Development Of Chronic Epilepsy Research Articles

Prediction of long-term unprovoked seizures after status epilepticus.

Possible long-term consequences of status epilepticus (SE) include cognitive and behavioral impairment and the development of chronic epilepsy. However, these aspects have not been systematically studied in clinical practice. We aimed to evaluate long-term seizure recurrence after SE and the potential risk factors for their development. Data were obtained from a prospective registry of all SE episodes occurring in adult patients who attended our center from February 2011 to April 2022. Clinical data, electroencephalographic findings, treatment, and long-term data were prospectively recorded. We performed a cross-sectional study of consecutive SE patients without previous epilepsy diagnosis, and analyzed the development of unprovoked remote seizures. A total of 849 patients were registered in the database. After excluding in-hospital mortality (198/849, 23.3%) and patients with prior epilepsy history (291/849, 44.7%), 360 patients (42.4%) with a first SE episode were included. The median age was 68 years (interquartile range [IQR] = 56-79), and 176 patients (48.9%) were women. The median time to first-line treatment initiation was 2 h (IQR = .7-7.4), and it was correlated with SE duration (R = .375, p < .001). One hundred nine patients (30.3%) presented unprovoked seizures during a median follow-up of 1.8 years (IQR = .5-4.3). After adjusting for identifiable confounders in a multivariable Cox regression analysis, progressive symptomatic etiology (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.17-3.33, p = .011), time to first-line treatment initiation > 1.5 h (HR = 1.89, 95% CI = 1.25-2.87, p = .003), and superrefractory SE (HR = 2.34, 95% CI = 1.26-4.33, p = .007) were independently associated with a greater risk of unprovoked seizure recurrence. In contrast, older patients (HR = .99, 95% CI = .97-.99, p = .021) and an acute symptomatic etiology (HR = .44, 95% CI .28-.68, p < .001) were at lower risk of unprovoked seizure recurrence. The etiology of SE, the delay in initiating SE treatment, and the presence of superrefractoriness have been identified as potentials factors associated with unprovoked remote seizures following a new onset SE. Therefore, prompt and appropriate management should be applied to avoid seizure recurrence.

Clinical Course and Features of Seizures Associated With LGI1-Antibody Encephalitis

To determine risk factors associated with clinical relapses and development of chronic epilepsy in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) immunoglobulin G encephalitis. Patients with seizures related to LGI1-antibody encephalitis with ≥24 months of follow-up from disease onset were identified in the Mayo Clinic electronic medical record and neuroimmunology laboratory records. Charts were reviewed to determine clinical factors, seizure types, imaging, treatment, occurrence of relapse, and outcome. Binary logistic regression analysis was performed to identify predictors of the development of chronic epilepsy. Univariate Cox proportional hazards regression was used to examine the influence of baseline characteristics on relapse risk. Forty-nine patients with LGI1-antibody encephalitis and acute symptomatic seizures were identified. Almost all patients (n = 48, 98%) were treated with immunotherapy. Eight had definite and 2 had possible chronic epilepsy at the last follow-up (10 of 49, 20.4%). Female sex (p = 0.048) and younger age at disease onset (p = 0.02) were associated with development of chronic epilepsy. Relapses occurred in 20 (40.8%), with a median time to first relapse of 7.5 months (range 3-94 months). Initial treatment with long-term steroid-sparing immunotherapy was associated with reduced risk of relapse (hazard ratio 0.28, 95% confidence interval 0.11-0.73, p = 0.009). Chronic epilepsy occurred in 20.4% of our patients with LGI1-antibody encephalitis despite aggressive immunotherapy. Risk factors for chronic epilepsy were female sex and earlier age at onset. Relapses occurred in 40.8% of patients with prolonged follow-up, and long-term steroid-sparing immunotherapy was associated with a lower relapse rate.

Factors underlying the development of chronic temporal lobe epilepsy in autoimmune encephalitis

PurposeLimbic encephalitis (LE) is an autoimmune condition characterized by amnestic syndrome, psychiatric features and seizures. Early diagnosis and prompt treatment are crucial to avoid long-term sequelae, including psycho-cognitive deficits and persisting seizures.The aim of our study was to analyze the characteristics of 33 LE patients in order to identify possible prognostic factors associated with the development of chronic epilepsy. MethodsThis is a retrospective cohort study including adult patients diagnosed with LE in the period 2010–2017 and followed up for ≥12 months. Demographics, seizure semiology, EEG pattern, MRI features, CSF/serum findings were reviewed. ResultsAll 33 LE patients (19 M/14F, mean age 61.2 years) presented seizures. Thirty subjects had memory deficits; 22 presented behavioural/mood disorders. Serum and/or CSF auto-antibodies were detected in 12 patients. In 31 subjects brain MRI at onset showed typical alterations involving temporal lobes. All patients received immunotherapy. At follow-up, 13/33 had developed chronic epilepsy; predisposing factors included delay in diagnosis (p = .009), low seizure frequency at onset (p = .02), absence of amnestic syndrome (p = .02) and absence/rarity of inter-ictal epileptic discharges on EEG (p = .06). ConclusionsLE with paucisymptomatic electro-clinical presentation seemed to be associated to chronic epilepsy more than LE presenting with definite and severe “limbic syndrome”.

Altered mitochondrial acetylation profiles in a kainic acid model of temporal lobe epilepsy

Impaired bioenergetics and oxidative damage in the mitochondria are implicated in the etiology of temporal lobe epilepsy, and hyperacetylation of mitochondrial proteins has recently emerged as a critical negative regulator of mitochondrial functions. However, the roles of mitochondrial acetylation and activity of the primary mitochondrial deacetylase, SIRT3, have not been explored in acquired epilepsy. We investigated changes in mitochondrial acetylation and SIRT3 activity in the development of chronic epilepsy in the kainic acid rat model of TLE. Hippocampal measurements were made at 48 h, 1 week and 12 weeks corresponding to the acute, latent and chronic stages of epileptogenesis. Assessment of hippocampal bioenergetics demonstrated a ≥ 27% decrease in the ATP/ADP ratio at all phases of epileptogenesis (p < 0.05), whereas cellular NAD+ levels were decreased by ≥ 41% in the acute and latent time points (p < 0.05), but not in chronically epileptic rats. In spontaneously epileptic rats, we found decreased protein expression of SIRT3 and a 60% increase in global mitochondrial acetylation, as well as enhanced acetylation of the known SIRT3 substrates MnSOD, Ndufa9 of Complex I and IDH2 (all p < 0.05), suggesting SIRT3 dysfunction in chronic epilepsy. Mass spectrometry-based acetylomics investigation of hippocampal mitochondria demonstrated a 79% increase in unique acetylated proteins from rats in the chronic phase vs. controls. Pathway analysis identified numerous mitochondrial bioenergetic pathways affected by mitochondrial acetylation. These results suggest SIRT3 dysfunction and aberrant protein acetylation may contribute to mitochondrial dysfunction in chronic epilepsy.

Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis

Cognitive dysfunction is a major comorbidity of the epilepsies; however, treatments targeting seizure-associated cognitive dysfunction, particularly deficits in learning and memory are not available. Isoketals and neuroketals, collectively known as gamma-ketoaldehydes are formed via the non-enzymatic, free radical catalyzed oxidation of arachidonic acid and docosahexaenoic acid, respectively. They are attractive candidates for oxidative protein damage and resultant cognitive dysfunction due to their formation within the plasma membrane and their high proclivity to form cytotoxic adducts on protein lysine residues. We tested the hypothesis that gamma-ketoaldehydes mechanistically contribute to seizure-associated memory impairment using a specific gamma-ketoaldehyde scavenger, salicylamine in the kainic acid and pilocarpine rat models of temporal lobe epilepsy. We show that gamma-ketoaldehydes are increased following epileptogenic injury in hippocampus and perirhinal cortex, two brain regions imperative for learning and memory. Treatment with an orally bioavailable, brain permeable scavenger, salicylamine attenuated 1) spatial memory deficits 2) reference memory deficits and 3) neuronal loss and astrogliosis in two mechanistically distinct models of epilepsy without affecting the epileptogenic injury or the development of chronic epilepsy. We have previously demonstrated that reactive oxygen species and the lipid peroxidation biomarkers, F2-isoprostanes are produced following status epilepticus. However, which reactive species specifically mediate oxidative damage to cellular macromolecules remains at large. We provide novel data suggesting that memory impairment occurs via gamma-ketoaldehyde production in two models of epilepsy and that treatment with a gamma-ketoaldehyde scavenger can protect vulnerable neurons. This work suggests a novel target and therapy to treat seizure-induced memory deficits in epilepsy.

Molecular pathways controlling inhibitory receptor expression

Epilepsy is a disease of complex etiology, and multiple molecular mechanisms contribute to its development. Temporal lobe epilepsy (TLE) may result from an initial precipitating event such as hypoxia, head injury, or prolonged seizure (i.e., status epilepticus [SE]), that is followed by a latent period of months to years before spontaneous seizures occur. γ-Aminobutyric acid (GABA)(A) receptor (GABA(A) R) subunit changes occur during this latent period and may persist following the onset of spontaneous seizures. Research into the molecular mechanisms regulating these changes and potential targets for intervention to reverse GABA(A) R subunit alterations have uncovered seizure-induced pathways that contribute to epileptogenesis. Several growth or transcription factors are known to be activated by SE, including (but not limited to): brain-derived neurotrophic factor (BDNF), cAMP response element binding protein (CREB), inducible cAMP early repressor (ICER), and early growth response factors (Egrs). Results of multiple studies suggest that these factors transcriptionally regulate GABA(A) R subunit gene expression in a way that is pertinent to the development of epilepsy. This article focuses on these signaling elements and describes their possible roles in gene regulatory pathways that may be critical in the development of chronic epilepsy.

N w‐Propyl‐l‐arginine (L‐NPA) reduces status epilepticus and early epileptogenic events in a mouse model of epilepsy: behavioural, EEG and immunohistochemical analyses

We investigated the anticonvulsant and neurobiological effects of a highly selective neuronal nitric oxide synthase (nNOS) inhibitor, N (w) -propyl-l-arginine (L-NPA), on kainic acid (KA)-induced status epilepticus (SE) and early epileptogenesis in C57BL/6J mice. SE was induced with 20 mg/kg KA (i.p.) and seizures terminated after 2 h with diazepam (10 mg/kg, i.p). L-NPA (20 mg/kg, i.p.) or vehicle was administered 30 min before KA. Behavioural seizure severity was scored using a modified Racine score and electrographic seizure was recorded using an implantable telemetry device. Neuronal activity, activity-dependent synaptogenesis and reactive gliosis were quantified immunohistochemically, using c-Fos, synaptophysin and microglial and astrocytic markers. L-NPA treatment reduced the severity and duration of convulsive motor seizures, the power of electroencephalogram in the gamma band, and the frequency of epileptiform spikes during SE. It also reduced c-Fos expression in dentate granule cells at 2 h post-KA, and reduced the overall rate of epileptiform spiking (by 2- to 2.5-fold) in the first 7 days after KA administration. Furthermore, treatment with L-NPA suppressed both hippocampal gliosis and activity-dependent synaptogenesis in the outer and middle molecular layers of the dentate gyrus in the early phase of epileptogenesis (72 h post-KA). These results suggest that nNOS facilitates seizure generation during SE and may be important for the neurobiological changes associated with the development of chronic epilepsy, especially in the early stages of epileptogenesis. As such, it might represent a novel target for disease modification in epilepsy.

Tetanus neurotoxin–induced epilepsy in mouse visual cortex

Tetanus neurotoxin (TeNT) is a metalloprotease that cleaves the synaptic protein VAMP/synaptobrevin, leading to focal epilepsy. Although this model is widely used in rats, the time course and spatial specificity of TeNT proteolytic action have not been precisely defined. Here we have studied the biochemical, electrographic, and anatomic characteristics of TeNT-induced epilepsy in mouse visual cortex (V1). We found that VAMP cleavage peaked at 10 days, was reduced at 21 days, and completely extinguished 45 days following TeNT delivery. VAMP proteolysis was restricted to the injected V1 and ipsilateral thalamus, whereas it was undetectable in other cortical areas. Electrographic epileptiform activity was evident both during and after the time window of TeNT effects, indicating development of chronic epilepsy. Anatomic analyses found no evidence for long-term tissue damage, such as neuronal loss or microglia activation. These data show that TeNT reliably induces nonlesional epilepsy in mouse cortex. Due to the excellent physiologic knowledge of the visual cortex and the availability of mouse transgenic strains, this model will be useful for examining the network and cellular alterations underlying hyperexcitability within an epileptic focus.

Diurnal variations in depression-like behavior of Wistar and spontaneously hypertensive rats in the kainate model of temporal lobe epilepsy

The purpose of this study was to explore whether the kainate (KA) model of temporal lobe epilepsy (TLE) can be used as a model of comorbid epilepsy and depression to study diurnal behavioral variations in rats. Development of chronic epilepsy was confirmed by the detection of spontaneous motor seizures (SMS) with video monitoring (24hours/3–5months after status epilepticus [SE]). KA-treated spontaneously hypertensive rats (SHRs) exhibited higher seizure frequency than Wistar rats during the light phase in the fourth and fifth months after SE. Although epileptic Wistar rats showed depression-like behavior and reduced anxiety mostly during the light phase, there were no diurnal variations in depression-like patterns in SHRs. Anxiety levels of control and epileptic SHRs were similar. Decreases in serotonin, tryptophan, and dopamine concentrations in the hippocampus were detected in epileptic Wistar rats compared with naive controls. However, monoamine levels of epileptic SHRs were close to those of their controls. Wistar rats and SHRs develop stable depression-like behavior during the chronic epileptic phase with strain-dependent diurnal differences.

Development of chronic epilepsy after recurrent episodes of Posterior Reversible Encephalopathy Syndrome associated with Periodic Lateralized Epileptiform Discharges

Posterior Reversible Encephalopathy Syndrome (PRES) is a syndrome comprising headache, altered mentation, and seizures, associated with neuroimaging findings characteristic of subcortical edema in the posterior regions. It is usually seen in patients treated with immunosuppressants, in renal failure, or with eclampsia. Recurrent episodes of PRES in the same patient are rarely observed. Although seizures are often seen in PRES, EEG findings are not well described and include generalized and focal slowing with epileptiform discharges; there are limited reports of Periodic Lateralized Epileptiform Discharges (PLEDs) occurring during PRES, and there are no reports of PRES associated with PLEDs with subsequent development of epilepsy. We report a patient we followed for one year with recurrent episodes of PRES associated with posteriorly dominant independent bilateral PLEDs who subsequently developed epilepsy. Patients with PRES and PLEDs should be treated aggressively with anti-hypertensive and anti-epileptic agents in order to avoid potential complications. Although PRES is typically thought of as a reversible syndrome, this case illustrates that PRES may have serious long term sequelae after the reversible syndrome has resolved. This case highlights the importance of aggressive management of PRES as well as the prevention of subsequent episodes of PRES as patients may develop permanent brain dysfunction.

Favorable effects of physical activity for recovery in temporal lobe epilepsy

Strategies that are efficacious for preventing or treating of epilepsy have been extensively used. This review discusses the positive effects of physical exercise program in experimental models of epilepsy, and considerations of the potential application of physical exercise strategy for preventing or treating temporal lobe epilepsy (TLE) are highlighted. Findings from animal studies indicate that exercise can modulate neuronal vulnerability to epileptic insults. Exercise treatment before a precipitating brain insult demonstrates a reduced brain susceptibility in the kindling or the pilocarpine model of epilepsy. In view of the beneficial effect of exercise during the epileptogenesis process, studies analyzed the influence of exercise after the development of chronic epilepsy. Behavioral analysis showed a reduced frequency of seizures during physical exercise program. Metabolic, electrophysiologic, and immunohistochemical studies have confirmed the positive influence of exercise on epilepsy. Taken into account that exercise can exert beneficial actions such as reduction of seizure susceptibility as observed in animal studies, and improvement of quality of life and reduction of anxiety and depression of individuals with epilepsy, physical exercise can be a potential candidate to be integrated with conventional therapy for epilepsy.

Could Hippocampal Neurogenesis be a Future Drug Target for Treating Temporal Lobe Epilepsy?

The dentate gyrus, a region of the hippocampal formation, displays the highest level of plasticity in the brain and exhibits neurogenesis all through life. Dentate neurogenesis, believed to be essential for learning and memory function, responds to physiological stimuli as well as pathological situations. The role of dentate neurogenesis in the pathophysiology of temporal lobe epilepsy (TLE) has received increased attention lately because of its disparate response in the early and chronic stages of the disease. Acute seizures or status epilepticus immensely enhance dentate neurogenesis and lead to an aberrant migration of newly born neurons into the dentate hilus and the formation of epileptogenic circuitry in the injured hippocampus. Conversely, spontaneous recurrent seizures that arise during chronic TLE are associated with dramatically reduced dentate neurogenesis. In this review, we discuss the potential significance of enhanced but abnormal neurogenesis taking place shortly after brain injury or the status epilepticus towards the development of chronic epilepsy, and prospective implications of dramatically waned dentate neurogenesis occurring during chronic epilepsy for learning and memory function and depression in TLE. Furthermore, we confer whether hippocampal neurogenesis is a possible drug target for preventing TLE after brain injury or the status epilepticus, and for easing learning and memory impairments during chronic epileptic conditions. Additionally, we discuss some possible drugs and approaches that need to be evaluated in future in animal models of TLE to further understand the role of neurogenesis in the pathogenesis of TLE and whether modulation of neurogenesis is useful for treating TLE.

Optimizing therapy of seizures in patients with HIV and cysticercosis

Worldwide, about 40 million people are living with HIV and 50 million people have neurocysticercosis (NCC). About 5% of patients with HIV and the majority of patients with NCC develop recurrent seizures. Mechanisms of seizure production in HIV include mass lesions, meningitis, encephalitis, and ischemia. Seizures in NCC may occur at all stages of cyst development, from the vesicular and colloidal to the calcified stages. Seizures in HIV present special problems with regard to choice of antiepileptic drug (AED) and the potential for drug-drug interactions with antiretroviral (ARV) treatments. Newer AEDs with simpler pharmacokinetic profiles may be the preferred agents, particularly when protease inhibitors form part of ARV regimens. Seizures in NCC are easily controlled with the older AEDs. Although there has been some debate about the value of antiparasitic drugs in NCC, accumulating data suggest that the use of these agents in active disease decreases the risk for development of chronic epilepsy.

Low-grade chronic metabolic acidosis is a contributory mechanism in the development of chronic epilepsy

In most people with epilepsy, the condition is readily controlled, but 20–30% develop chronic epilepsy. An estimated 80,000 patients with epilepsy require ongoing specialist care in the United Kingdom. Nutrition may be a factor in the development of chronic epilepsy. Modern Western diets are thought to produce a low-grade chronic metabolic acidosis. The hydrogen ion, H +, is a potent modulator of NMDA-activated currents, and in cultured neurons, increased external [H +] strongly suppresses these currents. The effect of chronic metabolic acidosis in vivo has not been fully studied. It is possible that low-grade chronic metabolic acidosis chronically inhibits the NMDA-activated currents, and this may lead to upregulation of the NMDA receptor. This would result in a greater hyperexcitable state and may contribute to the development of chronic epilepsy.

Changes in nucleotide hydrolysis in rat blood serum induced by pentylenetetrazol-kindling

There is growing pharmacological evidence from several animal models of seizure disorders that adenosine possesses endogenous anticonvulsant activity. Apart from being released from cells, adenosine can be produced by the degradation of adenine nucleotides by ectoenzymes or soluble nucleotidases. These enzymes constitute an important mechanism in synaptic modulation, as they hydrolyze ATP, an excitatory neurotransmitter, to adenosine, a neuroprotective compound. We recently demonstrated an increase in ectoenzyme activity in rat brain synaptosomes after pentylenetetrazol-kindling in rats resistant to kindling, suggesting a role for ectonucleotidases in the seizure control. The present work investigates the effect of seizures induced by pentylenetetrazol kindling on the enzymes that could be playing a role in ATP, ADP and AMP hydrolysis to adenosine in rat blood serum. Animals received injections of PTZ (30 mg/kg, i.p., dissolved in 0.9% saline) once every 48 h, totaling 10 stimulations and the controls animals were injected with saline. The hydrolysis of ATP, ADP and AMP were significantly increased (42, 40, and 45%, respectively), while phosphodiesterase activity was unchanged. These results suggest once more that an increase in the ATP diphosphohydrolase and 5′-nucleotidase activities and, possibly, in adenosine levels, could represent an important compensatory mechanism in the development of chronic epilepsy. Moreover, the fact that this increase can also be measured in serum could mean that these enzymes might be useful as plasma markers of seizures in epilepsy.

Treatment of A First Unprovoked Seizure

The Quality Standards Subcommittee of the AAN and Practice Committee of the CNS have reviewed published literature to determine when to begin treatment after a first unprovoked seizure, risk of recurrence, prevention of recurrence, development of chronic epilepsy, and side effects of AEDs.

Patterns of Status Epilepticus-Induced Neuronal Injury during Development and Long-Term Consequences

The lithium-pilocarpine model of status epilepticus (SE) was used to study the type and distribution of seizure-induced neuronal injury in the rat and its consequences during development. Cell death was evaluated in hematoxylin- and eosin-stained sections and by electron microscopy. Damage to the CA1 neurons was maximal in the 2- and 3-week-old pups and decreased as a function of age. On the other hand, damage to the hilar and CA3 neurons was minimal in the 2-week-old rat pups but reached an adult-like pattern in the 3-week-old animals, and damage to amygdalar neurons increased progressively with age. The 3-week-old animals also demonstrated vulnerability of the dentate granule cells. To evaluate neuronal apoptosis, we used terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) stain, confocal fluorescence microscopy of ethidium bromide-stained sections, electron microscopy, and DNA electrophoresis. Neurons displaying all of those features of apoptotic death in response to SE were seen in the CA1 region of the 2-week-old pups and in the hilar border of the dentate granule cells of the 3-week-old animals. Some (3/11) of the animals that underwent SE at 2 weeks of age and most of the animals that underwent SE at 3 or 4 weeks of age (8/11 and 6/8, respectively) developed spontaneous seizures later in life; the latter showed SE-induced synaptic reorganization as demonstrated by Timm methodology. These results provide strong evidence for the vulnerability of the immature brain to seizure-induced damage, which bears features of both necrotic and apoptotic death and contributes to synaptic reorganization and the development of chronic epilepsy.

Limbic epileptogenesis alters the anticonvulsant efficacy of phenytoin in Sprague-Dawley rats.

Studies on the anticonvulsant efficacy of the major antiepileptic drug phenytoin in kindled rats have often reported inconsistent effects. It has been proposed that technical and genetic factors or poor and variable absorption of phenytoin after i.p. or oral administration may be involved in the lack of consistent anticonvulsant activity of phenytoin in this model of temporal lobe epilepsy. We examined if kindling itself changes the anticonvulsant efficacy of phenytoin by testing this drug before and after amygdala kindling in male and female Sprague-Dawley rats. To exclude the possible bias of poor and variable absorption, blood was sampled in all experiments for drug analysis in plasma. The threshold for induction of focal seizures (afterdischarge threshold; ADT) was used for determining phenytoin's anticonvulsant activity. Before kindling, phenytoin, 75 mg/kg i.p., markedly increased ADT in both genders, although the effect was more pronounced in males. Following kindling, the anticonvulsant activity obtained with phenytoin, 75 mg/kg, before kindling was totally lost, and female rats even exhibited a proconvulsant effect upon administration of this dose, indicating that kindling had dramatically altered the anticonvulsant efficacy of phenytoin. Plasma levels of phenytoin were comparable before and after kindling, and were within or near to the 'therapeutic range' known from epileptic patients. When the dose of phenytoin was reduced to 50 or 25 mg/kg i.p., significant anticonvulsant effects on ADT were obtained. When phenytoin, 50 mg/kg, was administered i.p. or i.v. in the same group of fully kindled rats, both anticonvulsant activity and plasma drug levels were comparable with both routes, indicating that the i.p. route is suited for such studies. The data indicate that kindling alters the dose-response of phenytoin in that a high anticonvulsant dose becomes ineffective or proconvulsant after kindling, possibly by an increased sensitivity of the kindled brain to proconvulsant effects of phenytoin which normally only occur at much higher doses. If similar alterations evolve in humans during development of chronic epilepsy, this may be involved in the mechanisms leading to intractability of temporal lobe epilepsy.

Rapid Seizure-Induced Reduction of Benzodiazepine and Zn2+Sensitivity of Hippocampal Dentate Granule Cell GABAAReceptors

Fast synaptic inhibition in the forebrain is mediated primarily by GABA acting on GABAA receptors (GABARs). GABARs are regulated by numerous positive (barbiturates, benzodiazepines, and neurosteroids) and negative (picrotoxin, bicuculline, and Zn2+) allosteric modulators. The sensitivity of GABARs to GABA and to allosteric modulators changes gradually during normal development, during development of chronic epilepsy, and after prolonged exposure to GABAR agonists. Here we report the development of rapid functional plasticity of GABARs occurring over 45 min of continuous seizures (status epilepticus) in rats. Seizures induced in rats by administration of lithium followed by pilocarpine were readily terminated by the benzodiazepine diazepam when administered early during the seizures (after 10 min of seizures). However, during status epilepticus, there was a substantial reduction of diazepam potency for termination of the seizures. To determine whether the loss of sensitivity of the animals to diazepam was caused by an alteration of GABAR functional properties, we obtained whole-cell GABAR currents from hippocampal dentate granule cells isolated acutely from control rats and from rats undergoing status epilepticus. GABAR properties were characterized by determining GABA sensitivity and the sensitivity of GABARs to regulation by benzodiazepines, barbiturates, and Zn2+. When compared with those from naive controls, GABAR currents from rats undergoing status epilepticus were less sensitive to diazepam and Zn2+ but retained their sensitivity to GABA and pentobarbital. We conclude that the prolonged seizures of status epilepticus rapidly altered the functional properties of hippocampal dentate granule cell GABARs.

Transient expression of GAP-43 within the hippocampus after global brain ischemia in rat.

Neuroanatomical methods have been used to study selective vulnerability after global brain ischemia. A consistent pattern of ischemic neuronal damage is found in the rodent hippocampus with loss of CA1 neurons and of some cells in the hilus of the dentate gyrus. Very little is known about plastic changes that would be expected in ischemia-resistant areas such as CA3 neurons and granule cells. Neuronal plasticity after lesions may be indicated by changes in labeling with antibodies to the growth-associated protein 43 (GAP-43). Expression of GAP-43 as a marker for neuronal plasticity was studied here in the hippocampus after global brain ischemia. Halothane-anesthetized rats were subjected to 20 min of transient forebrain ischemia using four-vessel occlusion. In situ hybridization was used to study GAP-43 mRNA at 1, 3, 6, and 12 h and at 1, 3, and 7 days after ischemia. Immunostaining was carried out with two different antibodies to GAP-43 in brains which were perfusion-fixed after 1, 2, 4, and 7/8 days. In the control hippocampus, GAP-43 mRNA was localized to CA1-CA3 and the hilus. Moderate increases in cellular signals were seen in hilar cells and granule cells early after ischemia, and some changes occurred in CA3 at late stages. Hybridization was lost in CA1 due to cell death. With immunostaining, GAP-43 was not seen in the cytoplasm of neurons, whereas dense labeling occurred in a differentiated pattern in the axonal and dendritic layers. At 1 day after ischemia, neurons in the hilus of the dentate gyrus and in the stratum pyramidale and lucidum of CA3 showed strong cytoplasmic labeling for GAP-43. Few cells were labeled in these regions at 2 days, and none at later stages. Pyramidal cells in CA1 and CA3 areas and granule cells were never labeled. These studies demonstrate a transient expression of GAP-43 mRNA and protein in a subset of vulnerable neurons after transient brain ischemia. The cytoplasmic localization in hilar neurons could be due to increased synthesis of GAP-43 or to changes in axoplasmic transport. It is suggested that axonal damage occurs in hilar cells which stimulates GAP-43 expression. The increased production of trophic factors after ischemia in granule cells could also cause plastic changes in hilar cells. Since hilar neurons are in a strategic position to control the excitability of the dentate area, increased expression of GAP-43 may indicate an important pathophysiological process. In seizure experiments, strong expression of GAP-43 mRNA in granule cells was associated with abnormal mossy fiber sprouting and development of chronic epilepsy. The relevance of the minor GAP-43 mRNA upregulation after ischemia must be considered. The changes in CA3 neurons at several days after ischemia might represent a plastic response to a loss of CA1 neurons.