Nitric-oxide-synthase-mediated cyclic guanosine monophosphate production in neonatal rat cerebellar prisms is resistant to calcineurin inhibition

Malcolm R. Macleod*, Steven P. Butcher

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Although the macrolide immunosuppressant tacrolimus (FK506) is neuroprotective in animal models of focal and global cerebral ischaemia, the mechanism of this action is not known. FK506 inhibits the protein phosphatase calcineurin, whose substrates can include nitric oxide synthase (NOS), and the neuroprotective effect of FK506 has been attributed to inhibition of NOS activity. We have examined nitric oxide-mediated cyclic guanosine monophosphate (cGMP) accumulation in neonatal rat cerebellar prisms. As expected, N-methyl-D-aspartate (NMDA) induced a rapid, concentration dependent accumulation of cGMP that was inhibited by the NMDA receptor antagonist dizocilpine (MK801) and the NOS inhibitor L-nitro-arginine methyl ester. Phosphoserine immunopositivity following NMDA exposure was increased in the presence of FK506, confirming inhibition of calcineurin. However, FK506 had no effect on NMDA-stimulated cGMP accumulation. These findings suggest that the neuroprotective effect of FK506 may be mediated by mechanisms other than increased NOS phosphorylation.

Original languageEnglish
Pages (from-to)41-44
Number of pages4
JournalNeuroscience Letters
Volume322
Issue number1
DOIs
Publication statusPublished - 29 Mar 2002

Keywords

  • Calcineurin
  • Cerebellum
  • FK506
  • Neuroprotection
  • Nitric oxide synthase

Fingerprint Dive into the research topics of 'Nitric-oxide-synthase-mediated cyclic guanosine monophosphate production in neonatal rat cerebellar prisms is resistant to calcineurin inhibition'. Together they form a unique fingerprint.

Cite this