Rc. Gupta et al., Depletion of energy metabolites following acetylcholinesterase inhibitor-induced status epilepticus: Protection by antioxidants, NEUROTOXICO, 22(2), 2001, pp. 271-282
Status epilepticus (SE)-induced neuronal injury may involve excitotoxicity,
energy impairment and increased generation of reactive oxygen species (ROS
). Potential treatment therefore should consider agents that protect mitoch
ondrial function and ROS scavengers. In the present study we examined wheth
er the spin trapping agent N-tert-butyl-alpha -phenylnitrone (PBN) and the
antioxidant vitamin E (DL-alpha -tocopherol) protect levels of high-energy
phosphates during SE. In rats, SE was induced by either of two inhibitors o
f acetylcholinesterase (AChE), the organophosphate diisopropylphosphorofluo
ridate (DFP, 1.25 mg/kg, sc)- or the carbamate carbofuran (1.25 mg/kg, sc).
Rats were sacrificed 1 h or 3 days after onset of seizures by head-focused
microwave (power, 10 kW; duration 1.7 s) and levels of the energy-rich pho
sphates adenosine triphosphate (ATP) and phosphocreatine (PCr) and their me
tabolites adenosine diphosphate (ADP) and adenosine monophosphate (AMP), an
d creatine (Cr), respectively, were determined in the cortex, amygdala and
hippocampus. Within 1 h of seizure activity, marked declines were seen in A
TP (34-60%) and PCr (25-52%). Total adenine nucleotides (TAN = ATPS + ADP AMP) and total creatine compounds (TCC = PCr + Cr) were also reduced (TAN
38-60% and TCC 25-47%). No changes in ATP/AMP ratio were seen. Three days a
fter the onset of seizures, recovery of ATP and PCr was significant in the
amygdala and hippocampus, but not in the cortex. Pretreatment of rats with
PEN (200 mg/kg, ip, in a single dose), 30 min before DFP or carbofuran admi
nistration, prevented induced seizures and partially prevented depletion of
high-energy phosphates. Pretreatment with the natural antioxidant vitamin
E (100 mg/kg, ip.day for 3 days), partially prevented loss of high energy p
hosphates without affecting seizures. In controls, citrulline, a product of
nitric oxide synthesis, was found so be highest in tile amygdala, followed
by hippocampus, and lowest in the cortex. DFP- or carbofuran-induced seizu
res caused elevation of citrulline levels seven- to eight-fold in the corte
x and three- to four-fold in the amygdala and hippocampus. These results su
ggest a close relationship between SE, excitotoxicity and energy metabolism
. The involvement of oxidative stress is supported by the findings that DFP
and carbofuran trigger an excessive nitric oxide (NO) production in the se
izure relevant regions of the brain. (C) 2001 Elsevier Science Inc. All rig
hts reserved.