J Korean Soc Neonatol.  2007 May;14(1):1-10.

The Expression of Isoforms of Nitric Oxide Synthase (NOS) and Subunits of N-methyl-D-aspartate (NMDA) Receptor according to Administration of Mycophenolic Acid before or after Perinatal Hypoxic Ischemic Brain Injury

• Yang SH
• Shin JY
• Cha SH
• Park HJ
• Lee KH
• Lee GH
• Choi EJ
• Kim JK
• Chung HL
• Seo ES
• Kim WT

Abstract

PURPOSE: Mycophenolic acid (MPA), a potent inhibitor of inosine-monophosphate dehydrogenase (IMPDH), was used as a new immunosuppressive drug since 1990s. It was reported that MPA increased neuronal survival after excitotoxic injury, induced apoptosis in microglial cells, inhibited the induction of inducible nitric oxide synthase (iNOS) in astrocytes. and inhibited microglial cell proliferation in N-methyl-D-aspartate (NMDA) induced hippocampal cells. However, the effects of MPA on the perinatal hypoxic-ischemic (HI) brain injury had not been yet evaluated. Therefore, we examined whether MPA could be neuroprotective in the HI brain injury.
METHODS
Cortical cells were cultured using a 18-day-pregnant Sprague-Dawley (SD) rats and incubated in 1% O2 incubator for hypoxia. MPA (10 ug/mL) before or after a HI insult were treated. Seven-day-old SD rat pups were subjected to left carotid occlusion followed by 2.5 hours of hypoxic exposure (8% O2). MPA (10 mg/kg) were administrated intraperitoneally before or after a HI insult. Nitric oxide (NO) activity and expression of N-methyl-D-aspartate (NMDA) receptors also measured using Real-time PCR with primer pairs of isoforms of NOS; iNOS, endothelial NOS (eNOS), neuronal NOS (nNOS), and subunits of NMDA receptors; NR1, NR2A, NR2B, NR2C, NR2D.
RESULTS
The expression of iNOS was decreased in the hypoxia group but increased in the MPA-treated group. However express or that eNOS and nNOS were inversed. The expression of all NMDA receptor subunits except NR2B was decreased in the hypoxia group but increased in the MPA-treated group.
CONCLUSION
This study indicates that the administration of MPA before a HI insult could significantly protect against perinatal HI brain injury via some parts of NO-mediated or excitotoxic mechanisms.

Keyword

Mycophenolic acid; Hypoxic-Ischemia; Nitric oxide synthase (NOS); N-methyl-D-aspartate (NMDA)

MeSH Terms

Animals
Anoxia
Apoptosis
Astrocytes
Brain Injuries*
Brain*
Cell Proliferation
Incubators
Mycophenolic Acid*
N-Methylaspartate*
Neurons
Nitric Oxide Synthase Type II
Nitric Oxide Synthase*
Nitric Oxide*
Oxidoreductases
Protein Isoforms*
Rats
Rats, Sprague-Dawley
Real-Time Polymerase Chain Reaction
Receptors, N-Methyl-D-Aspartate
Mycophenolic Acid
N-Methylaspartate
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Oxidoreductases
Protein Isoforms
Receptors, N-Methyl-D-Aspartate