Necrosis of the Substantia Nigra, Pars Reticulate, in Flurothyl-Induced Status Epilepticus is Ameliorated by the Spin Trap α Phenyl-N-tert-butyl Nitrone
Introduction
Epileptic seizures, particularly if prolonged as in status epilepticus, are known to lead to cell lesions, affecting selectively vulnerable neuronal populations in hippocampus, neocortex and thalamus.1, 2, 3, 4, 5 Because such damage is incurred in ventilated, normothermic rats with adequate oxygenation of tissues, and because cerebral blood flow (CBF) is increased two- to three-fold,[6] neither hypoxia nor ischemia can be made responsible. Very likely, the neuronal lesions are related to the excessive increase in cerebral metabolic rate, as reflected in a two- to three-fold increase in neocortical oxygen consumption (CMRO2) and regional glucose utilization rates (CMRgl).6, 7, 8
In the rat, neuronal lesions of this type are only incurred if seizures are sustained for at least 1–2 h.[5] In that species, though, seizures of briefer duration (30–45 min) invariable lead to a bilateral necrosis of the substantia nigra, pars reticulata, and of parts of the globus pallidus.[5] Such damage to the pallidoreticularis system has the characteristics of a pannecrotic lesion, albeit with sparing of the endothelial cells of the microvessels.9, 10 Analyses of the metabolic state of the SNPR revealed that ongoing seizures are associated with massively increased lactate and reduced ATP concentrations.[11] Furthermore, because ultrastructural studies revealed high amplitude swelling of axonal and dendritic mitochondria, it seemed likely that the initially grossly enhanced metabolic rate-triggered mitochondrial damage. There was no ready explanation for why SNPR (and globus pallidus) suffered such damage when other areas did not. However, because this structure is known to contain a high iron content,12, 13 it was speculated that the mitochondrial damage reflected iron-catalysed production of free radicals.5, 14
In this article, we describe experiments in which the hydroxyl radical scavenger DMTU or free radical spin trap PBN was given prior to induction of flurothyl-induced seizures of 45-min duration. The results showed that DMTU was toxic to animals subjected to status epilepticus, and all drug-injected animals died, even if the dose was reduced to 100 mg/kg, and that although PBN failed to attenuate the electrographic seizures, it virtually eliminated the tissue damage. We assume that, in the dose given, PBN acted by scavenging OH radical. The results thus support the notion that the SNPR damage is related to enhanced production of free radical.
Section snippets
Animal Groups
The animals were divided into three groups. The experimental group contained 6 animals treated with PBN, and 11 animals treated with DMTU. The control group included 6 animals without drug treatment. PBN (100 mg/kg) was administrated IP 30 min before induction of seizures, the injection being repeated 3 hr after the first dosage. DMTU was given in the dose of 100–800 mg/kg IP at the same time points as PBN. Control animals were given the same amount of vehicle. Status epilepticus was induced by
Physiological Variables
Table 1 summarises the physiological variable in the vehicle- and PBN-treated groups. Results were similar in the animals given DMTU. Prior to seizure induction, blood glucose was about 7 mmol/l, while PaCO2 was kept close to 35–40 mmHg, PaO2 to 100–110 mmHg, and arterial pH around 7.45. At the onset of seizure activity blood pressure increased; however, with the combination of the blood and injection of phentolamine, the blood pressure could be kept in the normal range. Seizure activity was
Discussion
Although lesions affecting the SNPR and the globus pallidus in status epilepticus may be exclusive to rodents, it is justified that their pathophysiology is explored, particularly because the mechanisms involved may be of general importance in seizure-related disorders. It is not known why SNPR damage take on the characteristics of pan-necrotic lesions, but the pathology and the pathophysiological events have been mapped out in some detail. The pathology is one in which both axonal endings,
Acknowledgements
This study was supported by the Swedish Medical Research Council (14x-263), and the US Public Health Service via the NIH(5R01NS07838).
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