Seizure activity-induced changes in polyamine metabolism and neuronal pathology during the postnatal period in rat brain.
Systemic injection of kainic acid (KA) does not cause neuronal pathology in limbic structures in rat brain prior to postnatal day (PND) 21. The present study tested if the development of the pathogenic response is associated with the maturation of a link between seizure activity and polyamine metabolism. Pathology was assessed with histological techniques and with the binding of [3H]Ro5-4864, a ligand for the peripheral type benzodiazepine binding sites (PTBBS), a marker of glial cell proliferation. In agreement with previous results, peripherally administered kainate at doses sufficient to induce intense behavioral seizures produced a loss of Nissl staining in hippocampus after PND 21 but not at earlier ages. The pattern of neuronal damage observed after PND 21 resembled that found in adult animals: extensive losses of Nissl staining in area CA3 of hippocampus and in piriform cortex, more modest effects in CA1 and sparing of the granule cells of the dentate gyrus. Similarly, no increase in [3H]Ro5-4864 binding as a result of KA administration was observed in hippocampus and piriform cortex until PND 21. Ornithine decarboxylase (ODC) activity and putrescine levels were high in the neonatal brain and decreased to reach adult values by PND 21. KA-induced seizure activity did not significantly alter both variables until PND 21. After PND 21, ODC activity and putrescine levels markedly increased 16 h after KA-induced seizure activity in hippocampus and piriform cortex. The magnitude of the effects increased between PND 21 and PND 30, at which point the changes in both parameters were comparable to those found in adults. Polyamines stimulate the activity of the calcium-dependent proteases calpain in brain fractions and may increase calpain-mediated proteolysis in situ. In accord with this, kainate-induced breakdown of spectrin, a preferred substrate of calpain, measured 16 h after KA injection followed a developmental curve parallel to that for kainate-induced increases in putrescine levels. These results indicate that the onset of vulnerability to seizure activity triggered by kainic acid is correlated with the development of an ODC/polyamine response to the seizures and further support a critical role for the ODC/polyamine pathway in neuronal pathology following a variety of insults.
Najm
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Neurosciences Program, USC, Los Angeles 90089-2520.
el-Skaf
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Tocco
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Vanderklish
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Lynch
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Baudry
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D000818:Animals; D001570:Benzodiazepinones / Q000378:metabolism; D015317:Biogenic Polyamines / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000473:pathology*; D001923:Brain Chemistry / Q000502:physiology; D002540:Cerebral Cortex / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006624:Hippocampus / Q000473:pathology; D007608:Kainic Acid; D009474:Neurons / Q000187:drug effects*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011247:Pregnancy; D011700:Putrescine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D013049:Spectrin / Q000378:metabolism
D001570:Benzodiazepinones; D015317:Biogenic Polyamines; D011963:Receptors, GABA-A; D013049:Spectrin; C028513:4'-chlorodiazepam; D009955:Ornithine Decarboxylase; D007608:Kainic Acid; D011700:Putrescine