Postnatal Maturation of Cytochrome Oxidase and Lactate Dehydrogenase Activity and Age-Dependent Consequences of Lithium-Pilocarpine Status Epilepticus in the Rat: A Regional Histoenzymology Study

Abstract

The lithium-pilocarpine (Li-Pilo) model of epilepsy reproduces some pathophysiological, temporal, and developmental features of human temporal lobe epilepsy. In this model, rates of cerebral glucose utilization measured by the [ 14 C]2-deoxyglucose technique increased during the initial status epilepticus (SE) and decreased during the latent or chronic periods. To correlate these metabolic changes with the activities of the enzymes of the glycolytic and tricarboxylic acid cycle pathways, we measured by histoenzymology the regional activity of two key enzymes of glucose metabolism, lactate dehydrogenase (LDH) for the anaerobic pathway and cytochrome oxidase (CO) for the aerobic pathway coupled to oxidative phosphorylation, at various times after SE induced by Li-Pilo in 10-(P10), 21-d-old (P21) and adult rats for CO and in adult rats only for LDH. CO activity was slightly affected in P10 and P21 rats only at 4 and 24 h and normalized by 14 d after SE. In adult rats, CO activity decreased at 4 and 24 h in damaged areas, like entorhinal cortex, hippocampal CA3 area, amygdala, and thalamus. At 14 d after SE, CO activity was decreased only in entorhinal cortex and increased in brainstem regions involved in the remote control of seizures. In adult rats, LDH activity decreased at 24 h and 14 d after SE in sensorimotor and entorhinal cortex. These data show that the enzymatic equipment underlying the metabolism of glucose is not severely affected by Li-Pilo SE and confirm our previous observations concerning the relative metabolic hyperactivity of brain regions involved in the seizure circuit despite marked neuronal loss. Clinical studies suggest that the development of temporal lobe epilepsy is an age-dependent and progressive process (1-3). The nature of the underlying pathophysiological mechanisms and their differences in mature and immature brain remain poorly understood. In this respect, the model of epilepsy induced in rats by Li-Pilo is a useful tool because it reproduces most clinical, developmental, and neuropathological features of human temporal lobe epilepsy (4,5).The consequences of Li-Pilo are age dependent (4 -7). In adult rats, Li-Pilo leads to SE followed by a latent seizure-free phase of a mean duration of 14 -25 d. Thereafter, all animals enter the chronic phase of the disease and exhibit spontaneous recurrent limbic seizures with generalization. Neuronal damage is located mainly in the hippocampus, dentate gyrus, piriform and entorhinal cortices, septum, thalamus, amygdala, and neocortex (4,5,7). In 21-d-old rats (P21), a more moderate pattern of neuronal damage is observed in the hippocampus, amygdala, piriform and entorhinal cortices, and some thalamic nuclei. About 70 -80% of the rats display spontaneous recurrent limbic seizures after a latent phase of a mean duration of 73 d (5,7). In P10 rats, Li-Pilo-induced SE does not lead to neuronal damage or spontaneous recurrent seizures (5,7).In

Mitochondrial support of persistent presynaptic vesicle mobilization with age-dependent synaptic growth after LTP

“…Before weaning, rat diets consist primarily of fatty acids, which means their neurons rely on ketone bodies instead of glucose for energy (Edmond et al, 1985; Raffo et al, 2004; Yeh and Sheehan, 1985). Accordingly, rat hippocampal neurons begin to express glucose transporters at about P14, but expression does not approach adult levels until after P21 (Vannucci, 1994).…”

Diabetic Hyperglycemia Aggravates Seizures and Status Epilepticus-induced Hippocampal Damage

“…SE, were given a lithium chloride (Sigma-Aldrich Co., St Louis, MO) injection (3 meq/kg, i.p.) 18-20 h before a subcutaneous (s.c.) pilocarpine injection (60 mg/kg) (Sigma-Aldrich) to induce SE, and, to reduce the peripheral consequences of pilocarpine, methylscopolamine injection (25 mg/kg, s.c.) (Sigma-Aldrich) 30 min before the pilocarpine injection (Leroy et al 2004;Raffo et al 2004).…”

Decision letter: Mitochondrial support of persistent presynaptic vesicle mobilization with age-dependent synaptic growth after LTP

“…Developmental changes in glucose metabolism could explain why only those presynaptic boutons that contained mitochondria showed increased vesicular mobilization at P15 but some presynaptic boutons without mitochondria also had increased vesicle mobilization in adults. Before weaning, rat diets consist primarily of fatty acids, which means their neurons rely on ketone bodies instead of glucose for energy (Edmond et al, 1985;Raffo et al, 2004;Yeh and Sheehan, 1985). Accordingly, rat hippocampal neurons begin to express glucose transporters at about P14, but expression does not approach adult levels until after P21 (Vannucci, 1994).…”