Blockade of phencyclidine-induced cortical apoptosis and deficits in prepulse inhibition by M40403, a superoxide dismutase mimetic.
Repetitive administration of phencyclidine (PCP) in the perinatal period results in cortical apoptosis and a long-lasting deficit in sensorimotor gating. Because these changes are olanzapine-sensitive, we have suggested that the effects of perinatal PCP could be used to model certain aspects of schizophrenia. Studies of PCP and N-methyl-D-aspartate-induced cell death suggested that superoxide could play a role in the pathway leading to death after PCP administration. The purpose of the current study was to determine whether the in vivo administration of M40403, a superoxide dismutase mimetic, could prevent PCP-induced cortical apoptosis and/or deficits in prepulse inhibition. Perinatal rat pups were administered 10 mg/kg PCP on postnatal (PN) days 7, 9, and 11 with or without treatment with 10 mg/kg M40403. Pups were either killed on PN 12 for analysis of various apoptotic markers or they were assessed for prepulse inhibition on PN 24 to 26. Treatment with M40403 2 and 24 h after each PCP treatment prevented PCP-induced increases in two measures of apoptosis in the dorsolateral frontal cortex and in the olfactory cortex. PCP-induced proapoptotic changes in Bax and Bcl-X(L) were also prevented by M40403 treatment. This regimen did not prevent the deficit in prepulse inhibition caused by PCP treatment, but when the treatment regimen was extended through PN 23, M40403 completely prevented the PCP-induced deficit in prepulse inhibition. These data suggest that perinatal PCP treatment leads to long-lasting changes in the pathway(s), leading to cell death and behavioral deficits, and that the superoxide radical plays a critical role in the underlying mechanism.
Wang
Cheng
C
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555-1031, USA.
McInnis
Justin
J
West
J Brett
JB
Bao
Jinfeng
J
Anastasio
Noelle
N
Guidry
Jon A
JA
Ye
Yanping
Y
Salvemini
Daniela
D
Johnson
Kenneth M
KM
D000161:Acoustic Stimulation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D008345:Manganese; D018716:Molecular Mimicry; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000523:psychology; D009942:Organometallic Compounds / Q000494:pharmacology*; D010622:Phencyclidine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000494:pharmacology*
D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D009942:Organometallic Compounds; C121876:imisopasem manganese; D008345:Manganese; D013482:Superoxide Dismutase; D010622:Phencyclidine