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•PDS arise in the course of experimentally-provoked seizure-like activity.•PDS can also be induced by cellular processes typical of seizure aftermath.•PDS closely resemble modulatory ...electrical activity patterns in neurodevelopment.•L-type calcium channels are essential for formation of these PDS.•L-type calcium channels potentially a valuable target to interfere with PDS effects.
Since their discovery in the 1960s, the term paroxysmal depolarization shift (PDS) has been applied to a wide variety of reinforced neuronal discharge patterns. Occurrence of PDS as cellular correlates of electrographic spikes during latent phases of insult-induced rodent epilepsy models and their resemblance to giant depolarizing potentials (GDPs) nourished the idea that PDS may be involved in epileptogenesis. Both GDPs and – in analogy – PDS may lead to progressive changes of neuronal properties by generation of pulsatile intracellular Ca2+ elevations. Herein, a key element is the gating of L-type voltage gated Ca2+ channels (LTCCs, Cav1.x family), which may convey Ca2+ signals to the nucleus. Accordingly, the present study investigates various insult-associated neuronal challenges for their propensities to trigger PDS in a LTCC-dependent manner. Our data demonstrate that diverse disturbances of neuronal function are variably suited to induce PDS-like events, and the contribution of LTCCs is essential to evoke PDS in rat hippocampal neurons that closely resemble GDPs. These PDS appear to be initiated in the dendritic sub-compartment. Their morphology critically depends on the position of recording electrodes and on their rate of occurrence. These results provide novel insight into induction mechanisms, origin, variability, and co-existence of PDS with other discharge patterns and thereby pave the way for future investigations regarding the role of PDS in epileptogenesis.
Since their discovery in the 1960s, the term paroxysmal depolarization shift (PDS) has been applied to a wide variety of reinforced neuronal discharge patterns. Occurrence of PDS as cellular ...correlates of electrographic spikes during latent phases of insult-induced rodent epilepsy models and their resemblance to giant depolarizing potentials (GDPs) nourished the idea that PDS may be involved in epileptogenesis. Both GDPs and - in analogy - PDS may lead to progressive changes of neuronal properties by generation of pulsatile intracellular Ca
elevations. Herein, a key element is the gating of L-type voltage gated Ca
channels (LTCCs, Cav1.x family), which may convey Ca
signals to the nucleus. Accordingly, the present study investigates various insult-associated neuronal challenges for their propensities to trigger PDS in a LTCC-dependent manner. Our data demonstrate that diverse disturbances of neuronal function are variably suited to induce PDS-like events, and the contribution of LTCCs is essential to evoke PDS in rat hippocampal neurons that closely resemble GDPs. These PDS appear to be initiated in the dendritic sub-compartment. Their morphology critically depends on the position of recording electrodes and on their rate of occurrence. These results provide novel insight into induction mechanisms, origin, variability, and co-existence of PDS with other discharge patterns and thereby pave the way for future investigations regarding the role of PDS in epileptogenesis.
The lupin alkaloid sparteine is a well‐known chiral diamine with a range of applications in asymmetric synthesis, as well as a blocker of voltage‐gated sodium channels (VGSCs). However, there is only ...scarce information on the VGSC‐blocking activity of sparteine derivatives where the structure of the parent alkaloid is retained. Building on the recent renewed availability of sparteine and derivatives we report herein how modification of sparteine at position 2 produces irreversible blockers of VGSCs. These compounds could be clinically envisaged as long‐lasting local anesthetics.
Long lasting effect: The lupin alkaloid sparteine is a well‐known chiral diamine with a range of applications in asymmetric synthesis, as well as a blocker of voltage‐gated sodium channels (VGSCs). However, only scarce information on the VGSC‐blocking activity of sparteine derivatives is available. Herein we report how modification of sparteine at position 2 produces irreversible blockers of VGSCs. These compounds could be clinically envisaged as long‐lasting local anesthetics.
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