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Neuroprotection and acidosis induced by cortical spreading depression

Authors Kwong KK, Chan ST

Received 25 October 2016

Accepted for publication 26 October 2016

Published 12 December 2016 Volume 2016:12 Pages 3191—3194

DOI https://doi.org/10.2147/NDT.S125677

Checked for plagiarism Yes

Editor who approved publication: Dr Roger Pinder


Kenneth K Kwong, Suk-tak Chan
 
Department of Radiology, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA
 
We read with interest the article “Cortical spreading depression produces a neuroprotective effect activating mitochondrial uncoupling protein-5” published in Neuropsychiatr Dis Treat by Viggiano et al.1 The authors showed that cerebral spreading depression (CSD) triggered uncoupling protein-5 (UCP-5),1 which had been reported to exert a long-term effect upon neuron protection.2 The result is another piece in CSD literature on modifying gene expressions to provide neuroprotection to subsequent ischemic episodes.3,4 

Authors' reply
Giovanni Messina1,2
Emanuela Viggiano1,3
Vincenzo Monda1
Antonietta Messina1
Fiorenzo Moscatelli2
Anna Valenzano2
Domenico Tafuri4
Vincenzo De Luca5
Giuseppe Cibelli2
Marcellino Monda1
 
1Section of Human Physiology and Unit of Dietetic and Sport Medicine, Department of Experimental Medicine, Second University of Naples, Caserta, 2Department of Clinical and Experimental Medicine, University of Foggia, Foggia, 3Department of Medicine, University of Padua, Padua, 4Department of Motor Sciences and Wellness, University of Naples “Parthenope,” Napoli, Italy; 5Department of Psychiatry, University of Toronto, Toronto, ON, Canada
 
Thank you for the attention paid to our article entitled: “Cortical spreading depression produces a neuroprotective effect activating mitochondrial uncoupling protein-5”.1 We do agree that cerebral spreading depression (CSD)-induced acidosis is an intriguing aspect of the neuroprotection puzzle. It is well known that CSD is involved in the pathophysiology of migraine, cerebral ischemia, subarachnoid hemorrhage, and traumatic brain injury.2–7 
View the original paper by Viggiano and colleagues.

 

Dear editor

We read with interest the article “Cortical spreading depression produces a neuroprotective effect activating mitochondrial uncoupling protein-5” published in Neuropsychiatr Dis Treat by Viggiano et al.1 The authors showed that cerebral spreading depression (CSD) triggered uncoupling protein-5 (UCP-5),1 which had been reported to exert a long-term effect upon neuron protection.2 The result is another piece in CSD literature on modifying gene expressions to provide neuroprotection to subsequent ischemic episodes.3,4

An unmentioned but additional factor for neuroprotection in CSD could be acidosis.

Acidosis is a known consequence of CSD.5 In the literature, brief acidosis in ischemic conditions when oxygen supply is low has been shown to be cytoprotective and neuroprotective,610 a result related sometimes to the concept of the “pH paradox.”9,11,12 Acidosis had been reported to reduce stroke infarct size with CO2 applied for a short time after reperfusion6 as well as during ischemic stroke.10 Brief acidosis applied after birth asphyxia7 was reported to successfully suppress brain alkalosis, which led to seizures. Hence, brief and relatively mild acidosis induced under the condition of CSD may be one of the neuroprotective factors for CSD. The role of acidosis in neuroprotection by CSD warrants further investigation.

Interestingly, CSD-induced acidosis could be one explanation of impaired cerebral vascular reactivity1316 after CSD. It has been reported that once tissue reaches a certain low pH threshold, blood flow increase would be insignificant in response to even stronger CO2 challenge.10

Disclosure

The authors report no conflicts of interest in this communication.


References

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Viggiano E, Monda V, Messina A, et al. Cortical spreading depression produces a neuroprotective effect activating mitochondrial uncoupling protein-5. Neuropsychiatr Dis Treat. 2016;12:1705–1710.

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Nakase T, Yoshida Y, Nagata K. Amplified expression of uncoupling proteins in human brain ischemic lesions. Neuropathology. 2007;27(5):442–447.

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Passaro D, Rana G, Piscopo M, Viggiano E, De Luca B, Fucci L. Epigenetic chromatin modifications in the cortical spreading depression. Brain Res. 2010;1329:1–9.

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Taga K, Patel PM, Drummond JC, Cole DJ, Kelly PJ. Transient neuronal depolarization induces tolerance to subsequent forebrain ischemia in rats. Anesthesiology. 1997;87(4):918–925.

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Mutch WA, Hansen AJ. Extracellular pH changes during spreading depression and cerebral ischemia: mechanisms of brain pH regulation. J Cereb Blood Flow Metab. 1984;4(1):17–27.

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Fan YY, Shen Z, He P, et al. A novel neuroprotective strategy for ischemic stroke: transient mild acidosis treatment by CO2 inhalation at reperfusion. J Cereb Blood Flow Metab. 2014;34(2):275–283.

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Simon RP, Niro M, Gwinn R. Brain acidosis induced by hypercarbic ventilation attenuates focal ischemic injury. J Pharmacol Exp Ther. 1993;267(3):1428–1431.

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Authors’ reply

Giovanni Messina,1,2 Emanuela Viggiano,1,3 Vincenzo Monda,1 Antonietta Messina,1 Fiorenzo Moscatelli,2 Anna Valenzano,2 Domenico Tafuri,4 Vincenzo De Luca,5 Giuseppe Cibelli,2 Marcellino Monda1

1Section of Human Physiology and Unit of Dietetic and Sport Medicine, Department of Experimental Medicine, Second University of Naples, Caserta, 2Department of Clinical and Experimental Medicine, University of Foggia, Foggia, 3Department of Medicine, University of Padua, Padua, 4Department of Motor Sciences and Wellness, University of Naples “Parthenope,” Napoli, Italy; 5Department of Psychiatry, University of Toronto, Toronto, ON, Canada

Correspondence: Giovanni Messina, Department of Clinical and Experimental Medicine, University of Foggia, Via L Pinto, 71122 Foggia, Italy, Tel +39 81 566 5804, Fax +39 81 566 5844, Email gianni.messina@unina2.it

Dear editor

Thank you for the attention paid to our article entitled: “Cortical spreading depression produces a neuroprotective effect activating mitochondrial uncoupling protein-5”.1 We do agree that cerebral spreading depression (CSD)-induced acidosis is an intriguing aspect of the neuroprotection puzzle. It is well known that CSD is involved in the pathophysiology of migraine, cerebral ischemia, subarachnoid hemorrhage, and traumatic brain injury.27 Moreover, it is also involved in traumatic and spontaneous intracerebral hemorrhage, as well as in migraine aura and epilepsy.810 The induction of CSD during ischemia causes an increase in tissue damage, while preconditioning with CSD decreases the damage induced by a subsequent episode of ischemia.11 Anyway, the mechanisms underlying these effects, as well as the neuroprotection induced by CSD, remain unclear.

Our results are consistent with the hypothesis that CSD might induce its neuroprotective effect by means of uncoupling electron transport from ATP synthesis, mediated by the activation of the mitochondrial uncoupling proteins (UCPs). Such an idea is supported by the experimental evidence of the neuroprotective effect due to upregulation of UCPs in response to oxidative stress; in fact, reactive oxygen species seem to play a major role in the phenomenon of ischemia–reperfusion.12 But, reperfusion itself induces also an important inflammatory response, characterized by a massive production of free radicals and by the activation of the complement and leukocytes. Therefore, the intracellular acidosis, the oxidative stress, the production of cytokines, and the secondary mitochondrial lesions may represent competing factors involved in the CSD-induced neuroprotection.1115

Therefore, according to authors’ letter, further studies are needed to prove this multifaceted reality.

Disclosure

The authors report no conflicts of interest in this communication.


References

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Viggiano E, Monda V, Messina A, et al. Cortical spreading depression produces a neuroprotective effect activating mitochondrial uncoupling protein-5. Neuropsychiatr Dis Treat. 2016;12:1705–1710.

2.

Kramer DR, Fujii T, Ohiorhenuan I, Liu CY. Cortical spreading depolarization: pathophysiology, implications, and future directions. J Clin Neurosci. 2016;24:22–27.

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Bhaskar S, Saeidi K, Borhani P, Amiri H. Recent progress in migraine pathophysiology: role of cortical spreading depression and magnetic resonance imaging. Eur J Neurosci. 2013;38(11):3540–3551.

4.

Dreier JP, Körner K, Ebert N, et al. Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-L-arginine induces cortical spreading ischemia when K+ is increased in the subarachnoid space. J Cereb Blood Flow Metab. 1998;18(9):978–990.

5.

Gold L, Back T, Arnold G, et al. Cortical spreading depression-associated hyperemia in rats: involvement of serotonin. Brain Res. 1998;783(2):188–193.

6.

Hartings JA, Tortella FC, Rolli ML. AC electrocorticographic correlates of peri-infarct depolarizations during transient focal ischemia and reperfusion. J Cereb Blood Flow Metab. 2006;26(5):696–707.

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Nilsson P, Gazelius B, Carlson H, Hillered L. Continuous measurement of changes in regional cerebral blood flow following cortical compression contusion trauma in the rat. J Neurotrauma. 1996;13(4):201–207.

8.

Eising E, Shyti R, ‘t Hoen PA, et al. Cortical spreading depression causes unique dysregulation of inflammatory pathways in a transgenic mouse model of migraine. Mol Neurobiol. 2016. Epub Mar 31, 2016.

9.

Petrusic I, Zidverc-Trajkovic J. Cortical spreading depression: origins and paths as inferred from the sequence of events during migraine aura. Funct Neurol. 2014;29(3):207–212.

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Yeom JS, Kim YS, Lee JH, Jung S, Kwon OY. Temporal current-source of spikes suggests initial treatment failure in childhood absence epilepsy. Seizure. 2015;31:88–93.

11.

Viggiano A, Viggiano E, Valentino I, et al. Cortical spreading depression affects reactive oxygen species production. Brain Res. 2011;1368:11–18.

12.

Kim-Han JS, Dugan LL. Mitochondrial uncoupling proteins in the central nervous system. Antioxid Redox Signal. 2005;7(9–10):1173–1181.

13.

Betts J, Jaros E, Perry RH, et al. Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvement. Neuropathol Appl Neurobiol. 2006;32(4):359–373.

14.

Seitz I, Dirnagl U, Lindauer U. Impaired vascular reactivity of isolated rat middle cerebral artery after cortical spreading depression in vivo. J Cereb Blood Flow Metab. 2004;24(5):526–530.

15.

Gourdin MJ, Bree B, De Kock M. The impact of ischaemia-reperfusion on the blood vessel. Eur J Anaesthesiol. 2009;26(7):537–547.

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