Early metabolic responses to lithium/pilocarpine‐induced status epilepticus in rat brain

Abstract

The lithium-pilocarpine model of status epilepticus is a wellknown animal model of temporal lobe epilepsy. We combined this model with in vivo microdialysis to investigate energy metabolites and acute cellular membrane damage during seizure development. Rats were implanted with dialysis probes and pretreated with lithium chloride (127 mg/kg i.p.). Twenty-four hours later, they received pilocarpine (30 mg/kg s.c.) which initiated seizures within 30 min. In the dialysate from rat hippocampus, we observed a transient increase in glucose and a prominent, five-fold increase in lactate during seizures. Lactate release was because of neuronal activation as it was strongly reduced by infusion of tetrodotoxin, administration of atropine or when seizures were terminated by diazepam or ketamine. In ex vivo assays, mitochondrial function as measured by respirometry was not affected by 90 min of seizures. Extracellular levels of choline, however, increased two-fold and glycerol levels 10-fold, which indicate cellular phospholipid breakdown during seizures. Within 60 min of pilocarpine administration, hydroxylation of salicylate increased two-fold and formation of isoprostanes 20-fold, revealing significant oxidative stress in hippocampal tissue. Increases in lactate, glycerol and isoprostanes were abrogated, and increases in choline were completely prevented, when hippocampal probes were perfused with calcium-free solution. Similarly, administration of pregabalin (100 mg/kg i.p.), a calcium channel ligand, 15 min prior to pilocarpine strongly attenuated parameters of membrane damage and oxidative stress. We conclude that seizure development in a rat model of status epilepticus is accompanied by increases in extracellular lactate, choline and glycerol, and by oxidative stress, while mitochondrial function remains intact for at least 90 min. Membrane damage depends on calcium influx and can be prevented by treatment with pregabalin.

Effects of Three Anti-Seizure Drugs on Cholinergic and Metabolic Activity in Experimental Status Epilepticus

“…The basal glucose concentration in hippocampal microdialysates was 338 ± 133 µM (N=40). As described before (21), glucose levels rose after pilocarpine administration to 444 ± 198 µM (+31%) but returned to baseline within 60-90 min after seizures were terminated. Basal lactate and pyruvate levels in microdialysates were 319 ± 126 µM (N=40) and 21.5 ± 7.7 µM, yielding an L/P ratio of 14.8 ± 2.4 under basal conditions.…”

“…_________________________________________ Very recently, studies with microdialysis and studies using drug cocktails to terminate SE have pointed to a role of cholinergic system in seizure activity (19,20). In our work in rat hippocampus, extracellular acetylcholine (ACh) was found to increase several-fold when seizures developed (19) while neuronal hyperexcitation was reflected in an increase of aerobic glycolysis and ATP release (21,22). In parallel, membrane damage and oxidative stress were prominent (21).…”

“…In our work in rat hippocampus, extracellular acetylcholine (ACh) was found to increase several-fold when seizures developed (19) while neuronal hyperexcitation was reflected in an increase of aerobic glycolysis and ATP release (21,22). In parallel, membrane damage and oxidative stress were prominent (21). Moreover, recent work demonstrated the effectiveness of scopolamine, a muscarinic antagonist, to terminate drug-resistant seizures (20,23), and scopolamine also effectively reduced seizure activity induced by electrical stimulation of the basal amygdala (24).…”

“…4). In untreated animals, lactate levels remained at or above 400% for up to four hours (21). When anticonvulsant drugs were given, the L/P ratio was lowered to baseline levels while convulsions subsided (Fig.…”

A single seizure selectively impairs hippocampal‐dependent memory and is associated with alterations in PI3K/Akt/mTOR and FMRP signaling

“…Research using animal models of epilepsy such as pentylenetetrazol kindling, status epilepticus (SE) induced using kainate, or SE‐induced using pilocarpine has confirmed the presence of memory impairment following repeated or prolonged seizures . In addition to memory impairments, chronic models of epilepsy also produce seizures of sufficient duration and severity to result in pathologic alterations to the brain including neurodegeneration, abnormal neurogenesis, oxidative stress, inflammation, and disruption of the blood–brain barrier . Damage and other pathologic changes have been assumed to underlie memory impairment in chronic epilepsy; however, the concurrent presence of multiple alterations to the brain makes defining the direct cause of memory impairment difficult.…”