020

Apparent Reconsolidation Interference Without Generalized Amnesia

Memories remain dynamic after consolidation, and when reactivated, they can be rendered vulnerable to various pharmacological agents that disrupt the later expression of memory (i.e., amnesia). Such drug-induced post-reactivation amnesia has traditionally been studied in AAA experimental designs, where a memory is initially created for a stimulus A (be it a singular cue or a context) and later reactivated and tested through exposure to the exact same stimulus. Using a contextual fear conditioning procedure in rats and midazolam as amnestic agent, we recently demonstrated that drug-induced amnesia can also be obtained when memories are reactivated through exposure to a generalization stimulus (GS, context B) and later tested for that same generalization stimulus (ABB design). However, this amnestic intervention leaves fear expression intact when at test animals are instead presented with the original training stimulus (ABA design) or a novel generalization stimulus (ABC design). The underlying mechanisms of post-reactivation memory malleability and of MDZ-induced amnesia for a generalization context remain largely unknown. Here, we evaluated whether, like typical CS-mediated (or AAA) post-reactivation amnesia, GS-mediated (ABB) post-reactivation amnesia displays key features of a destabilization-based phenomenon. We first show that ABB post-reactivation amnesia is critically dependent on prediction error at the time of memory reactivation and provide evidence for its temporally graded nature. In line with the known role of GluN2B-NMDA receptor activation in memory destabilization, we further demonstrate that pre-reactivation administration of ifenprodil, a selective antagonist of GluN2B-NMDA receptors, prevents MDZ-induced ABB amnesia. In sum, our data reveal that ABB MDZ-induced post-reactivation amnesia exhibits the hallmark features of a destabilization-dependent phenomenon. Implication of our findings for a reconsolidation-based account of post-reactivation amnesia are discussed.

neuroscience↗