Correlation between hypermetabolism and neuronal damage during status epilepticus induced by lithium and pilocarpine in immature and adult rats. (1/712)

The correlation between seizure-induced hypermetabolism and subsequent neuronal damage was studied in 10-day-old (P10), 21-day-old (P21), and adult rats subjected to lithium-pilocarpine status epilepticus (SE). Local CMRglc (LCMRglc) values were measured by the [14C]2-deoxyglucose method for a duration of 45 minutes starting at 60 minutes after the onset of SE, and neuronal damage was assessed by cresyl violet staining at 6 days after SE. In P21 and adult rats, LCMRglc values were increased by 275 to 875% in all thalamic, cortical, forebrain, and hypothalamic regions plus the substantia nigra. In addition, at P21 there were also large increases in LCMRglc in brainstem regions. In P10 rats, metabolic increases were mostly located in cortical and forebrain regions plus the substantia nigra but did not affect hypothalamic, thalamic, or brainstem areas. In adult rats, there was an anatomical correlation between hypermetabolism and neuronal damage. At P21, although hypermetabolism occurred in regions with damage, the extent of damage varied considerably with the animals and ranged from an almost negligible to a very extended degree. Finally, in P10 rats, although quite pronounced hypermetabolism occurred, there was no neuronal damage induced by the seizures. Thus, in the present model of epilepsy, the correlation between marked hypermetabolism and neuronal damage can be shown in adult rats. Conversely, immature rats can sustain major metabolic activations that lead either to a variable extent of damage, as seen at P21, or no damage, as recorded at P10.  (+info)

Oligodendroglial vacuolar degeneration in the bilateral motor cortices and astrocytosis in epileptic beagle dogs. (2/712)

We performed a pathologic examination of the brains of three dogs in an epileptic beagle colony. Histologically, all the cases had diffuse astrocytosis in the cerebral cortex and basal ganglia as well as the hippocampus, whereas they showed acute nerve cell change in the hippocampus and some other areas of the cerebrum. One of these animals showed laminar myelin pallor associated with the presence of many vacuoles in the IV to VI layers of the bilateral motor cortices. Most of the vacuoles contained fine granules stained with luxol-fast-blue stain. Ultrastructural examination revealed that some oligodendrocytes and perineuronal satellite oligodendrocytes in the bilateral cerebral motor cortices of the two affected dogs had many vacuoles surrounded by myelin-like lamellar structures. These findings suggest a possibility that astrocytosis in the cerebrum and vacuolar degeneration of oligodendrocytes in the cerebral motor cortex may be, at least in part, related to the occurrence or development of seizures.  (+info)

Paradoxical GH response to TRH during status epilepticus in man. (3/712)

Information on GH in relation to epilepsy is sparse, and to our knowledge there is no information on GH levels during status epilepticus in man. We studied GH in serum in six patients during status epilepticus, and in a control group of six seizure-free patients with epilepsy, before and after injection of TRH. The baseline GH values before TRH administration were within the normal range in all patients. After injection of TRH all patients with status epilepticus showed a paradoxical peak-shaped increase of GH to at least twice their baseline levels within 45 min after the injection (median basal GH value 1.5 mU/l and median peak GH value 6. 5 mU/l, mean increase 330%). No uniform reaction to TRH was observed in the control group (median basal GH value 2.7 U/l and median of the highest value within 45 min 5.2mU/l). A paradoxical peak reaction of GH to TRH was significantly more frequent in the status epilepticus group compared with the control group (P=0.008, Fisher exact probability test). TRH is not considered a GH-releasing hormone in humans during normal conditions, but a paradoxical response of GH to TRH, similar to that observed during status epilepticus, has been reported in various other pathological conditions, such as acromegaly, liver cirrhosis, mental depression and hypothyroidism. Our results of GH release after TRH administration in patients with status epilepticus suggest an altered regulation of GH as a result of the long-standing epileptic activity.  (+info)

Recurrent mossy fiber pathway in rat dentate gyrus: synaptic currents evoked in presence and absence of seizure-induced growth. (4/712)

A common feature of temporal lobe epilepsy and of animal models of epilepsy is the growth of hippocampal mossy fibers into the dentate molecular layer, where at least some of them innervate granule cells. Because the mossy fibers are axons of granule cells, the recurrent mossy fiber pathway provides monosynaptic excitatory feedback to these neurons that could facilitate seizure discharge. We used the pilocarpine model of temporal lobe epilepsy to study the synaptic responses evoked by activating this pathway. Whole cell patch-clamp recording demonstrated that antidromic stimulation of the mossy fibers evoked an excitatory postsynaptic current (EPSC) in approximately 74% of granule cells from rats that had survived >10 wk after pilocarpine-induced status epilepticus. Recurrent mossy fiber growth was demonstrated with the Timm stain in all instances. In contrast, antidromic stimulation of the mossy fibers evoked an EPSC in only 5% of granule cells studied 4-6 days after status epilepticus, before recurrent mossy fiber growth became detectable. Notably, antidromic mossy fiber stimulation also evoked an EPSC in many granule cells from control rats. Clusters of mossy fiber-like Timm staining normally were present in the inner third of the dentate molecular layer at the level of the hippocampal formation from which slices were prepared, and several considerations suggested that the recorded EPSCs depended mainly on activation of recurrent mossy fibers rather than associational fibers. In both status epilepticus and control groups, the antidromically evoked EPSC was glutamatergic and involved the activation of both AMPA/kainate and N-methyl-D-aspartate (NMDA) receptors. EPSCs recorded in granule cells from rats with recurrent mossy fiber growth differed in three respects from those recorded in control granule cells: they were much more frequently evoked, a number of them were unusually large, and the NMDA component of the response was generally much more prominent. In contrast to the antidromically evoked EPSC, the EPSC evoked by stimulation of the perforant path appeared to be unaffected by a prior episode of status epilepticus. These results support the hypothesis that recurrent mossy fiber growth and synapse formation increases the excitatory drive to dentate granule cells and thus facilitates repetitive synchronous discharge. Activation of NMDA receptors in the recurrent pathway may contribute to seizure propagation under depolarizing conditions. Mossy fiber-granule cell synapses also are present in normal rats, where they may contribute to repetitive granule cell discharge in regions of the dentate gyrus where their numbers are significant.  (+info)

Platelet activating factor receptor expression is associated with neuronal apoptosis in an in vivo model of excitotoxicity. (5/712)

Platelet activating factor (PAF), an endogenous proinflammatory agent, mediates neuronal survival, glutamate release, and transcriptional activation following excitotoxin challenge. To determine whether PAF receptor (PAFR) expression is altered during excitotoxicity, changes in PAFR mRNA localization were compared with markers of neuronal apoptosis and reactive gliosis following systemic injection of kainic acid. Data from semi-quantitative RT-PCR, in situ hybridization, DNA fragmentation, cellular morphology analysis, and immunohistochemistry demonstrate that the localization of PAFR mRNA is altered during kainic acid-induced neurodegeneration. While PAFR mRNA is normally exhibited by neurons and microglia in rat hippocampus, expression becomes restricted to apoptotic neurons and to glia involved in phagocytosing apoptotic debris following treatment with excitotoxin. PAFR mRNA is rarely detected in surviving neurons. These data provide the first indication that PAFR-expressing neurons may be preferentially susceptible to excitotoxic challenge.  (+info)

Substance P is expressed in hippocampal principal neurons during status epilepticus and plays a critical role in the maintenance of status epilepticus. (6/712)

Substance P (SP), a member of the tachykinin family, is widely distributed in the central nervous system and is involved in a variety of physiological processes including cardiovascular function, inflammatory responses, and nociception. We show here that intrahippocampal administration of SP triggers self-sustaining status epilepticus (SSSE) in response to stimulation of the perforant path for periods too brief to have any effect in control rats, and this SSSE generates a pattern of acute hippocampal damage resembling that known to occur in human epilepsy. The SP receptor (SPR) antagonists, spantide II and RP-67,580, block both the initiation of SSSE and SSSE-induced hippocampal damage and terminate established anticonvulsant-resistant SSSE. SSSE results in a rapid and dramatic increase in the expression of preprotachykinin A (a precursor of SP) mRNA and SP in principal neurons in CA3, CA1, and the dentate gyrus as well as in hippocampal mossy fibers. SP also increases glutamate release from hippocampal slices. Enhanced expression of SP during SSSE may modulate hippocampal excitability and contribute to the maintenance of SSSE. Thus, SPR antagonists may constitute a novel category of drugs in antiepileptic therapy.  (+info)

Immunohistochemical evidence of seizure-induced activation of trk receptors in the mossy fiber pathway of adult rat hippocampus. (7/712)

Recent work suggests that limiting the activation of the trkB subtype of neurotrophin receptor inhibits epileptogenesis, but whether or where neurotrophin receptor activation occurs during epileptogenesis is unclear. Because the activation of trk receptors involves the phosphorylation of specific tyrosine residues, the availability of antibodies that selectively recognize the phosphorylated form of trk receptors permits a histochemical assessment of trk receptor activation. In this study the anatomy and time course of trk receptor activation during epileptogenesis were assessed with immunohistochemistry, using a phospho-specific trk antibody. In contrast to the low level of phosphotrk immunoreactivity constitutively expressed in the hippocampus of adult rats, a striking induction of phosphotrk immunoreactivity was evident in the distribution of the mossy fibers after partial kindling or kainate-induced seizures. The anatomic distribution, time course, and threshold for seizure-induced phosphotrk immunoreactivity correspond to the demonstrated pattern of regulation of BDNF expression by seizure activity. These results provide immunohistochemical evidence that trk receptors undergo activation during epileptogenesis and suggest that the mossy fiber pathway is particularly important in the pro-epileptogenic effects of the neurotrophins.  (+info)

Actions of brain-derived neurotrophic factor in slices from rats with spontaneous seizures and mossy fiber sprouting in the dentate gyrus. (8/712)

This study examined the acute actions of brain-derived neurotrophic factor (BDNF) in the rat dentate gyrus after seizures, because previous studies have shown that BDNF has acute effects on dentate granule cell synaptic transmission, and other studies have demonstrated that BDNF expression increases in granule cells after seizures. Pilocarpine-treated rats were studied because they not only have seizures and increased BDNF expression in granule cells, but they also have reorganization of granule cell "mossy fiber" axons. This reorganization, referred to as "sprouting," involves collaterals that grow into novel areas, i.e., the inner molecular layer, where granule cell and interneuron dendrites are located. Thus, this animal model allowed us to address the effects of BDNF in the dentate gyrus after seizures, as well as the actions of BDNF on mossy fiber transmission after reorganization. In slices with sprouting, BDNF bath application enhanced responses recorded in the inner molecular layer to mossy fiber stimulation. Spontaneous bursts of granule cells occurred, and these were apparently generated at the site of the sprouted axon plexus. These effects were not accompanied by major changes in perforant path-evoked responses or paired-pulse inhibition, occurred only after prolonged (30-60 min) exposure to BDNF, and were blocked by K252a. The results suggest a preferential action of BDNF at mossy fiber synapses, even after substantial changes in the dentate gyrus network. Moreover, the results suggest that activation of trkB receptors could contribute to the hyperexcitability observed in animals with sprouting. Because human granule cells also express increased BDNF mRNA after seizures, and sprouting can occur in temporal lobe epileptics, the results may have implications for understanding temporal lobe epilepsy.  (+info)