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Lazaroid Attenuates Edema by Stabilizing ATPase in the Traumatized Rat Brain

Published online by Cambridge University Press:  16 December 2016

Ramazan Durmaz ,
Güngör Kanbak ,
Fahrettin Akyüz ,
Serap Isiksoy ,
Ferruh Yücel ,
Mine Inal  and
Esref Tel
Ramazan Durmaz*
Affiliation:
Department of Neurosurgery, Medical Faculty of Osmangazi University, TR-26480, Eskisehir, Turkey
Güngör Kanbak
Affiliation:
Department of Biochemistry, Medical Faculty of Osmangazi University, TR-26480, Eskisehir, Turkey
Fahrettin Akyüz
Affiliation:
Department of Biochemistry, Medical Faculty of Osmangazi University, TR-26480, Eskisehir, Turkey
Serap Isiksoy
Affiliation:
Department of Pathology, Medical Faculty of Osmangazi University, TR-26480, Eskisehir, Turkey
Ferruh Yücel
Affiliation:
Department of Anatomy, Medical Faculty of Osmangazi University, TR-26480, Eskisehir, Turkey
Mine Inal
Affiliation:
Department of Biochemistry, Medical Faculty of Osmangazi University, TR-26480, Eskisehir, Turkey
Esref Tel
Affiliation:
Department of Neurosurgery, Medical Faculty of Osmangazi University, TR-26480, Eskisehir, Turkey
*
Neurosurgical Department, Medical Faculty of Osmangazi University, 26480, Eskisehir, Turkey
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Abstract:

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Objective:

The aim of the present study was to determine the potential therapeutic value of the lazaroid U-83836E on blood brain barrier (BBB) breakdown and edema with respect to the changes in the synaptosomal Na+/K+ and Mg2+/Ca2+- adenosinetriphosphatase (ATPase) activities, tissue malondialdehyde levels and the neuronal viability in the rat brain subjected to cerebral trauma.

Methods:

Traumatic brain injury (TBI) was introduced by applying a 75 gm. cm force to the right parietal cortex using the weight-drop method. The first set of animals was used for determining time course changes of the synaptosomal Na+/K+ and Mg2++/Ca2+-ATPase and the malondialdehyde levels and were sacrificed 2, 6 and 24h after lesion production. A group of the animals was treated with U-83836E proir to TBI and sacrificed 24h after cerebral injury. A second set of animals was used for evaluating the alterations in BBB disruption and tissue water content and were sacrificed 2, 6 and 24h after lesion production. Two groups of animals were treated with U-83836E and sacrificed after 2 and 24h following TBI. U-83836E was given intraperitoneally thirty minutes before trauma at a dose of 10 mg/kg. Neuronal necrosis was also evaluated in the groups of U-83836E and physiological saline-treated animals.

Results:

Extravasation of Evans blue into the traumatized hemisphere was maximum at 2h (p<0.001) and returned close to the control levels at 24h after TBI (p>0.05). Edema had developed progressively over time and reached the maximum degree of 2.1 % (p<0.001) at 24 h. U-83836E showed no effect on the BBB breakdown and the tissue water content at 2h and still had no effect on the BBB breakdown after 24h following the trauma (p>0.05), although it reduced edema after 24h (p<0.01). The losses of Na+/K+ and Mg2+/Ca2+-ATPase activities were found as 39.5 % (p<0.001) and 29.4 % (p<0.01) of the control value, respectively, and remained at the decreased levels throughout the experiment. Malondialdehyde level continued to increase over time reaching up to 209 % (p<0.001) of the control value 24h after TBI. Both ATPase activities were improved to near control values (p>0.05) by the effect of U-83836E. U-83836E inhibited the increase of lipid peroxidation (p<0.001) and also salvaged neuronal necrosis (p<0.05).

Conclusion:

U-83836E given prophylactically after cerebral trauma appears to reduce edema, possibly by inhibiting increases in lipid peroxidation and by stabilizing ATPase. Further studies are recommended to verify the similar effects of the brain penetrating lazaroids when they are given after trauma.

Résumé:

RÉSUMÉ:Objectif:

Le but de cette étude était de déterminer la valeur thérapeutique potentielle du lazaroïd U-83836E sur l'effondrement de la barrière hémato-encéphalique et l'œdème par l'évaluation des changements dans l'activité Na+/K+ et Mg2+/Ca2+-ATPase synaptosomale, les niveaux de malondialdéhyde tissulaire et la viabilité neuronale dans le cerveau de rats soumis à un traumatisme cérébral.

Méthodes:

La lésion traumatique était induite par la méthode de chute d'un poids appliquant une force de 75 g cm au niveau du cortex pariétal droit. Le premier groupe d'animaux a servi à déterminer les changements dans le temps au niveau des taux synaptosomaux de Na+/K+ et Mg2+/Ca2+-ATPase et de malondialdéhyde tissulaire et ils ont été sacrifiés 2, 6 et 24 heures après avoir subi le traumatisme. Un premier groupe d'animaux a été traité par le U-83836E et sacrifié 24 heures après le traumatisme. Un second groupe d'animaux a servi à évaluer les altérations de la barrière hémato-encéphalique et le contenu tissulaire aqueux. Ils ont été sacrifiés 2, 6 et 24 heures après le traumatisme. Deux groupes d'animaux ont été traités par le U-83836E et sacrifiés soit 2 heures ou 24 heures après la lésion. Le U-83836E a été administré par voie intrapéritonéale trente minutes avant le traumatisme à la dose de 10 mg/k. La nécrose neuronale a été évaluée chez le groupe d'animaux ayant reçu le U-83836E et chez le groupe ayant reçu du soluté physiologique.

Résultats:

L'extravasation du Bleu Evans dans l'hémisphère traumatisé était à son maximum 2 heures après le traumatisme (p<0,001) et rejoignait celle des témoins après 24 heures (p<0,05). L'œdème apparaissait progressivement et était à son maximum de 2,1% (p<0,001) après 24 heures. Le U-83836E n'avait aucun effet sur l'altération de la barrière hématoencéphalique et le contenu tissulaire aqueux après 2 heures et n'avait toujours pas d'effet sur l'altération de la barrière hémato-encéphalique après 24 heures (p<0,05), bien que l'œdème était diminué chez ces animaux après 24 heures (p<0,01). Les pertes d'activité Na+/K+ et Mg2+/Ca2+-ATPase étaient de l'ordre de 39,5% (p<0,001) et 29,4% (p<0,01) de la valeur témoin respectivement et sont demeurées à des niveaux abaissés pendant toute la durée d'observation. Le niveau de malondialdéhyde a continué à augmenter, atteignant 209% (p<0,001) de la valeur témoin 24 heures après le traumatisme. Les deux activités ATPase étaient améliorées par l'effet du U-83836E, à des niveaux voisins de ceux des témoins (p<0,05). Le U-83836E a inhibé l'augmentation de la peroxydation lipidique (p<0,001) et protégé de la nécroses neuronale (p<0,05).

Conclusion:

Le U-83836E administré de façon prophylactique après un traumatisme cérébral semble diminuer l'œdème. Il est possible que ce soit dû à l'inhibition de l'augmentation de la peroxydation lipidique et à la stabilisation des ATPases. Des études plus poussées devraient être entreprises afin de vérifier les effets des lazaroïds qui pénètrent dans le cerveau, quand ils sont administrés après un traumatisme.

Type
Experimental Neurosciences
Information
Canadian Journal of Neurological Sciences , Volume 30 , Issue 2 , May 2003 , pp. 143 - 149
Copyright
Copyright © The Canadian Journal of Neurological 2003

References

REFERENCES

1. Braughler, JM, Hall, ED. Central nervous system trauma and stroke. I. Biochemical considerations for oxygen radical formation and lipid peroxidation. Free Radic Biol Med 1989; 6: 289–301.Google Scholar
2. Chan, PH, Fishman, RA, Longar, S, Chen, S, Yu, A. Cellular and molecular effects of polyunsaturated fatty acids in brain ischemia and injury. Prog Brain Res 1985;63:227–235.Google Scholar
3. Faden, AI, Demediuk, P, Panter, SS, Vink, R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 1989;244:798–800.Google Scholar
4. Oury, TD, Piantadosi, CA, Crapo, JD. Cold-induced brain edema in mice. Involvement of extracellular superoxide dismutase and nitric oxide. J Biol Chem 1993;268:15394–15398.CrossRefGoogle ScholarPubMed
5. Lin, SC, Way, EL. A high affinity Ca2+-ATPase in enriched nerve-ending plasma membranes. Brain Res 1982;235: 387–392.Google Scholar
6. Sun, AY, Sun, GY, Samorajski, T. The effect of phospholipase C on the activity of adenosine triphosphatase and acetylcholinesterase in synaptic membranes isolated from the cerebral cortex of squirrel monkey. J Neurochem 1971;18:1711–1768.CrossRefGoogle ScholarPubMed
7. Klatzo, I. Evolution of brain edema concept. Acta Neurochir Suppl (Wien) 1994;60:3–4.Google Scholar
8. Klatzo, I. Presidental address. Neuropathological aspects of brain edema. J Neuropathol Exp Neurol 1967;26:1–14.Google Scholar
9. Braughler, JM, Pregenzer, JF. The 21-aminosteroid inhibitors of lipid peroxidation: reactions with lipid peroxyl and phenoxy radicals. Free Radic Biol Med 1989;7:125–130.Google Scholar
10. Hall, ED, Travis, MA. Inhibition of arachidonic acid-induced vasogenic brain edema by the non-glucocorticoid 21-aminostroid U74006F. Brain Res 1988;451:350–352.Google Scholar
11. Hall, ED, Pazara, KE, Braughler, JM, Linseman, KL, Jacobsen, EJ. Nonsteroidal lazaroid U78517F in models of focal and globalischemia. Stroke 1990; 21(11 Suppl):III83–III87.Google Scholar
12. Hall, ED, Braughler, JM, Yonkers, PA, et al. U-78517F: a potentinhibitor of lipid peroxidation with activity in experimental brain injury and ischemia. J Pharmacol Exp Ther 1991;258:688–694.Google Scholar
13. Hall, ED, McCall, JM, Means, ED. Therapeutic potential of the lazaroids (21-aminosteroids) in acute central nervous system trauma, ischemia and subarachnoid hemorrhage. Adv Pharmacol 1994;28:221–268.Google Scholar
14. Hall, ED, Andrus, PK, Smith, SL, et al. Neuroprotective efficacy of microvascularly-localized versus brain-penetrating antioxidants. Acta Neurochir Suppl (Wien) 1996;66:107–113.Google Scholar
15. McIntosh, TK, Banbury, M, Smith, D, Thomas, M. The novel 21-aminosteroid U-74006F attenuates cerebral oedema and improves survival after brain injury in the rat. Acta Neurochir Suppl (Wien) 1990;51:329–330.Google Scholar
16. Young, W, Wojak, JC, DeCrescito, V. 21-Aminosteroid reduces ion shifts and edema in the rat middle cerebral artery occlusion model of regional ischemia. Stroke 1988;19:1013–1019.Google Scholar
17. Feeney, DM, Boyeson, MG, Linn, RT, Murray, HM, Dail, WG. Responses to cortical injury: I. Methodology and local effects of contusions in the rat. Brain Res 1981;211:67–77.Google Scholar
18. Mayhew, TM, Gundersen, HJ. If you assume, you can make an assout of u and me’: a decade of the disector for stereological counting of particles in 3D space. J Anat 1996;188:1–15.Google Scholar
19. Palkovits, M, Magyar, P, Szentagothai, J. Quantitative histological analysis of the cerebellar cortex in the cat. II. Cell numbers and densities in the granular layer. Brain Res 1971;321:15–30.Google Scholar
20. Auer, RN, Siesjö, BK. Biological differences between ischemia, hypoglycemia and epilepsy. Ann Neurol 1988;24:699–707.Google Scholar
21. Sutton, RL, Lescaudron, L, Stein, DG. Unilateral cortical contusion injury in the rat: vascular disruption and temporal development of cortical necrosis. J Neurotrauma 1993;10:135–149.Google Scholar
22. Demediuk, P, Lemke, M, Faden, I. Spinal cord edema and changes in tissue content of Na, K, and Mg after impact trauma in rats. In: Long, D, et al (Eds). Advances in Neurology Vol 52, Raven Press 1990:225–232.Google Scholar
23. Shapira, Y, Setton, D, Artru, AA, Shohami, E. Blood-brain barrier permeability, cerebral edema, and neurologic function after closed head injury in rats. Anesth Analg 1993;77:141–148.Google Scholar
24. Braughler, JM, Hall, ED. Acute enhancement of spinal cord synaptosomal (Na+, K+)-ATPase activity in cats following intravenous methylprednisolone. Brain Res 1981;219:464–469.Google Scholar
25. Matteucci, E, Cocci, F, Pellegrini, L, Gregori, G, Giampietro, O. Measurement of ATPase in red cells: setting up and validation of a highly reproducible method. Enzyme Protein 1994–95;48:105–119.Google Scholar
26. Ohkawa, H, Ohishi, N, Yagi, K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351–358.Google Scholar
27. Lowry, OH, Rosebrough, NJ, Farr, AL, Randall, R. Protein measurement with the folin phenol reagent. J Biol Chem 1951;193:265–275.Google Scholar
28. Motulsky, HJ. GraphPad. San Diego: GraphPad Software Inc 1994–1995.Google Scholar
29. Adelson, PD, Whalen, MJ, Kochanek, PM, Robichaud, P, Carlos, TM. Blood brain barrier permeability and acute inflammation in two models of traumatic brain injury in the immature rat: a preliminary report. Acta Neurochir Suppl (Wien) 1998;71:104–106.Google Scholar
30. Whalen, MJ, Carlos, TM, Kochanek, PM, Heineman, S. Blood-brain barrier permeability, neutrophil accumulation and vascular adhesion molecule expression after controlled cortical impact in rats:a preliminary study. Acta Neurochir Suppl (Wien) 1998;71:212–214.Google Scholar
31. Barzo, P, Marmarou, A, Fatouros, P, Corwin, F, Dunbar, J. Magnetic resonance imaging-monitored acute blood-brain barrier changes in experimental traumatic brain injury. J Neurosurg 1996;85:1113–1121.Google Scholar
32. Fukuda, K, Tanno, H, Okimura, Y, Nakamura, M, Yamaura, A. The blood-brain barrier disruption to circulating proteins in the early period after fluid percussion brain injury in rats. J Neurotrauma 1995;12:315–324.Google Scholar
33. Barzo, P, Marmarou, A, Fatouros, P, Hayasaki, K, Corwin, F. Biphasic pathophysiological response of vasogenic and cellular edema in traumatic brain swelling. Acta Neurochir Suppl (Wien) 1997;70:119–122.Google ScholarPubMed
34. Ildan, F, Polat, S, Gocer, AI, et al. The effects of the pretreatment of intravenous high dose methylprednisolone on Na(+)-K(+)/Mg(+2)-ATPase and lipid peroxidation and early ultrastructural findings following middle cerebral artery occlusion in the rat. Acta Neurochir (Wien) 1996;138:338–345.CrossRefGoogle Scholar
35. Jamme, I, Petit, E, Gerbi, A, et al. Changes in ouabain affinity of Na+, K+-ATPase during focal cerebral ischaemia in the mouse. Brain Res 1997;774:123–130.Google Scholar
36. Parsons, JT, Churn, SB, DeLorenzo, RJ. Ischemia-induced inhibition of calcium uptake into rat brain microsomes mediated by Mg2+/Ca2+ATPase. J Neurochem 1997;68:1124–1134.Google Scholar
37. Boldyrev, AA, Bulygina, AR. Na+/K+-ATPase and oxidative stress. In: Beaugé, LA, Gadsby, DC, Garrahan, PJ (Eds). Na+/K+-ATPase and related transport ATPase: Structure, mechanism, and regulation. Ann NY Acad Sci 1997;834:666–668.Google Scholar
38. Kaplan, P, Matejovicova, M, Mezesova, V. Iron-induced inhibition of Na+, K+-ATPase and Na+/Ca2+ exchanger in synaptosomes: protection by the pyridoindole stobadine. Neurochem Res 1997;22:1523–1529.Google Scholar
39. Durmaz, R, Inal, M, Angin, M, Atasoy, MA, Tel, E. The effects of MK-801 and U-83836E on post-ischemic reperfusion injury rat brain. Acta Neurobiol Exp (Warsz) 1999;59:99–104.Google Scholar
40. Schneider, GH, Unterberg, A, Lanksch, WR. 21-Aminosteroid U-74389F reduces vasogenic brain edema. Acta Neurochir (Wien) Suppl 1994;60:516–518.Google Scholar
41. Audus, KL, Guillot, FL, Braughler, JM. Evidence for 21-aminosteroid association with the hydrophobic domains of brain microvessel endothelial cells. Free Radic Biol Med 1991;11:361–371.Google Scholar
42. Schoettle, RJ, Kochanek, PM, Magargee, MJ, Uhl, MW, Nemoto, EM. Early polymorphonuclear leukocyte accumulation correlates with the development of post-traumatic cerebral edema in rats. J Neurotrauma 1990;7:207–217.Google Scholar
43. Kimelberg, HK. Brain edema In: Kettenmannh, H, Ranson, BR (Eds).Neuroglia, New York, Oxford University Press, 1995: 919–935.Google Scholar
44. Cortez, SC, McIntosh, TK, Noble, LJ. Experimental fluid percussion brain injury: vascular disruption and neuronal and glial alterations. Brain Res 1989;482:271–282.Google Scholar