Original article<br>Delayed preconditioning with NMDA receptor antagonists in a rat model of perinatal asphyxia

Dorota Makarewicz; Dorota Sulejczak; Małgorzata Duszczyk; Michał Małek; Marta Słomka; Jerzy W. Lazarewicz

doi:10.5114/fn.2014.45568

eISSN: 1509-572x
ISSN: 1641-4640

Folia Neuropathologica

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3/2014
vol. 52

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abstract:

Original article
Delayed preconditioning with NMDA receptor antagonists in a rat model of perinatal asphyxia

Dorota Makarewicz

,

Dorota Sulejczak

,

Małgorzata Duszczyk

,

Michał Małek

,

Marta Słomka

,

Jerzy W. Lazarewicz

Folia Neuropathol 2014; 52 (3): 270-284

DOI: https://doi.org/10.5114/fn.2014.45568

Online publish date: 2014/09/26

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Introduction: In vitro experiments have demonstrated that preconditioning primary neuronal cultures by temporary application of NMDA receptor antagonists induces long-term tolerance against lethal insults. In the present study we tested whether similar effects also occur in brain submitted to ischemia in vivo and whether the potential benefit outweighs the danger of enhancing the constitutive apoptosis in the developing brain.

Material and methods: Memantine in pharmacologically relevant doses of 5 mg/kg or (+)MK-801 (3 mg/kg) was administered i.p. 24, 48, 72 and 96 h before 3-min global forebrain ischemia in adult Mongolian gerbils or prior to hypoxia/ischemia in 7-day-old rats. Neuronal loss in the hippocampal CA1 in gerbils or weight deficit of the ischemic hemispheres in the rat pups was evaluated after 14 days. Also, the number of apoptotic neurons in the immature rat brain was evaluated.

Results: In gerbils only the application of (+)MK-801 24 h before ischemia resulted in significant prevention of the loss of pyramidal neurons. In rat pups administration of (+)MK-801 at all studied times before hypoxia-ischemia, or pretreatment with memantine or with hypoxia taken as a positive control 48 to 92 h before the insult, significantly reduced brain damage. Both NMDA receptor antagonists equally reduced the number of apoptotic neurons after hypoxia-ischemia, while (+)MK-801-evoked potentiation of constitutive apoptosis greatly exceeded the effect of memantine.

Conclusions: We ascribe neuroprotection induced in the immature rats by the pretreatment with both NMDA receptor antagonists 48 to 92 h before hypoxia-ischemia to tolerance evoked by preconditioning, while the neuroprotective effect of (+)MK-801 applied 24 h before the insults may be attributed to direct consequences of the inhibition of NMDA receptors. This is the first report demonstrating the phenomenon of inducing tolerance against hypoxia-ischemia in vivo in developing rat brain by preconditioning with NMDA receptor antagonists.

keywords:

Original articleDelayed preconditioning with NMDA receptor antagonists in a rat model of perinatal asphyxia

Dorota Makarewicz , Dorota Sulejczak , Małgorzata Duszczyk , Michał Małek , Marta Słomka , Jerzy W. Lazarewicz

apoptosis, gerbil, ischemia, neuroprotection, perinatal asphyxia, NMDA receptor

Original article
Delayed preconditioning with NMDA receptor antagonists in a rat model of perinatal asphyxia

Dorota Makarewicz

,

Dorota Sulejczak

,

Małgorzata Duszczyk

,

Michał Małek

,

Marta Słomka

,

Jerzy W. Lazarewicz