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Lazaroid Attenuates Edema by Stabilizing ATPase in the Traumatized Rat Brain

  • Ramazan Durmaz (a1), Güngör Kanbak (a2), Fahrettin Akyüz (a2), Serap Isiksoy (a3), Ferruh Yücel (a4), Mine Inal (a2) and Esref Tel (a1)...



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.


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.


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).


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: 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.


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.


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).


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.

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Corresponding author

Neurosurgical Department, Medical Faculty of Osmangazi University, 26480, Eskisehir, Turkey


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Lazaroid Attenuates Edema by Stabilizing ATPase in the Traumatized Rat Brain

  • Ramazan Durmaz (a1), Güngör Kanbak (a2), Fahrettin Akyüz (a2), Serap Isiksoy (a3), Ferruh Yücel (a4), Mine Inal (a2) and Esref Tel (a1)...


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