NO-induced neuroprotection in ischemic preconditioning stimulates mitochondrial Mn-SOD activity and expression via RAS/ERK1/2 pathway

A. Scorziello, M. Santillo, A. Adornetto, C. Dell'Aversano, R. Sirabella, S. Damiano, L. M T Canzoniero, G. F. Di Renzo, L. Annunziato

Research output: Contribution to journalArticle

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Abstract

To identify the transductional mechanisms responsible for the neuroprotective effect of nitric oxide (NO) during ischemic preconditioning (IPC), we investigated the effects of this gaseous mediator on mitochondrial Mn-superoxide dismutase (Mn-SOD) expression and activity. In addition, the possible involvement of Ras/extracellular-regulated kinase (ERK) ERK1/2 pathway in preserving cortical neurons exposed to oxygen and glucose deprivation (OGD) followed by reoxygenation was also examined. Ischemic preconditioning was obtained by exposing neurons to a 30-min sublethal OGD (95% N2 and 5% CO2). Then, after a 24-h interval, neurons were exposed to 3 h of OGD followed by 24 h of reoxygenation (OGD/Rx). Our results revealed that IPC reduced cytochrome c (cyt c) release into the cytosol, improved mitochondrial function, and decreased free radical production. Moreover, it induced an increase in nNOS expression and NO production and promoted ERK1/2 activation. These effects were paralleled by an increase in Mn-SOD expression and activity that persisted throughout the following OGD phase. When the neurons were treated with L-NAME, a well known NOS inhibitor, the increase in Mn-SOD expression occurring during IPC was reduced and, as a result, IPC-induced neuroprotection was prevented. Similarly, when ERK1/2 was inhibited by its selective inhibitor PD98059, the increase in Mn-SOD expression observed during IPC was almost completely abolished. As a result, its neuroprotective effect on cellular survival was thwarted. The present findings indicate that during IPC the increase in Mn-SOD expression and activity are paralleled by NO production. This suggests that NO neuroprotective role occurs through the stimulation of Mn-SOD expression and activity. In particular, NO via Ras activation stimulates downstream ERK1/2 cascade. This pathway, in turn, post-transcriptionally activates Mn-SOD expression and activity, thus promoting neuroprotection during preconditioning.

Original languageEnglish
Pages (from-to)1472-1480
Number of pages9
JournalJournal of Neurochemistry
Volume103
Issue number4
DOIs
Publication statusPublished - Nov 2007

Fingerprint

Ischemic Preconditioning
MAP Kinase Signaling System
Superoxide Dismutase
Nitric Oxide
Neurons
Oxygen
Glucose
Neuroprotective Agents
Gasotransmitters
Chemical activation
Mitogen-Activated Protein Kinase 3
NG-Nitroarginine Methyl Ester
Cytochromes c
Neuroprotection
Cytosol
Free Radicals
Phosphotransferases

Keywords

  • Cortical neurons
  • ERK1/2
  • Manganese superoxide dismutase
  • Neuronal nitric oxide synthase
  • Nitric oxide
  • Preconditioning

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

NO-induced neuroprotection in ischemic preconditioning stimulates mitochondrial Mn-SOD activity and expression via RAS/ERK1/2 pathway. / Scorziello, A.; Santillo, M.; Adornetto, A.; Dell'Aversano, C.; Sirabella, R.; Damiano, S.; Canzoniero, L. M T; Di Renzo, G. F.; Annunziato, L.

In: Journal of Neurochemistry, Vol. 103, No. 4, 11.2007, p. 1472-1480.

Research output: Contribution to journalArticle

Scorziello, A, Santillo, M, Adornetto, A, Dell'Aversano, C, Sirabella, R, Damiano, S, Canzoniero, LMT, Di Renzo, GF & Annunziato, L 2007, 'NO-induced neuroprotection in ischemic preconditioning stimulates mitochondrial Mn-SOD activity and expression via RAS/ERK1/2 pathway', Journal of Neurochemistry, vol. 103, no. 4, pp. 1472-1480. https://doi.org/10.1111/j.1471-4159.2007.04845.x
Scorziello, A. ; Santillo, M. ; Adornetto, A. ; Dell'Aversano, C. ; Sirabella, R. ; Damiano, S. ; Canzoniero, L. M T ; Di Renzo, G. F. ; Annunziato, L. / NO-induced neuroprotection in ischemic preconditioning stimulates mitochondrial Mn-SOD activity and expression via RAS/ERK1/2 pathway. In: Journal of Neurochemistry. 2007 ; Vol. 103, No. 4. pp. 1472-1480.
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AU - Santillo, M.

AU - Adornetto, A.

AU - Dell'Aversano, C.

AU - Sirabella, R.

AU - Damiano, S.

AU - Canzoniero, L. M T

AU - Di Renzo, G. F.

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N2 - To identify the transductional mechanisms responsible for the neuroprotective effect of nitric oxide (NO) during ischemic preconditioning (IPC), we investigated the effects of this gaseous mediator on mitochondrial Mn-superoxide dismutase (Mn-SOD) expression and activity. In addition, the possible involvement of Ras/extracellular-regulated kinase (ERK) ERK1/2 pathway in preserving cortical neurons exposed to oxygen and glucose deprivation (OGD) followed by reoxygenation was also examined. Ischemic preconditioning was obtained by exposing neurons to a 30-min sublethal OGD (95% N2 and 5% CO2). Then, after a 24-h interval, neurons were exposed to 3 h of OGD followed by 24 h of reoxygenation (OGD/Rx). Our results revealed that IPC reduced cytochrome c (cyt c) release into the cytosol, improved mitochondrial function, and decreased free radical production. Moreover, it induced an increase in nNOS expression and NO production and promoted ERK1/2 activation. These effects were paralleled by an increase in Mn-SOD expression and activity that persisted throughout the following OGD phase. When the neurons were treated with L-NAME, a well known NOS inhibitor, the increase in Mn-SOD expression occurring during IPC was reduced and, as a result, IPC-induced neuroprotection was prevented. Similarly, when ERK1/2 was inhibited by its selective inhibitor PD98059, the increase in Mn-SOD expression observed during IPC was almost completely abolished. As a result, its neuroprotective effect on cellular survival was thwarted. The present findings indicate that during IPC the increase in Mn-SOD expression and activity are paralleled by NO production. This suggests that NO neuroprotective role occurs through the stimulation of Mn-SOD expression and activity. In particular, NO via Ras activation stimulates downstream ERK1/2 cascade. This pathway, in turn, post-transcriptionally activates Mn-SOD expression and activity, thus promoting neuroprotection during preconditioning.

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