Rolipram, a selective phosphodiesterase type-IV inhibitor, prevents induction of heat shock protein HSP-70 and hsp-70 mRNA in rat retrosplenial cortex by the NMDA receptor antagonist dizocilpine.
The non-competitive NMDA receptor antagonists, such as (+)-MK-801 (dizocilpine), cause the expression of heat shock protein HSP-70 and pathomorphological damage in the retrosplenial cortex of the rat brain. However, the precise mechanism(s) underlying the neurotoxicity of NMDA receptor antagonists is unknown. The present study was undertaken to examine the role of phosphodiesterase type IV in the expression of heat shock genes induced by dizocilpine. Heat shock protein HSP-70, which is known as a sensitive marker of neuron injury, was induced in the retrosplenial cortex of the rat brain 24 h after a single administration of dizocilpine (1 mg/kg). Pretreatment with the specific phosphodiesterase type IV inhibitor rolipram (2.5, 5 or 10 mg/kg, 15 min before dizocilpine) attenuated the expression of HSP-70 and hsp-70 mRNA induced by dizocilpine (1 mg/kg) in a dose-dependent manner. Furthermore, another phosphodiesterase type IV inhibitor, Ro 20-1724 (5 or 10 mg/kg, 15 min before dizocilpine), and a non-selective phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX) (5 or 10 mg/kg, 15 min before dizocilpine), significantly attenuated the expression of HSP-70 protein and hsp-70 mRNA induced in the retrosplenial cortex by dizocilpine. However, the induction of the immediate early gene c-fos and microglial activation in the retrosplenial cortex after administration of dizocilpine was not attenuated by pretreatment with rolipram (5 or 10 mg/kg, 15 min before dizocilpine). Moreover, histopathological study indicated that pretreatment with rolipram (5 or 10 mg/kg, 15 min before dizocilpine) did not prevent the formation of vacuoles caused by treatment with dizocilpine. The present findings suggest that phosphodiesterase type IV may play a significant role in the expression of HSP-70 protein and hsp-70 mRNA in the rat retrosplenial cortex after administration of dizocilpine, and that phosphodiesterase type IV may not play a role in the neurotoxicity of NMDA receptor antagonists such as dizocilpine.
Hashimoto
K
K
Division of Cortical Function Disorders, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Tomitaka
S
S
Bi
Y
Y
Narita
N
N
Minabe
Y
Y
Iyo
M
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D017628:Microglia / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D011760:Pyrrolidinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D020889:Rolipram
D018691:Excitatory Amino Acid Antagonists; D018840:HSP70 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; D010726:Phosphodiesterase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D011760:Pyrrolidinones; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D020889:Rolipram