Comparison of neuroprotective effects induced by alpha-phenyl-N-tert-butyl nitrone (PBN) and N-tert-butyl-alpha-(2 sulfophenyl) nitrone (S-PBN) in lithium-pilocarpine status epilepticus.
The status epilepticus (SE) induced in rats by lithium-pilocarpine (Li-pilo) shares many common features with soman-induced SE including extensive limbic neuropathology. Reactive oxygen species are hypothesized to play a role in the SE induced neuropathology and we propose that the free radical scavengers alpha-phenyl-N-tert-butyl nitrone (PBN) and N-tert-butyl-alpha-(2 sulfophenyl) nitrone (S-PBN) may be neuroprotective. PBN or S-PBN were administered either immediately following pilocarpine (exposure treatment) or 5 min after the onset of SE as determined by ECoG activity. SE was allowed to continue for 3 h before termination with propofol. The rats were sacrified 24 h following pilocarpine administration. S-PBN induced minor effects to reduce SE duration and improve neurological deficit 24 h following pilocarpine administration. One hundred and fifty milligrams per kilograms PBN administered 5 min after SE onset produced significant neuroprotection in the parietal, occipital, perirhinal and piriform cortices as well as the lateral amygdala. One hundred and fifty milligrams per kilograms S-PBN was neuroprotective only in the occipital and perirhinal cortex while 300 mg/kg S-PBN exacerbated cortical neuropathology. S-PBN administered 5 min after SE onset exacerbated neuropathology in thalamic regions. In contrast, PBN and S-PBN administered as exposure treatment exacerbated neuropathology in thalamic and CA3 regions. The differential neuroprotective effects of PBN and S-PBN may be the result of the poor brain penetration by S-PBN. The results suggest that free radical scavenger activity is neuroprotective in cortical regions during cholinergic convulsions. Regional variations in drug-induced neuroprotectant activity in Li-pilo SE are common and suggest multiple mechanisms of neuropathology.
Peterson
Steven L
SL
College of Pharmacy, MSC09 5360, 1 University of New Mexico, Albuquerque, NM 87131-0001, USA. bonfire@unm.edu
Purvis
Rebecca S
RS
Griffith
James W
JW
D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D003497:Cyclic N-Oxides; D004195:Disease Models, Animal; D004569:Electroencephalography; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000627:therapeutic use; D008094:Lithium; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009589:Nitrogen Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D001557:Benzenesulfonates; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; D010862:Pilocarpine; C094272:N-tert-butyl-(2-sulfophenyl)nitrone; C029217:phenyl-N-tert-butylnitrone; D008094:Lithium