Summary:Purpose: Nutritional insults early in life have a profound and often permanent effect on the development of the central nervous system. A direct relationship between malnutrition and epilepsy has not been established; however, it is believed that inadequate nutrition may predispose the brain to seizures. This study was designed to determine whether neonatally malnourished rats are different from nourished rats in terms of flurothyl seizure susceptibility at postnatal day (P)15, in the behavioral manifestations of seizures, and in status epilepticus-induced hippocampal injury.Methods: Sprague-Dawley rat pups were maintained on a starvation regimen from P2 until P17. Age-matched control rats were not exposed to starvation. At P15, all animals were exposed to flurothyl-induced status epilepticus. At P17, the rats received a single injection of bromodeoxyuridine (50 mg/kg intraperitoneal) to determine the extent of genesis of new cells in the dentate gyrus. At P18, the rats were killed, and the brains were processed for histology and immunohistochemistry.Results: Preliminary analysis indicates that early malnutrition did not modify flurothyl seizure susceptibility or the behavioral manifestations of seizures at P15. Histological assessment did not reveal any evidence of hippocampal cell loss after status epilepticus in either group. Malnutrition per se induced an increase in the genesis of new cells in the anterior dentate granule cell layer. Although exposure to status epilepticus augmented the expression of new cells in the dentate gyrus in both groups, this expression was more pronounced in the malnourished group.Conclusions: The findings suggest that malnutrition early in life alters dentate plasticity but not the susceptibility to flurothy1 seizures. Although status epilepticus can increase the expression of new cells in the dentate gyrus in immature rats, malnutrition followed by status epilepticus further increases dentate granule cell proliferation. Key Words: EpilepsyMalnutrition-Plasticity-CNS development-Hippocampus-Dentate gyrus.Malnutrition is one of the most important health problems in developing and underdeveloped countries. Nutritional insults early in life have a profound and often permanent effect on the subsequent development of the central nervous system. Clinical studies indicate that malnourished children have more learning and behavioral problems than well-nourished children (1-3). In a cross-sectional study from a pediatric population residing in a governmental institution, there was a trend toward a greater number of epilepsy cases among malnourished children compared with controls (4). However, a direct relationship between malnutrition and epilepsy has not been established in clinical studies.Many animal studies suggest that malnutrition may have detrimental effects on the brain and predispose the A decrease in the number of dendritic spines of pyramidal neurons of lamina I11 or V of the anterior cingulate cortex and in the CA3 hippocampal region was also described (6,7). Furtherm...

Summary: Purpose: With intraperitoneal N-methyl-D-aspartate (NMDA; 15-200 mgikg) administration, we attempted to develop an animal model of age-specific West syndrome to serve for testing of putative anticonvulsant drugs and to determine the mechanisms of this disorder.Methods: Experiments were performed in 12-, 18-, and 60-day-old (adult) rats. The effects of systemic pretreatment with hydrocortisone (5-25 mg/kg), pyridoxine (20-250 mgkg), and sodium valproate (VPA; 200 and 400 mg/kg) against the NMDA-induced automatisms, emprosthotonic (hyperflexion), and clonic-tonic seizures were determined. NMDA-induced EEG changes and alterations of the performance in horizontal bar, rotorod, open field, and elevated plus-maze tests were recorded.Results: In young rats, hydrocortisone had proconvulsant effects. High doses of pyridoxine induced epileptiform activity independent of and distinct from that induced by NMDA. Only VPA had moderate effects against the NMDA-induced syndrome. EEG consisted of periods of suppression mixed with ictal activity of serrated waves and high-voltage chaotic EEG activity. In adult rats, EEG alterations involved spike and spike-and-wave activity. NMDA also deteriorated performance of young rats in the open field, rotorod, and elevated plus maze tests.Conclusions: NMDA syndrome in rats fulfills some, but not all, criteria of the West syndrome model, such as occurrence of flexion seizures, nonspecific diffuse EEG changes, refractoriness to antiepileptic therapy (but a response to VPA), as well as long-term alteration of behavioral tasks. However, NMDAinduced seizures represent an acute model without the occurrence of spontaneous seizures, whereas in the clinical situation, both the seizures and neurologic deterioration are chronic. Further, in the West syndrome and the NMDA seizure model, there is an incongruent response to therapy with antiepileptic drugs.

Summary:Purpose: To determine the effects of a newly synthesized epalon, ganaxolone (GNX), on primarily generalized seizures in rats of various ages during development. Epalons are classified as neuroactive steroids that interact at unique site of the GABA, receptor-CI-channel complex in the central nervous system.Methods: Sprague-Dawley male rats were used at 9, 15, 30, and 60 postnatal days (PN). GNX dissolved in 2-hydroxypropyl-P-cyclodextrine was administered intraperitoneally in different doses at various time points before flurothyl testing. The incidence and threshold of clonic and tonic-clonic flurothyl seizures were evaluated. Behavioral changes were also assessed.Results: In all age groups, the effects of GNX were dose dependent and more prominent 10 min after its administration.In PN 60 and PN 30 rats, GNX had dose-dependent anticonvulsant effects; tonic-clonic seizures were more sensitive to GNX treatment than clonic seizures. In PN 15 and PN 9 rats, GNX demonstrated dose-and time-dependent anticonvulsant effects against both types of flurothyl-induced seizures. GNX was more effective in PN 15 rats than in other age groups, but at doses that altered motor behavior.Conclusions: GNX has anticonvulsant effects against flurothylinduced seizures in all age groups tested. Its effects are more prominent in the two younger age groups, especially in PN 15 rats, but are associated with motor side effects. Key Wards: Ganaxolone-Seizures-Rats-Development-Flurothy I.Neurosteroids (also called neuroactive steroids) are steroid hormones that can be formed de novo in the central nervous system (CNS) (1). Neurosteroids can also be produced in brain tissues from the conversion of peripheral steroid hormones such as progesterone, deoxycorticosterone, and testosterone, which can cross the blood-brain barrier (2). Endogenous or synthetic neuroactive steroids' alter neuronal excitability by rapidly acting on the neuronal membrane within seconds to minutes (3,4).The endogenous metabolites of progesterone (501-pregnan-3a-ol-20-one and 5ci-pregnan-3rx,20c~-diol), deoxycorticosterone (5a-pregnan-301,2 1 -diol-20-one), and their synthetic analogue alphaxalone (501-pregnan-301-01-1 1,20-dione) are the best described neurosteroids (45).There is a class of neuroactive steroids called "epalons" that are devoid of hormonal effects with high specific activity for the GABA, receptor complex (4,6,7). Epalons interact as positive allosteric modulators at a unique receptor site of the GABA, receptor-C1-channel com- Ganaxolone (301-hydroxy-3P-methyl-Sol-pregnan-20-one; GNX) is a newly developed 3P-methylated synthetic epalon derived from the endogenous neuroactive steroid 3a-hydroxy-5a-pregnan-20-one (301,501-P) (11,12). In vitro studies show that GNX has a positive allosteric modulatory effect at the GABA, receptor-Clchannel complex (11). Data from in vivo studies demonstrate that GNX is a potent anticonvulsant against clonic pentylenetetrazol (PTZ)-, bicuculline-, t-butylbicyclophosphorothionate-, cocaine-, and aminophylline-induced s...

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