Dantrolene, a Calcium-Induced Calcium Release Inhibitor, Prevents the Acquisition of Amygdaloid Kindling in Rats, a Model of Experimental Epilepsy

Abstract

Kindling phenomenon (an experimental model of acquired epilepsy) and long-term potentiation (LTP) have many features in common. LTP is associated with an increase in intracellular Ca 2+ concentration where intracellular Ca 2+ stores play an important role. Dantrolene has an inhibitory action against Ca 2+ release from intracellular Ca 2+ stores. This substance has been reported to inhibit the induction of LTP. We investigated whether or not the development of kindling would be inhibited by dantrolene. We first determined at the right amygdala afterdischarge threshold (ADT) that is the minimal electric current necessary to evoke afterdischarge. For investigating the effects of dantrolene on the development of kindling, rats were stimulated once daily at the right amygdala with a current, 10% larger than ADT, one hour after either dantrolene or vehicle had been injected intraperitoneally. We observed daily the progress of both intensities of behavioral seizures (stages of seizures) and the duration of afterdischarge. Dantrolene significantly delayed both the progression of kindling stages and the elongation of afterdischarge duration at a dose of 10 mg/kg or 20 mg/kg, as compared with control vehicle. To investigate the effects of dantrolene on seizures in already kindled rats, we determined generalized seizure threshold (GST) that is the minimum electric current necessary to evoke generalized seizures in fully kindled rats. Rats were stimulated at a current, 10% larger than GST, one hour after treated with the drug or vehicle. Dantrolene showed no anticonvulsant action against either the stages of seizures or afterdischarge durations in fully kindled rats. Therefore, the inhibitory effect of dantrolene on the acquisition of kindling was not attributed to an anticonvulsant action. These results suggest that the prevention of kindling acquisition is associated with an inhibitory action of dantrolene on calcium-induced calcium release from intracellular Ca 2+ stores.

Dantrolene inhibits the calcium plateau and prevents the development of spontaneous recurrent epileptiform discharges following in vitro status epilepticus

“…It has been demonstrated that animals pre-treated with dantrolene require significantly greater stimuli to generate seizures (Yoshida & Sakai, 2006). Moreover, after the animals are kindled, during the chronic phase of epilepsy, dantrolene has no anti-convulsant effects (Kulak et al, 2004;Yoshida & Sakai, 2006). In agreement with this, our studies have shown that dantrolene does not block SREDs when administered after in vitro SE.…”

“…Moreover, after the animals are kindled, during the chronic phase of epilepsy, dantrolene has no anti‐convulsant effects (Kulak et al. , 2004; Yoshida & Sakai, 2006). In agreement with this, our studies have shown that dantrolene does not block SREDs when administered after in vitro SE.…”

“…Our data suggest that RyR, a regulator of CICR, may contribute to the maintenance of the Ca 2+ plateau. It has been demonstrated that animals pre‐treated with dantrolene require significantly greater stimuli to generate seizures (Yoshida & Sakai, 2006). Moreover, after the animals are kindled, during the chronic phase of epilepsy, dantrolene has no anti‐convulsant effects (Kulak et al.…”

Age‐ and region‐dependent patterns of Ca2+ accumulations following status epilepticus

“…A number of regions resistant to injury had large increases of [Ca 2+ ] i even at the adult age such as the dorsal blade of the dentate gyrus and dorsal preoptic nucleus further suggesting that elevated Ca 2+ is not always correlated with cell death. While rises in Ca 2+ may lead to seizure‐induced injury, release from intracellular stores is also required for seizure propagation which may explain why elevations herein were observed in a variety of limbic structures as early as 5 h in the absence of cell death (Yoshida and Sakai, 2006).…”

Dantrolene and ryanodine receptors in COVID‐19: The daunting task and neglected warden

“…Chemically, DTN is a derivative of hydantoin like phenytoin, but its anti‐epileptic activity is contradictory 1 . Previous studies supported the anti‐epileptic effects of DTN in animal model studies by inhibiting epileptogenesis 2,3 . A recent experimental study revealed that DTN reduces the risk of epilepsy after hippocampal neurodegeneration 4 .…”