We evaluated the
anticonvulsant effect of
Chai-Hu-Long-Ku-Mu-Li-Tan (TW-001), a Chinese herbal medicine, and its mechanisms in several standard rodent models of
generalized seizure.
TW-001 (4 g/kg, p.o.) significantly increased the threshold for tonic electroconvulsions and the threshold for
tonic seizures in response to i.v. infusion of
pentylenetetrazole (PTZ). In the s.c. PTZ seizure test, both the incidence and severity of
seizures were decreased by
TW-001.
TW-001 (1-10 mg/ml) did not alter resting membrane potential or input resistance of the hippocampal CA1 neurons, but elicited a reversible suppression of stimulus-triggered epileptiform activity in area CA1 and spontaneously occuring epileptiform burst discharges in area CA3 elicited by
picrotoxin. Both field excitatory postsynaptic potentials and population spikes were reversibly depressed by
TW-001 (0.5-15 mg/ml) in a concentration-dependent manner. The sensitivity of postsynaptic neurons to a
glutamate-receptor agonist, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic
acid or
N-methyl-D-aspartate, was not altered by
TW-001 (10 mg/ml). However,
TW-001 (5 mg/ml) clearly increased the magnitude of paired-pulse facilitation.
TW-001 (5-10 mg/ml) reversibly limited the repetitive firing and reduced the maximal rate of rise of action potentials elicited by injection of depolarizing current pulses (0.4 nA, 200 ms) into the pyramidal cells.
TW-001 (1-10 mg/ml) exerted a concentration-dependent reduction of the
tetrodotoxin-sensitive
sodium currents and high voltage-activated
calcium currents. These results suggest that
TW-001 is an interesting new
anticonvulsant agent that exerts its
anticonvulsant activity through inhibition of
sodium and
calcium channels, stabilizing neuronal membrane excitability and inhibiting
glutamate release.