Synergistic neuroprotection by epicatechin and quercetin: Activation of convergent mitochondrial signaling pathways

M. Nichols, J. Zhang, B. M. Polster, P. A. Elustondo, A. Thirumaran, Evgeny Pavlov, G. S. Robertson

Research output: Contribution to journalArticle

Abstract

In view of evidence that increased consumption of epicatechin (E) and quercetin (Q) may reduce the risk of stroke, we have measured the effects of combining E and Q on mitochondrial function and neuronal survival following oxygen-glucose deprivation (OGD). Relative to mouse cortical neuron cultures pretreated (24h) with either E or Q (0.1-10μM), E+Q synergistically attenuated OGD-induced neuronal cell death. E, Q and E+Q (0.3μM) increased spare respiratory capacity but only E+Q (0.3μM) preserved this crucial parameter of neuronal mitochondrial function after OGD. These improvements were accompanied by corresponding increases in cyclic AMP response element binding protein (CREB) phosphorylation and the expression of CREB-target genes that promote neuronal survival (Bcl-2) and mitochondrial biogenesis (PGC-1α). Consistent with these findings, E+Q (0.1 and 1.0μM) elevated mitochondrial gene expression (MT-ND2 and MT-ATP6) to a greater extent than E or Q after OGD. Q (0.3-3.0μM), but not E (3.0μM), elevated cytosolic calcium (Ca<sup>2+</sup>) spikes and the mitochondrial membrane potential. Conversely, E and E+Q (0.1 and 0.3μM), but not Q (0.1 and 0.3μM), activated protein kinase B (Akt). Nitric oxide synthase (NOS) inhibition with L-N<sup>G</sup>-nitroarginine methyl ester (1.0μM) blocked neuroprotection by E (0.3μM) or Q (1.0μM). Oral administration of E+Q (75mg/kg; once daily for 5days) reduced hypoxic-ischemic brain injury. These findings suggest E and Q activate Akt- and Ca<sup>2+</sup>-mediated signaling pathways that converge on NOS and CREB resulting in synergistic improvements in neuronal mitochondrial performance which confer profound protection against ischemic injury.

Original languageEnglish (US)
Article number16568
Pages (from-to)75-94
Number of pages20
JournalNeuroscience
Volume308
DOIs
StatePublished - Nov 12 2015

Fingerprint

Catechin
Quercetin
Cyclic AMP Response Element-Binding Protein
Oxygen
Glucose
Nitric Oxide Synthase
Proto-Oncogene Proteins c-akt
Calcium Signaling
Mitochondrial Genes
Mitochondrial Membrane Potential
NG-Nitroarginine Methyl Ester
Organelle Biogenesis
Brain Injuries
Oral Administration
Cell Death
Stroke
Phosphorylation
Gene Expression
Neurons
Neuroprotection

Keywords

  • CAMP response element-binding protein
  • Flavonoid
  • Mitochondria
  • Neuroprotection
  • Nitric oxide synthase
  • Protein kinase B

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Nichols, M., Zhang, J., Polster, B. M., Elustondo, P. A., Thirumaran, A., Pavlov, E., & Robertson, G. S. (2015). Synergistic neuroprotection by epicatechin and quercetin: Activation of convergent mitochondrial signaling pathways. Neuroscience, 308, 75-94. [16568]. https://doi.org/10.1016/j.neuroscience.2015.09.012

Synergistic neuroprotection by epicatechin and quercetin : Activation of convergent mitochondrial signaling pathways. / Nichols, M.; Zhang, J.; Polster, B. M.; Elustondo, P. A.; Thirumaran, A.; Pavlov, Evgeny; Robertson, G. S.

In: Neuroscience, Vol. 308, 16568, 12.11.2015, p. 75-94.

Research output: Contribution to journalArticle

Nichols, M. ; Zhang, J. ; Polster, B. M. ; Elustondo, P. A. ; Thirumaran, A. ; Pavlov, Evgeny ; Robertson, G. S. / Synergistic neuroprotection by epicatechin and quercetin : Activation of convergent mitochondrial signaling pathways. In: Neuroscience. 2015 ; Vol. 308. pp. 75-94.
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abstract = "In view of evidence that increased consumption of epicatechin (E) and quercetin (Q) may reduce the risk of stroke, we have measured the effects of combining E and Q on mitochondrial function and neuronal survival following oxygen-glucose deprivation (OGD). Relative to mouse cortical neuron cultures pretreated (24h) with either E or Q (0.1-10μM), E+Q synergistically attenuated OGD-induced neuronal cell death. E, Q and E+Q (0.3μM) increased spare respiratory capacity but only E+Q (0.3μM) preserved this crucial parameter of neuronal mitochondrial function after OGD. These improvements were accompanied by corresponding increases in cyclic AMP response element binding protein (CREB) phosphorylation and the expression of CREB-target genes that promote neuronal survival (Bcl-2) and mitochondrial biogenesis (PGC-1α). Consistent with these findings, E+Q (0.1 and 1.0μM) elevated mitochondrial gene expression (MT-ND2 and MT-ATP6) to a greater extent than E or Q after OGD. Q (0.3-3.0μM), but not E (3.0μM), elevated cytosolic calcium (Ca2+) spikes and the mitochondrial membrane potential. Conversely, E and E+Q (0.1 and 0.3μM), but not Q (0.1 and 0.3μM), activated protein kinase B (Akt). Nitric oxide synthase (NOS) inhibition with L-NG-nitroarginine methyl ester (1.0μM) blocked neuroprotection by E (0.3μM) or Q (1.0μM). Oral administration of E+Q (75mg/kg; once daily for 5days) reduced hypoxic-ischemic brain injury. These findings suggest E and Q activate Akt- and Ca2+-mediated signaling pathways that converge on NOS and CREB resulting in synergistic improvements in neuronal mitochondrial performance which confer profound protection against ischemic injury.",
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