C. Ito et al., U-92032, A T-TYPE CA2+ CHANNEL BLOCKER AND ANTIOXIDANT, REDUCES NEURONAL ISCHEMIC INJURIES, European journal of pharmacology, 257(3), 1994, pp. 203-210
Several diphenylmethylpiperazine derivatives are potential therapeutic
agents for prevention of ischemic injuries in the heart and brain, be
cause of their ability to block Ca2+ currents and their antioxidant ac
tivity. In this study, the current lead compound, U-99032 o)-4-(1-meth
ylethyl)-2,4,6-cycloheptatrien-1-one), has been compared with flunariz
ine and nifedipine (well-known T- and L-type Ca2+ channel antagonists,
respectively) for their effects on Ca2+ channels in a mouse neuronal
cell line, N1E-115 cells, and their ability to preserve the phenomenon
of long-term potentiation and to improve neurological symptoms in ger
bil ischemic models. U-92032, like flunarizine, blocked transient Ba2 currents (I-Ba) through T-type Ca2+ channels with no effect on nifedi
pine-sensitive non-inactivating currents. Transient I-Ba was reduced b
y U-92032 at a constant rate, the magnitude of which depended on the d
rug concentration, probably because of a time-dependent accumulation o
f the lipophilic drug in the membrane phase. For instance, the drug at
6 mu M reduced I-Ba by 21% per min and abolished it in less than 5 mi
n, about 3 times faster than flunarizine at the same concentration. Ot
herwise, U-92032 behaved like flunarizine, showing a use-dependent blo
ck without noticeable effects on the current-voltage relationship for
transient I-Ba. Oral administration of U-92032 (1 and 25 mg/kg) or flu
narizine (25 mg/kg), but not nifedipine (50 mg/kg), to gerbils 1 h pri
or to bilateral carotid artery occlusion, preserved long-term potentia
tion in hippocampal CA1 neurons, which were largely abolished by ische
mia without the drug treatment. Also, U-92032 and flunarizine (10 mg/k
g) improved neurological symptoms in gerbils with unilateral carotid a
rtery occlusion. Similar improvements by nifedipine were observed at a
higher dose (30 mg/kg). It appears that U-92032 is a potent, selectiv
e T-type Ca2+ channel antagonist, and possesses the ability to protect
neurons from ischemic injuries at least as effectively as flunarizine
. At present, we do not know the extent of contribution by the antioxi
dant activity of U-92032 to its neuroprotective actions, but are certa
in of its beneficial effects because of the involvement of the oxygen-
induced toxicity in the cascade of neuronal ischemic injuries.