Depletion of energy metabolites following acetylcholinesterase inhibitor-induced status epilepticus: Protection by antioxidants

Citation
Rc. Gupta et al., Depletion of energy metabolites following acetylcholinesterase inhibitor-induced status epilepticus: Protection by antioxidants, NEUROTOXICO, 22(2), 2001, pp. 271-282
Citations number
73
Categorie Soggetti
Neurosciences & Behavoir
Journal title
NEUROTOXICOLOGY
ISSN journal
0161813X → ACNP
Volume
22
Issue
2
Year of publication
2001
Pages
271 - 282
Database
ISI
SICI code
0161-813X(200104)22:2<271:DOEMFA>2.0.ZU;2-L
Abstract
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.