Hung-Ming Wu1, Chiung-Chun Huang1, Li-Hsin Li1,
Jing-Jane Tsai2 and Kuei-Sen Hsu1,*
1Departmentﾊof Pharmacology and 2Department of
Neurology, College of Medicine, National Cheng-Kung University,
Tainan City, Taiwan 70101
*ﾊTo whom correspondence should be addressed.
Abstract: 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ﾊg/kg,ﾊ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ﾊ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ﾊmg/ml)
in a concentration-dependent manner. The sensitivity of postsynaptic neurons
to a glutamate-receptor agonist, a-amino-3-hydroxy-5-methylisoxazole-4-propionic
acid or N-methyl-D-aspartate, was not altered
by TW-001 (10ﾊmg/ml). However, TW-001 (5ﾊmg/ml) clearly increased the magnitude
of paired-pulse facilitation. TW-001 (5-10ﾊ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ﾊnA, 200ﾊms) into
the pyramidal cells. TW-001 (1-10ﾊ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.
Keywords: Chai-Hu-Long-Ku-Mu-Li-Tan (TW-001), Epileptiform activity,
Paired-pulse facilitation,
Sodium channel, Calcium channel