Spatial and temporal evolution of neuronal activation, stress and injury in lithium-pilocarpine seizures in adult rats.

In order to follow the spatial and temporal evolution of neuronal damage, cellular activation and stress responses subsequent to lithium-pilocarpine seizures of various durations in the adult rat, we analyzed the expression of Fos protein and local cerebral glucose utilization as markers of cellular activation, HSP72 immunoreactivity and acid fuchsin staining as indicators of cellular stress and injury, and Cresyl violet staining for the assessment of neuronal damage. The expression of Fos appeared very early, 2-30 min after the onset of polyspikes and intensified during the following 4 h. Fos immunoreactivity was especially high in the hippocampus, cerebral cortex, amygdala and anterior olfactory nuclei. Local cerebral glucose utilization measured during the second hour of seizures was largely increased (350-580%) over control levels in cortical areas, amygdala, dentate gyrus, caudate nucleus and mediodorsal thalamus. HSP72 immunoreactivity never appeared earlier than 40-50 min after the onset of polyspikes, and was most prominent in hippocampal CA3 area, cerebral cortex (except the piriform cortex) and anterior olfactory nuclei. Acid fuchsin staining was maximal in the piriform cortex and the polymorphic layer of the dentate gyrus. Staining was moderate in the sensorimotor cortex and the amygdala. Neuronal damage was extensive in the piriform and entorhinal cortices, the hippocampal CA3 area and the polymorphic layer of the dentate gyrus, basal amygdala, mediodorsal thalamus and anterior olfactory nuclei. In conclusion, the present study shows that brain regions with the highest expression of Fos and the largest metabolic activation were also highly stained with acid fuchsin and most heavily damaged. Conversely, there is no clear relationship between HSP72 expression, cellular activation and neuronal damage

Neuroprotective Properties of Topiramate in the Lithium- Pilocarpine Model of Epilepsy

ABSTRACT The lithium-pilocarpine model reproduces the main characteristics of human temporal lobe epilepsy. After status epilepticus (SE), rats exhibit a latent seizure-free phase characterized by development of extensive damage in limbic areas and occurrence of spontaneous recurrent seizures. Neuroprotective and antiepileptogenic effects of topiramate were investigated in this model. SE was induced in adult male rats by LiCl (3 mEq/kg) followed 20 h later by pilocarpine (25 mg/kg). Topiramate (10, 30, or 60 mg/kg) was injected at 1 and 10 h of SE. Injections were repeated twice a day for six additional days. Another group received two injections of diazepam on the day of SE and of vehicle for 6 days. Neuronal damage was assessed at 14 days after SE by cell counting on thionin-stained sections. Occurrence of spontaneous recurrent seizures (SRS) was videorecorded for 10 h per day in other groups of rats. In diazepam-treated rats, the number of neurons was dramatically reduced after SE in all subregions of hippocampus and layers II-IV of ventral cortices. At all doses, topiramate induced a 24 to 30% neuroprotection in layer CA1 of hippocampus (p Ͻ 0.05). In CA3b, the 30-mg/kg dose prevented neuronal death. All rats subjected to SE became epileptic. The latency (14 -17 days) to and frequency of SRS were similar in topiramate-and diazepam-treated rats. The high mortality in the 30 mg/kg topiramate group (84%) was possibly the result of interaction between lithium and topiramate. In conclusion, topiramate displayed neuroprotective properties only in CA1 and CA3 that were not sufficient to prevent epileptogenesis

Global and regional brain metabolic scaling and its functional consequences

Background: Information processing in the brain requires large amounts of metabolic energy, the spatial distribution of which is highly heterogeneous reflecting complex activity patterns in the mammalian brain. Results: Here, it is found based on empirical data that, despite this heterogeneity, the volume-specific cerebral glucose metabolic rate of many different brain structures scales with brain volume with almost the same exponent around -0.15. The exception is white matter, the metabolism of which seems to scale with a standard specific exponent -1/4. The scaling exponents for the total oxygen and glucose consumptions in the brain in relation to its volume are identical and equal to $0.86\pm 0.03$, which is significantly larger than the exponents 3/4 and 2/3 suggested for whole body basal metabolism on body mass. Conclusions: These findings show explicitly that in mammals (i) volume-specific scaling exponents of the cerebral energy expenditure in different brain parts are approximately constant (except brain stem structures), and (ii) the total cerebral metabolic exponent against brain volume is greater than the much-cited Kleiber's 3/4 exponent. The neurophysiological factors that might account for the regional uniformity of the exponents and for the excessive scaling of the total brain metabolism are discussed, along with the relationship between brain metabolic scaling and computation.Comment: Brain metabolism scales with its mass well above 3/4 exponen

The Depolarizing Action of GABA in Cultured Hippocampal Neurons Is Not Due to the Absence of Ketone Bodies

Two recent reports propose that the depolarizing action of GABA in the immature brain is an artifact of in vitro preparations in which glucose is the only energy source. The authors argue that this does not mimic the physiological environment because the suckling rats use ketone bodies and pyruvate as major sources of metabolic energy. Here, we show that availability of physiologically relevant levels of ketone bodies has no impact on the excitatory action of GABA in immature cultured hippocampal neurons. Addition of β-hydroxybutyrate (BHB), the primary ketone body in the neonate rat, affected neither intracellular calcium elevation nor membrane depolarizations induced by the GABA-A receptor agonist muscimol, when assessed with calcium imaging or perforated patch-clamp recording, respectively. These results confirm that the addition of ketone bodies to the extracellular environment to mimic conditions in the neonatal brain does not reverse the chloride gradient and therefore render GABA hyperpolarizing. Our data are consistent with the existence of a genuine “developmental switch” mechanism in which GABA goes from having a predominantly excitatory role in immature cells to a predominantly inhibitory one in adults