title: Methylene blue induces macroautophagy through 5' adenosine monophosphate-activated protein kinase pathway to protect neurons from serum deprivation.
abstract: Methylene blue has been shown to be neuroprotective in multiple experimental neurodegenerative disease models. However, the mechanisms underlying the neuroprotective effects have not been fully elucidated. Previous studies have shown that macroautophagy has multiple beneficial roles for maintaining normal cellular homeostasis and that induction of macroautophagy after myocardial ischemia is protective. In the present study we demonstrated that methylene blue could protect HT22 hippocampal cell death induced by serum deprivation, companied by induction of macroautophagy. We also found that methylene blue-mediated neuroprotection was abolished by macroautophagy inhibition. Interestingly, 5' adenosine monophosphate-activated protein kinase (AMPK) signaling, but not inhibition of mammalian target of rapamycin signaling, was activated at 12 and 24 h after methylene blue treatment in a dose-dependent manner. Methylene blue-induced macroautophagy was blocked by AMPK inhibitor. Consistent with in vitro data, macroautophagy was induced in the cortex and hippocampus of mouse brains treated with methylene blue. Our findings suggest that methylene blue-induced neuroprotection is mediated, at least in part, by macroautophagy though activation of AMPK signaling.
authors: Department of Pharmacology and Neuroscience, Institute for Alzheimer's Disease and Aging Research, University of North Texas Health Science Center at FortWorth FortWorth, TX, USA.
authors: Luokun
authors: L
authors: Xie
authors: Wenjun
authors: W
authors: Li
authors: Ali
authors: A
authors: Winters
authors: Fang
authors: F
authors: Yuan
authors: Kunlin
authors: K
authors: Jin
authors: Shaohua
authors: S
authors: Yang
keywords: AMPK; Alzheimer disease; macroautophagy; methylene blue; neuroprotection
references: Autophagy. 2010 Nov;6(8):1206-8
references: 20935460
references: J Oncol Pharm Pract. 2011 Dec;17(4):372-80
references: 20861178
references: Science. 2010 Dec 3;330(6009):1344-8
references: 21127245
references: Parasitol Res. 2012 Jul;111(1):1-6
references: 22411634
references: Nat Cell Biol. 2011 May;13(5):568-79
references: 21499257
references: J Neurosci. 1995 Dec;15(12):7837-46
references: 8613723
references: J Neurosci. 2003 Jun 1;23(11):4420-7
references: 12805282
references: Anesthesiology. 2006 Jul;105(1):228
references: 16810025
references: Autophagy. 2009 Jul;5(5):738-40
references: 19395865
references: PLoS One. 2009;4(5):e5318
references: 19415120
references: Apoptosis. 2009 Nov;14(11):1274-88
references: 19757066
references: Curr Opin Cell Biol. 2011 Apr;23(2):198-206
references: 21030235
references: Crit Care Med. 2000 Apr;28(4):958-61
references: 10809266
references: CNS Neurol Disord Drug Targets. 2010 Dec;9(6):701-19
references: 20942791
references: Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16982-7
references: 20833817
references: J Biol Chem. 2011 May 6;286(18):16504-15
references: 21454572
references: Cell. 2008 Jan 11;132(1):27-42
references: 18191218
references: Biochim Biophys Acta. 2009 Sep;1793(9):1496-507
references: 19339210
references: Autophagy. 2008 Jan;4(1):94-6
references: 18000396
references: Neonatal Netw. 2001 Aug;20(5):62-8
references: 12144224
references: PLoS One. 2008 Feb 20;3(2):e1630
references: 18286187
references: J Pediatr Hematol Oncol. 2004 Feb;26(2):116
references: 14767201
references: Nature. 2006 Jun 15;441(7095):880-4
references: 16625205
references: J Ethnopharmacol. 2011 Mar 24;134(2):313-22
references: 21172413
references: Eur J Clin Pharmacol. 2004 Dec;60(10):709-15
references: 15619134
references: Brain Res Mol Brain Res. 1997 Apr;45(1):127-32
references: 9105678
references: J Neurosci Res. 1996 Feb 15;43(4):465-75
references: 8699532
references: Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251-62
references: 22436748
references: Nat Cell Biol. 2011 Sep 02;13(9):1016-23
references: 21892142
references: Neuroscientist. 2010 Aug;16(4):335-41
references: 20360601
references: Ann Pharmacother. 2006 Feb;40(2):299-303
references: 16391008
references: Autophagy. 2012 Apr;8(4):609-22
references: 22361619
references: Cold Spring Harb Perspect Med. 2012 Apr;2(4):a009357
references: 22474616
references: Apoptosis. 2005 Dec;10(6):1243-59
references: 16215683