Minocycline prevents glutamate-induced apoptosis of cerebellar granule neurons by differential regulation of p38 and Akt pathways

Rongbiao Pi, Wenming Li, Nelson T K Lee, Hugh H N Chan, Yongmei Pu, Nga Chan Ling, Nikolaus J. Sucher, Donald C. Chang, Mingtao Li, Yifan Han

Research output: Journal article publicationJournal articleAcademic researchpeer-review

120 Citations (Scopus)

Abstract

Minocycline has been shown to have remarkably neuroprotective qualities, but underlying mechanisms remain elusive. We reported here the robust neuroprotection by minocycline against glutamate-induced apoptosis through regulations of p38 and Akt pathways. Pre-treatment of cerebellar granule neurons (CGNs) with minocycline (10-100 μM) elicited a dose-dependent reduction of glutamate excitotoxicity and blocked glutamate-induced nuclear condensation and DNA fragmentations. Using patch-clamping and fluorescence Ca2+ imaging techniques, it was found that minocycline neither blocked NMDA receptors, nor reduced glutamate-caused rises in intracellular Ca2+. Instead, confirmed by immunoblots, minocycline in vivo and in vitro was shown to directly inhibit the activation of p38 caused by glutamate. A p38-specific inhibitor, SB203580, also attenuated glutamate excitotoxicity. Furthermore, the neuroprotective effects of minocycline were blocked by phosphatidylinositol 3-kinase (PI3-K) inhibitors LY294002 and wortmannin, while pharmacologic inhibition of glycogen synthase kinase 3β (GSKSβ) attenuated glutamate-induced apoptosis. In addition, immunoblots revealed that minocycline reversed the suppression of phosphorylated Akt and GSKSβ caused by glutamate, as were abolished by PI3-K inhibitors. These results demonstrate that minocycline prevents glutamate-induced apoptosis in CGNs by directly inhibiting p38 activity and maintaining the activation of PI3-K/Akt pathway, which offers a novel modality as to how the drug exerts protective effects.
Original languageEnglish
Pages (from-to)1219-1230
Number of pages12
JournalJournal of Neurochemistry
Volume91
Issue number5
DOIs
Publication statusPublished - 1 Dec 2004
Externally publishedYes

Keywords

  • Apoptosis
  • Glutamate
  • Minocycline
  • NMDA receptors
  • p38
  • Phosphatidylinositol 3-kinase/Akt

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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