Cerebral nitric oxide and mitochondrial function in patients suffering aneurysmal subarachnoid hemorrhage-a translational approach.
Microdialysis
Mitochondrial function
Nitric oxide
Subarachnoid hemorrhage
Journal
Acta neurochirurgica
ISSN: 0942-0940
Titre abrégé: Acta Neurochir (Wien)
Pays: Austria
ID NLM: 0151000
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
17
03
2020
accepted:
11
08
2020
pubmed:
26
8
2020
medline:
13
7
2021
entrez:
26
8
2020
Statut:
ppublish
Résumé
Cerebral ischemia and neuroinflammation following aneurysmal subarachnoid hemorrhage (SAH) are major contributors to poor neurological outcome. Our study set out to investigate in an exploratory approach the interaction between NO and energy metabolism following SAH as both hypoxia and inflammation are known to affect nitric oxide (NO) metabolism and NO in turn affects mitochondria. In seven patients under continuous multimodality neuromonitoring suffering poor-grade aneurysmal SAH, cerebral metabolism and NO levels (determined as a sum of nitrite plus nitrate) were determined in cerebral microdialysate for 14 days following SAH. In additional ex vivo experiments, rat cortex homogenate was subjected to the NO concentrations determined in SAH patients to test whether these NO concentrations impair mitochondrial function (determined by means of high-resolution respirometry). NO levels showed biphasic kinetics with drastically increased levels during the first 7 days (74.5 ± 29.9 μM) and significantly lower levels thereafter (47.5 ± 18.7 μM; p = 0.02). Only during the first 7 days, NO levels showed a strong negative correlation with brain tissue oxygen tension (r = - 0.78; p < 0.001) and a positive correlation with cerebral lactate (r = 0.79; p < 0.001), pyruvate (r = 0.68; p < 0.001), glutamate (r = 0.65; p < 0.001), as well as the lactate-pyruvate ratio (r = 0.48; p = 0.01), suggesting mitochondrial dysfunction. Ex vivo experiments confirmed that the increase in NO levels determined in patients during the acute phase is sufficient to impair mitochondrial function (p < 0.001). Mitochondrial respiration was inhibited irrespectively of whether glutamate (substrate of complex I) or succinate (substrate of complex II) was used as mitochondrial substrate suggesting the inhibition of mitochondrial complex IV. The latter was confirmed by direct determination of complex IV activity. Exploratory analysis of our data suggests that during the acute phase of SAH, NO plays a key role in the neuronal damage impairing mitochondrial function and facilitating accumulation of mitochondrial substrate; further studies are required to understand mechanisms underlying this observation.
Sections du résumé
BACKGROUND
Cerebral ischemia and neuroinflammation following aneurysmal subarachnoid hemorrhage (SAH) are major contributors to poor neurological outcome. Our study set out to investigate in an exploratory approach the interaction between NO and energy metabolism following SAH as both hypoxia and inflammation are known to affect nitric oxide (NO) metabolism and NO in turn affects mitochondria.
METHODS
In seven patients under continuous multimodality neuromonitoring suffering poor-grade aneurysmal SAH, cerebral metabolism and NO levels (determined as a sum of nitrite plus nitrate) were determined in cerebral microdialysate for 14 days following SAH. In additional ex vivo experiments, rat cortex homogenate was subjected to the NO concentrations determined in SAH patients to test whether these NO concentrations impair mitochondrial function (determined by means of high-resolution respirometry).
RESULTS
NO levels showed biphasic kinetics with drastically increased levels during the first 7 days (74.5 ± 29.9 μM) and significantly lower levels thereafter (47.5 ± 18.7 μM; p = 0.02). Only during the first 7 days, NO levels showed a strong negative correlation with brain tissue oxygen tension (r = - 0.78; p < 0.001) and a positive correlation with cerebral lactate (r = 0.79; p < 0.001), pyruvate (r = 0.68; p < 0.001), glutamate (r = 0.65; p < 0.001), as well as the lactate-pyruvate ratio (r = 0.48; p = 0.01), suggesting mitochondrial dysfunction. Ex vivo experiments confirmed that the increase in NO levels determined in patients during the acute phase is sufficient to impair mitochondrial function (p < 0.001). Mitochondrial respiration was inhibited irrespectively of whether glutamate (substrate of complex I) or succinate (substrate of complex II) was used as mitochondrial substrate suggesting the inhibition of mitochondrial complex IV. The latter was confirmed by direct determination of complex IV activity.
CONCLUSIONS
Exploratory analysis of our data suggests that during the acute phase of SAH, NO plays a key role in the neuronal damage impairing mitochondrial function and facilitating accumulation of mitochondrial substrate; further studies are required to understand mechanisms underlying this observation.
Identifiants
pubmed: 32839865
doi: 10.1007/s00701-020-04536-x
pii: 10.1007/s00701-020-04536-x
pmc: PMC7778629
doi:
Substances chimiques
Nitric Oxide
31C4KY9ESH
Lactic Acid
33X04XA5AT
Glutamic Acid
3KX376GY7L
Pyruvic Acid
8558G7RUTR
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
139-149Références
Asano T, Ikegaki I, Suzuki Y, Satoh S, Shibuya M (1989) Endothelin and the production of cerebral vasospasm in dogs. Biochem Biophys Res Commun 159(3):1345–1351
pubmed: 2649099
Bayir H, Kagan VE, Clark RSB, Janesko-Feldman K, Rafikov R, Huang Z, Zhang X, Vagni V, Billiar TR, Kochanek PM (2007) Neuronal NOS-mediated nitration and inactivation of manganese superoxide dismutase in brain after experimental and human brain injury. J Neurochem 101(1):168–181
pubmed: 17394464
Brown GC (1997) Nitric oxide inhibition of cytochrome oxidase and mitochondrial respiration: implications for inflammatory, neurodegenerative and ischaemic pathologies. Mol Cell Biochem 174(1–2):189–192
pubmed: 9309686
Carpenter KLH, Timofeev I, Al-Rawi PG, Menon DK, Pickard JD, Hutchinson PJ (2008) Nitric oxide in acute brain injury: a pilot study of NO(x) concentrations in human brain microdialysates and their relationship with energy metabolism. Acta Neurochir Suppl 102:207–213
pubmed: 19388318
Chaudhry SR, Hafez A, Rezai Jahromi B, Kinfe TM, Lamprecht A, Niemelä M, Muhammad S (2018) Role of damage associated molecular pattern molecules (DAMPs) in Aneurysmal Subarachnoid Hemorrhage (aSAH). Int J Mol Sci. https://doi.org/10.3390/ijms19072035
Fathi AR, Pluta RM, Bakhtian KD, Qi M, Lonser RR (2011) Reversal of cerebral vasospasm via intravenous sodium nitrite after subarachnoid hemorrhage in primates. J Neurosurg 115(6):1213–1220
pubmed: 21888479
pmcid: 4749030
Fisher CM, Kistler JP, Davis JM (1980) Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 6(1):1–9
pubmed: 7354892
Friedrich B, Müller F, Feiler S, Schöller K, Plesnila N (2012) Experimental subarachnoid hemorrhage causes early and long-lasting microarterial constriction and microthrombosis: an in-vivo microscopy study. J Cereb Blood Flow Metab 32(3):447–455
pubmed: 22146194
Goligorsky MS, Tsukahara H, Magazine H, Andersen TT, Malik AB, Bahou WF (1994) Termination of endothelin signaling: role of nitric oxide. J Cell Physiol 158(3):485–494
pubmed: 8126072
Guo Z-N, Shao A, Tong L-S, Sun W, Liu J, Yang Y (2016) The role of nitric oxide and sympathetic control in cerebral autoregulation in the setting of subarachnoid hemorrhage and traumatic brain injury. Mol Neurobiol 53(6):3606–3615
pubmed: 26108186
Hashiguchi A, Yano S, Morioka M, Hamada J, Ushio Y, Takeuchi Y, Fukunaga K (2004) Up-regulation of endothelial nitric oxide synthase via phosphatidylinositol 3-kinase pathway contributes to ischemic tolerance in the CA1 subfield of gerbil hippocampus. J Cereb Blood Flow Metab 24(3):271–279
pubmed: 15091107
Helbok R, Kofler M, Schiefecker AJ, Gaasch M, Rass V, Pfausler B, Beer R, Schmutzhard E (2017) Clinical use of cerebral microdialysis in patients with aneurysmal subarachnoid hemorrhage—state of the art. Front Neurol 8:565
pubmed: 29163332
pmcid: 5676489
Helbok R, Schiefecker AJ, Beer R et al (2015) Early brain injury after aneurysmal subarachnoid hemorrhage: a multimodal neuromonitoring study. Crit Care 19:75
pubmed: 25887441
pmcid: 4384312
Iqbal S, Hayman EG, Hong C, Stokum JA, Kurland DB, Gerzanich V, Simard JM (2016) Inducible nitric oxide synthase (NOS-2) in subarachnoid hemorrhage: Regulatory mechanisms and therapeutic implications. Brain Circ 2(1):8–19
pubmed: 27774520
pmcid: 5074544
Jung CS, Lange B, Zimmermann M, Seifert V (2012) The CSF concentration of ADMA, but not of ET-1, is correlated with the occurrence and severity of cerebral vasospasm after subarachnoid hemorrhage. Neurosci Lett 524(1):20–24
pubmed: 22796469
Jung CS, Oldfield EH, Harvey-White J, Espey MG, Zimmermann M, Seifert V, Pluta RM (2007) Association of an endogenous inhibitor of nitric oxide synthase with cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 107(5):945–950
pubmed: 17977265
Khaldi A, Zauner A, Reinert M, Woodward JJ, Bullock MR (2001) Measurement of nitric oxide and brain tissue oxygen tension in patients after severe subarachnoid hemorrhage. Neurosurgery 49(1):33–38 discussion 38-40
pubmed: 11440457
Khurana VG, Sohni YR, Mangrum WI, McClelland RL, O’Kane DJ, Meyer FB, Meissner I (2004) Endothelial nitric oxide synthase gene polymorphisms predict susceptibility to aneurysmal subarachnoid hemorrhage and cerebral vasospasm. J Cereb Blood Flow Metab 24(3):291–297
pubmed: 15091109
Kleinert H, Pautz A, Linker K, Schwarz PM (2004) Regulation of the expression of inducible nitric oxide synthase. Eur J Pharmacol 500(1–3):255–266
pubmed: 15464038
Kobayashi H, Ide H, Ishii H, Kabuto M, Handa Y, Kubota T (1995) Endothelin-1 levels in plasma and cerebrospinal fluid following subarachnoid haemorrhage. J Clin Neurosci 2(3):252–256
pubmed: 18638823
Kolias AG, Sen J, Belli A (2009) Pathogenesis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage: putative mechanisms and novel approaches. J Neurosci Res 87(1):1–11
pubmed: 18709660
Kozlov AV, Lancaster JR, Meszaros AT, Weidinger A (2017) Mitochondria-meditated pathways of organ failure upon inflammation. Redox Biol 13:170–181
pubmed: 28578275
pmcid: 5458092
Macdonald RL (2014) Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 10(1):44–58
pubmed: 24323051
Miller BA, Turan N, Chau M, Pradilla G (2014) Inflammation, vasospasm, and brain injury after subarachnoid hemorrhage. Biomed Res Int 2014:384342
pubmed: 25105123
pmcid: 4106062
Ng WH, Moochhala S, Yeo TT, Ong PL, Ng PY (2001) Nitric oxide and subarachnoid hemorrhage: elevated level in cerebrospinal fluid and their implications. Neurosurgery 49(3):622–626 discussion 626-627
pubmed: 11523672
Palmer RM, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327(6122):524–526
pubmed: 3495737
Park S, Yamaguchi M, Zhou C, Calvert JW, Tang J, Zhang JH (2004) Neurovascular protection reduces early brain injury after subarachnoid hemorrhage. Stroke 35(10):2412–2417
pubmed: 15322302
Petrov T, Rafols JA (2001) Acute alterations of endothelin-1 and iNOS expression and control of the brain microcirculation after head trauma. Neurol Res 23(2–3):139–143
pubmed: 11320592
Pluta RM, Dejam A, Grimes G, Gladwin MT, Oldfield EH (2005) Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage. JAMA 293(12):1477–1484
pubmed: 15784871
Pluta RM, Oldfield EH, Boock RJ (1997) Reversal and prevention of cerebral vasospasm by intracarotid infusions of nitric oxide donors in a primate model of subarachnoid hemorrhage. J Neurosurg 87(5):746–751
pubmed: 9347984
Reilly C, Amidei C, Tolentino J, Jahromi BS, Macdonald RL (2004) Clot volume and clearance rate as independent predictors of vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg 101(2):255–261
pubmed: 15309916
Sabri M, Ai J, Knight B, Tariq A, Jeon H, Shang X, Marsden PA, Loch Macdonald R (2011) Uncoupling of endothelial nitric oxide synthase after experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab 31(1):190–199
pubmed: 20517322
Sabri M, Ai J, Lakovic K, D’abbondanza J, Ilodigwe D, Macdonald RL (2012) Mechanisms of microthrombi formation after experimental subarachnoid hemorrhage. Neuroscience 224:26–37
pubmed: 22902542
Sakowitz OW, Wolfrum S, Sarrafzadeh AS, Stover JF, Dreier JP, Dendorfer A, Benndorf G, Lanksch WR, Unterberg AW (2001) Relation of cerebral energy metabolism and extracellular nitrite and nitrate concentrations in patients after aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab 21(9):1067–1076
pubmed: 11524611
Sakowitz OW, Wolfrum S, Sarrafzadeh AS, Stover JF, Lanksch WR, Unterberg AW (2002) Temporal profiles of extracellular nitric oxide metabolites following aneurysmal subarachnoid hemorrhage. Acta Neurochir Suppl 81:351–354
pubmed: 12168345
Sayama T, Suzuki S, Fukui M (1999) Role of inducible nitric oxide synthase in the cerebral vasospasm after subarachnoid hemorrhage in rats. Neurol Res 21(3):293–298
pubmed: 10319339
Schneider UC, Xu R, Vajkoczy P (2018) Inflammatory events following subarachnoid hemorrhage (SAH). Curr Neuropharmacol 16(9):1385–1395
pubmed: 29651951
pmcid: 6251050
Sehba FA, Mostafa G, Friedrich V, Bederson JB (2005) Acute microvascular platelet aggregation after subarachnoid hemorrhage. J Neurosurg 102(6):1094–1100
pubmed: 16028769
Sehba FA, Pluta RM, Zhang JH (2011) Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury. Mol Neurobiol 43(1):27–40
pubmed: 21161614
Sehba FA, Schwartz AY, Chereshnev I, Bederson JB (2000) Acute decrease in cerebral nitric oxide levels after subarachnoid hemorrhage. J Cereb Blood Flow Metab 20(3):604–611
pubmed: 10724124
Sprague AH, Khalil RA (2009) Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 78(6):539–552
pubmed: 19413999
pmcid: 2730638
Staub F, Graf R, Gabel P, Köchling M, Klug N, Heiss WD (2000) Multiple interstitial substances measured by microdialysis in patients with subarachnoid hemorrhage. Neurosurgery 47(5):1106–1115 discussion 1115-1116
pubmed: 11063103
Suzuki Y, Osuka K, Noda A, Tanazawa T, Takayasu M, Shibuya M, Yoshida J (1997) Nitric oxide metabolites in the cisternal cerebral spinal fluid of patients with subarachnoid hemorrhage. Neurosurgery 41(4):807–811 discussion 811-812
pubmed: 9316041
Toda N, Ayajiki K, Okamura T (2009) Cerebral blood flow regulation by nitric oxide: recent advances. Pharmacol Rev 61(1):62–97
pubmed: 19293146
Van Mil AHM, Spilt A, Van Buchem MA, Bollen ELEM, Teppema L, Westendorp RGJ, Blauw GJ (2002) Nitric oxide mediates hypoxia-induced cerebral vasodilation in humans. J Appl Physiol 92(3):962–966
pubmed: 11842027
Verhaar MC, Strachan FE, Newby DE, Cruden NL, Koomans HA, Rabelink TJ, Webb DJ (1998) Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation 97(8):752–756
pubmed: 9498538
Weir B, Grace M, Hansen J, Rothberg C (1978) Time course of vasospasm in man. J Neurosurg 48(2):173–178
pubmed: 624965
Woszczyk A, Deinsberger W, Böker D-K (2003) Nitric oxide metabolites in cisternal CSF correlate with cerebral vasospasm in patients with a subarachnoid haemorrhage. Acta Neurochir 145(4):257–263 discussion 263-264
pubmed: 12748885
Wu C, Hu Q, Chen J, Yan F, Li J, Wang L, Mo H, Gu C, Zhang P, Chen G (2013) Inhibiting HIF-1α by 2ME2 ameliorates early brain injury after experimental subarachnoid hemorrhage in rats. Biochem Biophys Res Commun 437(3):469–474
pubmed: 23850688
Xie A, Aihara Y, Bouryi VA, Nikitina E, Jahromi BS, Zhang Z-D, Takahashi M, Macdonald RL (2007) Novel mechanism of endothelin-1-induced vasospasm after subarachnoid hemorrhage. J Cereb Blood Flow Metab 27(10):1692–1701
pubmed: 17392694
Yatsushige H, Calvert JW, Cahill J, Zhang JH (2006) Limited role of inducible nitric oxide synthase in blood-brain barrier function after experimental subarachnoid hemorrhage. J Neurotrauma 23(12):1874–1882
pubmed: 17184195