Biology subjects

Thomsen, M. S.

Publications and source records attributed to Thomsen, M. S..

2 recordsLinked to original sources

bioRxiv2021

Systemic administration of Ivabradine, an HCN channel inhibitor, blocks spontaneous absence seizures

ObjectiveHyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to be involved in the generation of absence seizures (ASs), and there is evidence that cortical and thalamic HCN channel dysfunctions may have a pro-absence role. Many HCN channel blockers are available, but their role in ASs has been investigated only by localized brain injection or in in vitro model systems due to their limited brain availability. Here, we investigated the effect on ASs of orally administered ivabradine (an HCN channel blocker approved for the treatment of heart failure in humans) following injection of the P-glycoprotein inhibitor elacridar, that is known to increase penetration into the brain of drug substrates for this efflux transporter. The action of ivabradine was also tested following in vivo microinjection in the cortical initiation network (CIN) of the somatosensory cortex and in the thalamic ventrobasal nucleus (VB) as well as on cortical and thalamocortical neurons in brain slices. MethodsWe used EEG recordings in freely moving Genetic Absence Epilepsy from Strasbourg Rats (GAERS) to assess the action of oral administration of ivabradine, with and without elacridar, on ASs. Ivabradine was also microinjected in the CIN and VB of GAERS in vivo and applied to Wistar CIN and GAERS VB slices while recording patch-clamped cortical layer 5/6 and thalamocortical neurons, respectively. ResultsOral administration of ivabradine markedly and dose-dependently reduced ASs. Ivabradine injection in CIN abolished ASs and elicited small-amplitude 4-7 Hz waves (without spikes), whereas in the VB it was less potent. Moreover, ivabradine applied to GAERS VB and Wistar CIN slices selectively decreased HCN-channel-dependent properties of cortical layer 5/6 pyramidal and thalamocortical neurons, respectively. SignificanceThese results provide the first demonstration of the anti-absence action of a systemically administered HCN channel blocker, indicating the potential of this class of drugs as a novel therapeutic avenue for ASs.

neuroscience↗

bioRxiv2020

The blood-brain barrier studied in vitro across species

The blood-brain barrier (BBB) is formed by brain capillary endothelial cells (BECs) supported by pericytes and astrocytes. The BBB maintains homeostasis and protects the brain against toxic substances circulating in the blood, which consequently means that only a few drugs can pass the BBB. Thus for drug screening, understanding cell interactions, and pathology, in vitro BBB models have been developed using BECs from various animal sources. When comparing models of different species, differences exist especially in regards to the transendothelial electrical resistance (TEER). Thus, in the present study, we compared primary mice, rat, and porcine BECs (mBECs, rBECs, and pBECs) cultured in mono- and co-culture with astrocytes, to identify potential species-dependent differences that could explain the variations in TEER and aid to the selection of models for future in vitro BBB studies. The in vitro BBB models based on primary mBECs, rBECs, and pBECs were evaluated and compared in regards to major BBB characteristics. The barrier integrity was evaluated by the expression of tight junction proteins and measurements of TEER and apparent permeability (Papp). Furthermore, the cell size, the functionality of the P-glycoprotein (P-gp) efflux transporter, and the expression of the transferrin receptor were evaluated and compared. pBECs exhibit the highest TEER followed by rBECs and mBECs, but surprisingly the Papp was not that different, which might be explained by a significantly larger cell size of pBECs than rBECs and mBECs. The expression and organization of many tight junction proteins were in all three species influenced by co-culturing, which supports the findings that the TEER increases after co-culturing with astrocytes. Furthermore, all models had functional polarised P-gp efflux transporters and expressed the transferrin receptor. In conclusion, the choice of species for in vitro BBB modeling should be based on the purpose of the study.

neuroscience↗