Effects of morphine or naloxone on kainic acid neurotoxicity.

Intraperitoneal or subcutaneous administration of kainic acid (KA) (5–15 mg/kg) to adult rats included a syndrome of wef wet dog shakes (WDS), convulsions and brain damage. Components of the syndrome were evoked in a dose-related manner with low doses inducing WDS only and progressively higher doses being associated with an increasing incidence of naloxone (4 mg/kg) 5 minutes prior to KA (12 mg/kg) resulted in a moderate reduction in the incidence of WDS, convulsions and brain damage. Administering morphine (5 or 10 mg/kg) 10 minutes prior to KA (7 mg/kg) markedly enhanced the neurotoxicity of KA as was evidenced in an increase in the incidence of convulsions and brain damage from 7% (KA alone) to 100% (morphine + KA). KA, a structural analog of the putative excitatory transmitter glutamate (Glu), is thought to exert its excitotoxic activity through Glu excitatory receptors. Additional studies are needed to elucidate the mechanism by which morphine and naloxone respectively enhance and suppress KA neurotoxicity and to clarify whether interaction of these agents at either opioid or Glu receptors plays a role in such phenomena.     

Antioxidant, Anticonvulsive and Neuroprotective Effects of Dapsone and Phenobarbital Against Kainic Acid-Induced Damage in Rats

Excitotoxicity due to glutamate receptors (GluRs) overactivation is a leading mechanism of oxidative damage and neuronal death in various diseases. We have shown that dapsone (DDS) was able to reduce both neurotoxicity and seizures associated to the administration of kainic acid (KA), an agonist acting on AMPA/KA receptors (GluK1–GluK5). Recently, it has been shown that phenobarbital (PB) is also able to reduce epileptic activity evoked by that receptor. In the present study, we tested the antioxidative, anticonvulsive and neuroprotective effects of DDS and PB administered alone or in combination upon KA toxicity to rats. Results showed that KA increased lipid peroxidation and diminished reduced glutathione (GSH), 24 h after KA administration and both drugs in combination or individually inhibited these events. Likewise, KA promotes mortality and this event was antagonized by effect of both treatments. Additionally, the behavioral evaluation showed that DDS and PB administered alone or in combination decreased the number of limbic seizures and reduced the percentage of animals showing tonic–clonic seizures versus the control group, which was administered only with KA. Finally, our study demonstrated that all of the treatments prevented the neuronal death of the pyramidal cell layer of hippocampal CA-3. In conclusion, the treatment with DDS and PB administrated alone or in combination exerted antioxidant, anticonvulsive and neuroprotective effects against the neurotoxicity induced by KA in rats, but their effects were not additive. Thus, it may be good options of treatment in diseases such as epilepsy and status epilepicus, administered separately.     

Does phenobarbital protect against trimethyltin-induced neuropathology of limbic structures?

Because of the similarity in the pattern of limbic sites damaged by both compounds, it has been suggested that trimethyltin (TMT) may be an excitotoxin like kainic acid (KA). KA produces seizures which eventually result in neuronal damage similar to that found in epilepsy. Anticonvulsants reduce both the seizures and pathology associated with KA. Because TMT may also produce seizures, we undertook to determine whether or not some of the TMT-induced limbic neuropathology could result from seizure activity. To do this, a single dose of TMT chloride (either 7.5 or 15 mg/kg) was given per os to rats, and then phenobarbital (30 mg/kg) was administered subcutaneously in repeated doses. Treatment with phenobarbital did not prevent pathologic changes in the hippocampus, dentate gyrus, and pyriform or prepyriform cortex. Since phenobarbital did not protect against TMT-induced neuronal damage, as it has been reported by others to protect against KA-induced damage, the present findings suggest that these two toxicants probably produce hippocampal pathology via different mechanisms and that the TMT-induced pathologic changes do not require sustained electrical seizure activity.     

Prevention of kainic acid-induced changes in nitric oxide level and neuronal cell damage in the rat hippocampus by manganese complexes of curcumin and diacetylcurcumin

Curcumin is a natural antioxidant isolated from the medicinal plant Curcuma longa Linn. We previously reported that manganese complexes of curcumin (Cp-Mn) and diacetylcurcumin (DiAc-Cp-Mn) exhibited potent superoxide dismutase (SOD)-like activity in an in vitro assay. Nitric oxide (NO) is a free radial playing a multifaceted role in the brain and its excessive production is known to induce neurotoxicity. Here, we examined the in vivo effect of Cp-Mn and DiAc-Cp-Mn on NO levels enhanced by kainic acid (KA) and L-arginine (L-Arg) in the hippocampi of awake rats using a microdialysis technique. Injection of KA (10 mg/kg, i.p.) and L-Arg (1000 mg/kg, i.p.) significantly increased the concentration of NO and Cp-Mn and DiAc-Cp-Mn (50 mg/kg, i.p.) significantly reversed the effects of KA and L-Arg without affecting the basal NO concentration. Following KA-induced seizures, severe neuronal cell damage was observed in the CA1 and CA3 subfields of hippocampal 3 days after KA administration. Pretreatment with Cp-Mn and DiAc-Cp-Mn (50 mg/kg, i.p.) significantly attenuated KA-induced neuronal cell death in both CA1 and CA3 regions of rat hippocampus compared with vehicle control, and Cp-Mn and DiAc-Cp-Mn showed more potent neuroprotective effect than their parent compounds, curcumin and diacetylcurcumin. These results suggest that Cp-Mn and DiAc-Cp-Mn protect against KA-induced neuronal cell death by suppression of KA-induced increase in NO levels probably by their NO scavenging activity and antioxidative activity. Cp-Mn and DiAc-Cp-Mn have an advantage to be neuroprotective agents in the treatment of acute brain pathologies associated with NO-induced neurotoxicity and oxidative stress-induced neuronal damage such as epilepsy, stroke and traumatic brain injury.     

Role of IFN-gamma in an experimental murine model of West Nile virus-induced seizures

Seizures are a major complication of viral encephalitis. However, the mechanisms of seizure-associated neuronal dysfunction remain poorly understood. We report that intranasal inoculation with West Nile virus (WNV) (Sarafend) causes limbic seizures in C57BL/6 mice, but not in interferon (IFN)-gamma-deficient (IFN-gamma-/-) mice. Both strains showed similar levels of virus in the brain, as well as similar concentrations of the cytokines, tumor necrosis factor and interleukin-6, both of which can alter neuronal excitability. Experiments in chimeric IFN-gamma-/- mice reconstituted with IFN-gamma-producing leukocytes showed that IFN-gamma is not required during central nervous system infection for limbic seizure development, suggesting a role for IFN-gamma in the developing brain. This was supported responses to pentylenetetrazole, kainic acid (KA), and N-methyl-d-aspartate (NMDA). Both strains of mice exhibited similar behavior after pentylenetetrazole challenge. However, while NMDA and KA treatment resulted in characteristic seizures in C57BL/6 mice, these responses were diminished (NMDA treatment) or absent (KA treatment) in IFN-gamma-/- mice. Furthermore, NMDA-receptor blockade with MK-801 in WNV-infected C57BL/6 mice abrogated seizures and prolonged survival. Our data show that IFN-gamma plays an important role in the development of the excitatory seizure pathways in the brain and that these cascades become pathogenic in encephalitic WNV infection.     

Levetiracetam protects against kainic acid-induced toxicity

We investigated the Levetiracetam (LVT) ability to protect the brain against kainic acid (KA) induced neurotoxicity. Brain injury was induced by intraperitoneal administration of KA (10 mg/kg). Sham brain injury rats were used as controls. Animals were randomized to receive either LVT (50 mg/kg) or its vehicle (1 ml/kg) 30 min. before KA administration. Animals were sacrificed 6 hours after KA injection to measure brain malonildialdehyde (MDA), glutathione levels (GSH) and the mRNA for interleukin-1beta (IL-1beta) in the cortex and in the diencephalon. Behavioral changes were also monitored. Intraperitoneal administration of LVT decreased significantly MDA in the cortex (KA + vehicle = 0.25 +/- 0.03 nmol/mg protein; KA + LVT = 0.13 +/- 0.01 nmol/mg protein; P < 0.005), and in the diencephalons (KA + vehicle = 1,01 +/- 0.2 nmol/mg protein; KA + LVT = 0,33 +/- 0,08 nmol/mg protein; P < 0.005), prevented the brain loss of GSH in both cortex (KA + vehicle = 5 +/- 1 micromol/g protein; KA + LVT = 15 +/- 2 micromol/g protein; P < 0.005) and diencephalons (KA + vehicle = 9 +/- 0.8 micromol/g protein; KA + LVT = 13 +/- 0.3 micromol/g protein; P < 0.05), reduced brain IL-1beta mRNA and markedly controlled seizures. Histological analysis showed a reduction of cell damage in LVT treated samples. The present data indicate that LVT displays neuro-protective effects against KA induced brain toxicity and suggest that these effects are mediated, at least in part, by inhibition of lipid peroxidation.     

Cerebral metabolic response to systematic kainic acid: 14-C-deoxyglucose studies

Kainic acid (KA) given once intravenously in a dose of 12 mg/kg results successively in staring spells, wet dog shakes, and overt behavioral convulsions over a 90 minute time period. Convulsions last up to 18 hours and are followed by aphagia, adipsia and startle. behavior. Five minutes after KA, deoxyglucose autoradiography reveals a 3–6 fold increase in glucose utilization in ventral CA3 of hippocampus, ventral subiculum, lateral septum with a less intense increase in dorsal hippocampus. During severe behavioral convulsions the entire limbic system and its subcortical projections are metabolically active, while sensory pathways and neocortex are depressed. One to three days following convulsions many limbic areas that participated in seizures are necrotic, while metabolism in the rest of the brain has returned toward normal.     

Changes in Polyamine Levels in Rat Brain After Systemic Kainic Acid Administration: Relationship to Convulsant Activity and Brain Damage

We have examined the effects of systemic kainic acid (KA) administration (9 mg/kg, i.p.) on rat behavior, brain damage, and polyamine levels and the action of the specific ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) on these effects. KA elicited convulsant activity in 63% of the animals. In the acute convulsant phase (1-3 h after KA), a rapid decline (-39% at 3 h) of spermidine content in frontal cortex was found. After the acute convulsant phase, levels of hippocampal spermidine and spermine were reduced (-70 and -66%, respectively, at 8 h). A dramatic increase of putrescine content (68.1, 1,382, and 336% at 8 h, 24 h, and 9 days, respectively, after KA) was found, associated with histological signs of cortical brain damage (ischemia and necrosis). There was a close relationship between the concentration of putrescine and signs of delayed toxicity (body weight losses) 24 h and 9 days after KA. DFMO partially antagonized the convulsant activity and reduced the increased putrescine levels to approximately 50% of values in KA-treated animals at 24 h but did not change the pattern of histological damage. The role of polyamines in the early and late phases of KA-induced neurotoxicity is discussed.     

Effect of oxcarbazepine pretreatment on convulsive activity and brain damage induced by kainic acid administration in rats

Temporal lobe epilepsy is one of the most common types of epilepsy. Progress in the understanding and treatment of this type of epilepsy would be greatly facilitated by the availability of an animal model, which reproduced the behavioral and electrographic features of this condition. In this context, kainic acid (KA, 2-carboxy-3-carboxymethyl-4-isopropenylpyrrolidine) administration causes a syndrome characterized by an acute status epilepticus and subsequent brain damage similar to that in temporal lobe epilepsy of humans. The aim of the present study was to investigate whether oxcarbazepine (10,11-dihydro-10-oxo-5 H -dibenz(b,f)azepine-5-carboxamide), an antiepileptic drug, protects against both epileptic activity and brain damage induced by KA administration. Chronically implanted adult male Wistar rats were polygraphically recorded during 10 continuous hours under 4 different conditions: a) control, b) after KA administration alone, c) after KA administration in oxcarbazepine pretreated animals and d) after the administration of oxcarbazepine alone. Animals treated with KA alone presented behavioral and electrophysiological convulsive activity as well as brain damage. Latency of seizure installation was lengthened significantly and convulsive activity was slightly reduced, however, brain damage was still present in oxcarbazepine pretreated animals. Administration of oxcarbazepine alone induced a hypnotic behavior and brain damage was also present.     

Formation of the base modification 8-hydroxyl-2'-deoxyguanosine and DNA fragmentation following seizures induced by systemic kainic acid in the rat

The formation of oxidative DNA damage as a consequence of seizures remains little explored. We therefore investigated the regional and temporal profile of 8-hydroxyl-2'-deoxyguanosine (8-OHdG) formation, a hallmark of oxidative DNA damage and DNA fragmentation in rat brain following seizures induced by systemic kainic acid (KA). Formation of 8-OHdG was determined via HPLC with electrochemical detection, and single- and double-stranded DNA breaks were detected using in situ DNA polymerase I-mediated biotin-dATP nick-translation (PANT) and terminal deoxynucleotidyl-transferase-mediated nick end-labeling (TUNEL), respectively. Systemic KA (11 mg/kg) significantly increased levels of 8-OHdG within the thalamus after 2 h, within the amygdala/piriform cortex after 4 h, and within the hippocampus after 8 h. Levels remained elevated up to sevenfold within these areas for 72 h. Smaller increases in 8-OHdG levels were also detected within the parietal cortex and striatum. PANT-positive cells were detected within the thalamus, amygdala/piriform cortex, and hippocampus 24-72 h following KA injection. TUNEL-positive cells appeared within the same brain regions and over a similar time course (24-72 h) but were generally lower in number. The present data suggest oxidative damage to DNA may be an early consequence of epileptic seizures and a possible initiation event in the progression of seizure-induced injury to DNA fragmentation and cell death.     

Differential subcellular redistribution of protein kinase C isozymes in the rat hippocampus induced by kainic acid

Protein kinase C (PKC) consists of a family of Ca2+/phospholipid-dependent isozymes that has been implicated in the delayed neurotoxic effects of glutamate in vitro. In the present study, we assessed the effect of the glutamate analogue kainic acid (KA) on the subcellular expression of PKC isozymes in the hippocampus (HPC) in the period preceding (0.5, 1.5, 12, and 24 h) and during (120 h) hippocampal necrosis using western blot analysis and PKC isozyme-specific antibodies. Before subcellular fractionation (cytosol + membrane), hippocampi were microdissected into "HPC" (fields CA1-CA3) and "dentate gyrus" (DG; granule cells + hilus) regions. Four general patterns of alterations in PKC isozyme expression/distribution were observed following KA treatment. The first pattern was a relative stability in expression following KA treatment and was most apparent for cytosol PKCalpha (HPC + DG) and membrane (HPC) and cytosol (DG) PKCbetaII. The second pattern, observed with PKCgamma and PKCepsilon, was characterized by an initial increase in expression in both membrane and cytosolic fractions before seizure activity (0.5 h) followed by a gradual decrease until significant reductions are observed by 120 h. The third pattern, exhibited by PKCdelta, involved an apparent translocation, increasing in the membrane and decreasing in the cytosol, followed by down-regulation in both fractions and subsequent recovery. The fourth pattern was observed with PKCzeta only and entailed a significant reduction in expression before and during limbic motor seizures followed by a dramatic fivefold increase in the membrane fraction during the period of hippocampal necrosis (120 h). Although these patterns did not segregate according to conventional PKC isozyme classifications, they do indicate dynamic isozyme-specific regulation by KA. The subcellular redistribution of PKC isozymes may contribute to the histopathological sequelae produced by KA in the hippocampus and may model the pathogenesis associated with diseases involving glutamate-induced neurotoxicity.     

Antagonism of intrastriatal and intravenous kainic acid by 1-nuciferine: Comparison with various anticonvulsants and gabamimetics

1-Nuciferine has been proposed as an antagonist of kainic acid (KA) and/or glutamate on the basis of iontophoretic experimental results. Its effectiveness against KA-induced destruction of rat striatal cholinergic neurons was therefore evaluated and compared with that of diazepam, phenobarbital, baclofen, haloperidol, and related substances. Drugs were administered intraperitoneally before and after intrastriatal microinjection of KA (0.5–1.5 μg), and choline acetyltransferase activity in striatum was assessed 24 hr later. Among the substances tested, only 1-nuciferine attenuated KA-induced depletions of striatal choline acetyltransferase. This effect was not secondary to anticonvulsant activity, because (a) 1-nuciferine did not block metrazol-, maximal electroshock-, or intravenous KA-induced seizures, and (b) anticonvulsants such as phenobarbital and diazepam, which are effective in these procedures, failed to modify KA-induced striatal neurotoxicity. 1-Nuciferine antagonized certain other neurological effects of intravenous KA, but antagonism was also seen with some of the other drugs tested. Intrastriatal microinjection of KA and/or glutamate may offer a means to detect selective antagonism of KA and/or glutamate, as distinguished from simple anticonvulsant activity.     

Strain-Dependent Effects of Sub-chronically Infused Losartan Against Kainic Acid-Induced Seizures,Oxidative Stress,and Heat Shock Protein 72 Expression

We studied the involvement of angiotensin (Ang) II AT₁ receptors in the pathophysiology of kainate (KA)-induced neurotoxicity, focusing on the regulation of the oxidative stress state and expression of HSP 72 in the frontal cortex and hippocampus in two strains, spontaneously hypertensive rats (SHRs) and normotensive Wistar rats. The KA injection was executed after the rats were infused subcutaneously via osmotic mini-pumps with losartan (10 mg/kg day) for 14 days. Losartan delayed the onset of KA-induced seizures in SHRs but not in Wistar rats without affecting the seizure intensity score. This selective AT₁ receptor antagonist decreased the lipid peroxidation only in naive SHRs. However, it attenuated the KA-induced increase in lipid peroxidation in both SHRs and Wistar rats. The adaptive enhancement of cytosolic superoxide dismutase (SOD) activity in KA-treated SHRs was recovered to control level after sub-chronic losartan infusion while no change in mitochondrial SOD activity was detected in the two strains. Both losartan and KA produced a higher expression of HSP 72 in the hippocampus of the two strains compared to naive rats infused with vehicle. Taken together, our findings demonstrate that the efficacy of a sub-chronic systemic losartan infusion in preventing the KA-induced seizure activity and neurotoxicity is more pronounced in SHRs, considered as a model of essential hypertension, than in normotenisve Wistar rats. The results suggest that the blockade of AT1 receptors, commonly used as a strategy for prevention of high blood pressure, may be useful as an adjunctive treatment in status epilepticus to reduce oxidative stress and neurotoxicity.     

A pharmacokinetic approach to morphine analgesia and its relation to regional turnover of rat brain catecholamines.

Morphine concentrations in plasma and four discrete areas of the rat brain following intravenous administration, can be described by a three-compartment open model. The pharmacokinetic behavior of morphine was the same in each of the different parts of the brain. When relating this behavior to the effects of morphine on the threshold for vocalisation and vocalisation-after-discharge, it was possible to develop a pharmacokinetic model which suggests that morphine induces its analgesic effect by a change of activities in at least two neurophysiological systems.As a result of investigations of morphine-induced changes of catecholamine turnover in different parts of the brain and of the consequences of modulating central monoaminergic activity prior to morphine administration, it was suggested that one of the two neurophysiological systems could be dopaminergic. In this system morphine increases the turnover of dopamine, most probably by releasing this transmitter from limbic structures that initiate the effect of morphine on the threshold for vocalisation-afterdischarge (the emotional component of pain reactions).     

Capsaicin prevents kainic acid-induced epileptogenesis in mice

Epilepsy is a neurodegenerative disease with periodic occurrences of spontaneous seizures as the main symptom. The aim of this study was to investigate the neuroprotective effects of capsaicin, the major ingredient of hot peppers, in a kainic acid (KA)-induced status epilepticus model. After intraperitoneal injections of KA (30mg/kg) in 8-week-old male ICR mice, the animals were treated subcutaneously with capsaicin (0.33mg/kg or 1mg/kg) and then examined for any anti-ictogenic, hypothermic, antioxidative, anti-inflammatory, and anti-apoptotic effects of the capsaicin treatment 3 days after KA treatment. KA injections significantly enhanced neurodegenerative conditions but co-injection with capsaicin reduced the detrimental effects of KA in a dose-dependent manner in mice. The co-administered group that received KA and 1mg/kg of capsaicin showed significantly decreased behavioral seizure activity and body temperature for 3h and also remarkably blocked intense and high-frequency seizure discharges in the parietal cortex for 3 days compared with those that received KA alone. Capsaicin treatment significantly diminished the levels of oxidant activity and malondialdehyde concentration and increased the antioxidant activity in the blood and brain of KA-treated mice. In addition, capsaicin significantly lowered the KA-induced increase in the concentration of the cytokines IL-1β and TNF-α in the brain. Furthermore, co-treatment of KA and capsaicin (1mg/kg) resulted in considerably decreased apoptotic cell death in the cornu ammonis sections of the hippocampus compared with that seen in the KA-alone group. These findings indicate that capsaicin is preventative for the epileptogenesis induced by KA in mice.     

Detection of 14-3-3ζ in cerebrospinal fluid following experimentally evoked seizures

Surrogate and peripheral (bio)markers of neuronal injury may be of value in assessing effects of seizures on the brain or epilepsy development following trauma. The presence of 14-3-3 isoforms in cerebrospinal fluid (CSF) is a diagnostic indicator of Creutzfeldt–Jakob disease but these proteins may also be present following acute neurological insults. Here, we examined neuronal and 14-3-3 proteins in CSF from rats after seizures. Seizures induced by intra-amygdala microinjection of 0.1 µg kainic acid (KA) caused damage which was mainly restricted to the ipsilateral CA3 subfield of the hippocampus. 14-3-3ζ was detected at significant levels in CSF sampled 4 h after seizures compared with near absence in control CSF. Neuron-specific nuclear protein (NeuN) was also elevated in CSF in seizure rats. CSF 14-3-3ζ levels were significantly lower in rats treated with 0.01 µg KA. These data suggest the presence of 14-3-3ζ within CSF may be a biomarker of acute seizure damage.     

Prolonged exposure to cigarette smoke blocks the neurotoxicity induced by kainic acid in rats

We examined the effects of cigarette smoke (CS) on three parameters associated with kainic acid (KA)-induced neurotoxicity: seizure activity, cell loss in the hippocampus, and increased Fos-related antigen (FRA) expression. Animals were exposed to the main stream of CS from 15 Kentucky 2R1F research cigarettes containing 28.6 mg tar and 1.74 mg nicotine per cigarette, for 10 min a day, 6 days per week, for 4 weeks, using an automatic smoking machine. KA administration (10 mg/kg, i.p.) produced robust behavioral convulsions lasting 4-5 h. Pre-exposure to CS significantly reduced the seizures, mortality, and severe loss of cells in regions CA1 and CA3 of the hippocampus after KA administration. Consistently, pre-exposure to CS significantly attenuated the KA-induced increased FRA immunoreactivity in the hippocampus. In contrast, pretreatment with central nicotinic antagonist, mecamylamine (2 or 10 mg/kg, i.p.) blocked the neuroprotective effects mediated by CS in a dose-dependent manner. These results indicate that CS exposure provides neuroprotection against the KA insult via nicotinic receptor activation.     

Systemic administration of kainic acid produces elevations in TRH in rat central nervous system

Several studies have suggested that the concentration of thyrotropin releasing hormone (TRH) in the central nervous system (CNS) is influenced by the level of CNS activation. Hibernation in the ground squirrel and estivation in the lungfish result in region-specific decreases in TRH concentrations. Repeated electroconvulsive shock (ECS) and amygdaloid kindling have been shown to result in elevations of TRH in limbic brain regions. In the present study, limbic seizures induced by systemic administration of kainic acid resulted in substantial increases in the TRH content of posterior cortex and of dorsal and ventral hippocampus, and in moderate elevations in anterior cortex, amygdala/piriform cortex and corpus striatum. Maximal elevations in TRH were observed 2-4 days after kainic acid administration, and by 14 days TRH levels were similar to control values, with the exception of the dorsal hippocampus, which exhibited more prolonged elevations in TRH levels. Prior exposure to limbic seizure activity attenuated the magnitude of TRH elevation in response to a second administration of kainic acid in the posterior cortex but in no other region. These results indicate that seizure-related processes or events influence TRH systems in the CNS. Neuronal populations involved in limbic seizure induced damage may be involved in the modulation of posterior cortical TRH levels.     

3H-kainic acid binding: relevance for evaluating the neurotoxicity of kainic acid.

Binding of ³H-kainic acid (KA) to brain membranes is saturable (K_D = 72 nM) and displays markes specificity for compounds that bear relation to excitatory amino acids. Its regional distribution correlates roughly with the regional neurotoxicity of in situ KA injections. Striatal kainate lesions, but not interruption of striatal afferents, reduce striatal KA binding by 36%. This decrease is due to a loss in the number of neuronal binding sites without affecting the affinity for the ligand. It is suggested that ³HKA binding to neuronal elements may be a valuable instrument for studies of the mechanism of neuronal degeneration caused by KA.     

NaK ATPase activity in the rat hippocampus: A study in the pilocarpine model of epilepsy

Biochemical abnormalities have been implicated in possible mechanisms underlying the epileptic phenomena. Some of these alterations include changes in the activity of several enzymes present in epileptic tissues. Systemic administration of pilocarpine in rats induces electrographic and behavioral limbic seizures and status epilepticus, that is followed by a transient seizure-free period (silent period). Finally a chronic phase ensues, characterized by spontaneous and recurrent seizures (chronic period), that last for the rest of the animal's life. The present work aimed to study the activity of the enzyme Na⁺ K⁺ ATPase, in rat hippocampus, during the three phases of this epilepsy model. The enzyme activity was determined at different time points from pilocarpine administration (1 and 24 h of status epilepticus, during the silent and chronic period) using a spectrophotometric assay previously described by Mishra and Delivoria-Papadopoulos [Neurochem. Res. (1988) 13, 765–770]. The results showed decreased enzyme activities during the acute and silent periods and increased Na⁺K⁺ ATPase activity during the chronic phase. These data show that changes in Na⁺K⁺ ATPase activity could be involved in the appearance of spontaneous and recurrent seizures following brain damage induced by pilocarpine injection.