TLR3 preconditioning induces anti-inflammatory and anti-ictogenic effects in mice mediated by the IRF3/IFN-ß axis.

Activation of Toll-like receptor 3 (TLR3) was previously shown to contribute to the generation of epileptic seizures in rodents by evoking a proinflammatory response in the forebrain. This suggests that TLR3 blockade may provide therapeutic effects in epilepsy. We report that brain activation of TLR3 using the synthetic receptor ligand Poly I:C may also result in remarkable dose- and time-dependent inhibitory effects on acute seizures in mice without inducing inflammation. These inhibitory effects are associated with reduced neuronal excitability in the hippocampus as shown by a decrease in the population spike amplitude of CA1 pyramidal neurons following Schaffer collaterals stimulation. TLR3 activation which results in seizure inhibition does not evoke NF-kB-dependent inflammatory molecules or morphological activation of glia, however, it induces the alternative interferon (IFN) regulatory factor (IRF)-3/IFN-ß signaling pathway. IFN-ß reproduced the inhibitory effects of Poly I:C on neuronal excitability in hippocampal slices. Seizure inhibition attained with activation the TLR3-IRF3/IFN-ß axis should be carefully considered when TLR3 are targeted for therapeutic purposes.

Review: Neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies.

Accumulating evidence indicates an important pathophysiological role of brain inflammation in epilepsy. In this review, we will provide an update of specific inflammatory pathways that have been proposed to be crucial in the underlying molecular mechanisms of epilepsy, including the interleukin-1 receptor/toll-like receptor signalling, cyclooxygenase-2, tumour necrosis factor-alpha, complement signalling and chemokines. Furthermore, by drawing on evidence from preclinical and clinical studies we will discuss the potential of these signalling pathways targets for novel therapeutic interventions that control drug-resistant seizures or have disease-modifying effects. Finally, we will assess the use of these inflammatory pathways as potential biomarkers for the development of epilepsy or to measure the effectiveness of therapeutic interventions.

Pharmacological blockade of IL-1ß/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy.

We studied whether pharmacological blockade of the IL-1ß-mediated signaling, rapidly activated in forebrain by epileptogenic injuries, affords neuroprotection in two different rat models of status epilepticus (SE). As secondary outcome, we measured treatment's effect on SE-induced epileptogenesis. IL-1ß signaling was blocked by systemic administration of two antiinflammatory drugs, namely human recombinant IL-1 receptor antagonist (anakinra), the naturally occurring and clinically used competitive IL-1 receptor type 1 antagonist, and VX-765 a specific non-peptide inhibitor of IL-1ß cleavage and release. Antiinflammatory drugs were given 60min after antiepileptic (AED) drug-controlled SE induced by pilocarpine, or 180min after unrestrained electrical SE, for 7days using a protocol yielding therapeutic drug levels in brain. This drug combination significantly decreased both IL-1ß expression in astrocytes and cell loss in rat forebrain. Neuroprotection and the antiinflammatory effect were more pronounced in the electrical SE model. Onset of epilepsy, and frequency and duration of seizures 3months after electrical SE were not significantly modified. Transcriptomic analysis in the hippocampus showed that the combined treatment did not affect the broad inflammatory response induced by SE during epileptogenesis. In particular, the treatment did not prevent the induction of the complement system and Toll-like receptors, both contributing to cell loss and seizure generation. We conclude that the IL-1ß signaling represents an important target for reducing cell loss after SE. The data highlight a new class of clinically tested agents affording neuroprotection after a delayed post-injury intervention. Earlier blockade of this rapid onset inflammatory pathway during SE, or concomitant treatment with antiinflammatory drugs targeting additional components of the broad inflammatory response to SE, or co-treatment with AEDs, is likely to be required for optimizing beneficial outcomes.

Interleukin-1 type 1 receptor/Toll-like receptor signalling in epilepsy: the importance of IL-1beta and high-mobility group box 1.

Inflammatory processes in brain tissue have been described in human epilepsy of various aetiologies and in experimental models of seizures. This, together with the anticonvulsant properties of anti-inflammatory therapies both in clinical and in experimental settings, highlights the important role of brain inflammation in the aetiopathogenesis of seizures. Preclinical investigations in experimental models using pharmacological and genetic tools have identified a significant contribution of interleukin-1 (IL-1) type 1 receptor/Toll-like receptor (IL-1R/TLR) signalling to seizure activity. This signalling can be activated by ligands associated with infections (pathogen-associated molecular patterns) or by endogenous molecules, such as proinflammatory cytokines (e.g. IL-1beta) or danger signals [damage-associated molecular patterns, e.g. high-mobility group box 1 (HMGB1)]. IL-1beta and HMGB1 are synthesized and released by astrocytes and microglia in the rodent brain during seizures. Notably, a rapid release of HMGB1 from neurons appears to be triggered by proconvulsant drugs even before seizure occurrence and is involved in their precipitation of seizures. The activation of IL-1R/TLR signalling mediates rapid post-translational changes in N-methyl-d-aspartate-gated ion channels in neurons. A long-term decrease in seizure threshold has also been observed, possibly mediated by transcriptional activation of genes contributing to molecular and cellular plasticity. This emerging evidence identifies specific targets with potential anticonvulsant effects in drug-resistant forms of epilepsy.

[New developments in epileptogenesis and therapeutic perspectives]. / Neue Entwicklungen der Epileptogenese und therapeutische Perspektiven.

Epileptogenesis describes the mechanisms of how epilepsies are generated. We have chosen four areas in which significant progress has been achieved in understanding epileptogenesis. Those are (1) inflammatory processes which play an increasingly important role for the generation of temporal lobe epilepsy with hippocampal sclerosis (TLE with HS), (2) disturbances of intrinsic properties of neuronal compartments, in particular acquired defects of ion channels of which those in dendrites are described here for TLE with HS, (3) epigenetic effects, which affect for example the methylation of promoters and secondarily can change the expression of specific genes in TLE with HS, and finally (4) the epileptogenesis of idiopathic epilepsies which are caused by inborn genetic alterations affecting mainly ion channels. Apart from aspects of basic research, we will describe clinical consequences and therapeutic perspectives.

Anticonvulsant effects and behavioural outcomes of rAAV serotype 1 vector-mediated neuropeptide Y overexpression in rat hippocampus.

Neuropeptide Y (NPY) is an endogenous peptide with powerful anticonvulsant properties. Its overexpression in the rat hippocampus, mediated by the local application of recombinant adeno-associated viral (rAAV) vectors carrying the human NPY gene, results in significant reduction of seizures in acute and chronic seizure models. In this study, we characterized a more efficient rAAV-NPY vector to improve cell transfection in the injected area. The changes included pseudotyping with the AAV vector serotype 1 (rAAV1), and using the strong constitutive hybrid CBA promoter, which contains a cytomegalovirus enhancer and chicken beta-actin promoter sequences. We compared NPY expression and the associated anticonvulsant effects of this new vector, with those mediated by the former rAAV vector with chimeric serotype 1/2 (rAAV1/2). In addition, we investigated whether rAAV serotype 1 vector-mediated chronic NPY overexpression causes behavioural deficits that may detract from the clinical utility of this therapeutic approach. We report that rAAV-NPY serotype 1 vector has significantly improved anticonvulsant activity when compared with serotype 1/2 vector, as assessed by measuring EEG seizure activity in kainic acid treated rats. rAAV1-mediated NPY overexpression in naive rats did not result in alterations of physiological functions such as learning and memory, anxiety and locomotor activity. In addition, we did not observe glia activation, or humoral immune responses against serotype 1 vector, which could inactivate gene expression. Our findings show that rAAV1-NPY vector with the CBA promoter mediates powerful anticonvulsant effects and seems to be safe in rodents, thus it may be considered a vector of choice for possible clinical applications.

Complex phase ordering of the one-dimensional Heisenberg model with conserved order parameter.

We study the phase-ordering kinetics of the one-dimensional Heisenberg model with conserved order parameter by means of scaling arguments and numerical simulations. We find a rich dynamical pattern with a regime characterized by two distinct growing lengths. Spins are found to be coplanar over regions of a typical size LV(t), while inside these regions smooth rotations associated to a smaller length LC(t) are observed. Two different and coexisting ordering mechanisms are associated to these lengths, leading to different growth laws LV(t) approximately t1/3 and LC(t) approximately t1/4 violating dynamical scaling.

Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood-brain barrier permeability.

Systemic application of the muscarinic agonist, pilocarpine, is commonly utilized to induce an acute status epilepticus that evolves into a chronic epileptic condition characterized by spontaneous seizures. Recent findings suggest that the status epilepticus induced by pilocarpine may be triggered by changes in the blood-brain barrier (BBB) permeability. We tested the role of the BBB in an acute pilocarpine model by using the in vitro model brain preparation and compared our finding with in vivo data. Arterial perfusion of the in vitro isolated guinea-pig brain with <1 mM pilocarpine did not cause epileptiform activity, but rather reduced synaptic transmission and induced steady fast (20-25 Hz) oscillatory activity in limbic cortices. These effects were reversibly blocked by co-perfusion of the muscarinic antagonist atropine sulfate (5 microM). Brain pilocarpine measurements in vivo and in vitro suggested modest BBB penetration. Pilocarpine induced epileptiform discharges only when perfused with compounds that enhance BBB permeability, such as bradykinin (n=2) or histamine (n=10). This pro-epileptic effect was abolished when the BBB-impermeable muscarinic antagonist atropine methyl bromide (5 microM) was co-perfused with histamine and pilocarpine. In the absence of BBB permeability enhancing drugs, pilocarpine induced epileptiform activity only after arterial perfusion at concentrations >10 mM. Ictal discharges correlated with a high intracerebral pilocarpine concentration measured by high pressure liquid chromatography. We propose that acute epileptiform discharges induced by pilocarpine treatment in the in vitro isolated brain preparation are mediated by a dose-dependent, atropine-sensitive muscarinic effect promoted by an increase in BBB permeability. Pilocarpine accumulation secondary to BBB permeability changes may contribute to in vivo ictogenesis in the pilocarpine epilepsy model.

Phase-ordering kinetics on graphs.

We study numerically the phase-ordering kinetics following a temperature quench of the Ising model with single spin-flip dynamics on a class of graphs, including geometrical fractals and random fractals, such as the percolation cluster. For each structure we discuss the scaling properties and compute the dynamical exponents. We show that the exponent a_{chi} for the integrated response function, at variance with all the other exponents, is independent of temperature and of the presence of pinning. This universal character suggests a strict relation between a_{chi} and the topological properties of the networks, in analogy to what is observed on regular lattices.

Ground-state properties of small-size nonlinear dynamical lattices.

We investigate the ground state of a system of interacting particles in small nonlinear lattices with M >or=3 sites, using as a prototypical example the discrete nonlinear Schrödinger equation that has been recently used extensively in the contexts of nonlinear optics of waveguide arrays and Bose-Einstein condensates in optical lattices. We find that, in the presence of attractive interactions, the dynamical scenario relevant to the ground-state and the lowest-energy modes of such few-site nonlinear lattices reveals a variety of nontrivial features that are absent in the large/infinite lattice limits: the single-pulse solution and the uniform solution are found to coexist in a finite range of the lattice intersite coupling where, depending on the latter, one of them represents the ground state; in addition, the single-pulse mode does not even exist beyond a critical parametric threshold. Finally, the onset of the ground-state (modulational) instability appears to be intimately connected with a nonstandard ("double transcritical") type of bifurcation that, to the best of our knowledge, has not been reported previously in other physical systems.

How the site degree influences quantum probability on inhomogeneous substrates.

We investigate the effect of the node degree and energy E on the electronic wave function for regular and irregular structures, namely, regular lattices, disordered percolation clusters, and complex networks. We evaluate the dependency of the quantum probability for each site on its degree. For a class of biregular structures formed by two disjoint subsets of sites sharing the same degree, the probability P_{k}(E) of finding the electron on any site with k neighbors is independent of E≠0, a consequence of an exact analytical result that we prove for any bipartite lattice. For more general nonbipartite structures, P_{k}(E) may depend on E as illustrated by an exact evaluation of a one-dimensional semiregular lattice: P_{k}(E) is large for small values of E when k is also small, and its maximum values shift towards large values of |E| with increasing k. Numerical evaluations of P_{k}(E) for two different types of percolation clusters and the Apollonian network suggest that this observed feature might be generally valid.

Neuropeptide Y: emerging evidence for a functional role in seizure modulation.

The high concentration of the tyrosine-rich polypeptide, neuropeptide Y (NPY), and the increase in the number of its receptor subtypes that have been characterized in the brain, raise the question of a functional role for NPY in the CNS. In addition to its peripheral actions on cardiovascular regulation, much attention has, therefore, been devoted to the CNS effects of NPY because of its stimulatory properties on food intake, its role in anxiolysis and its putative involvement in memory retention. Emerging evidence points to an important role for NPY in the regulation of neuronal activity both under physiological conditions and during pathological hyperactivity such as that which occurs during seizures. This article reviews recent studies that have shown the changes induced by seizures in the level and distribution of NPY, its receptor subtypes and their respective mRNAs in rat forebrain. Biochemical and electrophysiological findings in experimental models and tissue from human epilepsy sufferers suggest that NPY-mediated neurotransmission is altered by seizures. The pharmacological evidence and functional studies in NPY knockout mice highlight a crucial role for endogenous NPY, acting on different NPY receptors, in the control of seizures.

Status epilepticus induces time-dependent neuronal and astrocytic expression of interleukin-1 receptor type I in the rat limbic system.

Interleukin-1beta is rapidly synthesized by glia after the induction of seizures. Recent evidence shows that endogenous IL-1beta has proconvulsant actions mediated by interleukin-1 receptor type I. This receptor also mediates interleukin-1beta effects on neuronal susceptibility to neurotoxic insults. In this study, we investigated the basal and seizure-induced expression of interleukin-1 receptor type I in rat forebrain to identify the cells targeted by interleukin-1beta during epileptic activity. Self-sustained limbic status epilepticus was induced in rats by electrical stimulation of the ventral hippocampus. Interleukin-1 receptor type I immunoreactivity was barely detectable in neurons in control brain tissue. During status epilepticus, interleukin-1 receptor type I was induced in the hippocampal neurons firstly, and several hours later in astrocytes localized in limbic and extralimbic areas. Neuronal interleukin-1 receptor type I expression in the hippocampus outlasted the duration of spontaneous electroencephalographic seizure and was not observed in degenerating neurons. Astrocytic expression occurred transiently, between six and 18 h after the induction of status epilepticus and was invariably found in regions of neuronal damage. These time-dependent, cell- and region-specific changes in interleukin-1 receptor type I expression during status epilepticus suggest that interleukin-1 receptor type I in neurons mediates interleukin-1beta-induced fast changes in hippocampal excitability while interleukin-1 receptor type I receptors in astrocytes may mediate interleukin-1beta effects on neuronal survival in hostile conditions.

Topological filters and high-pass/low-pass devices for solitons in inhomogeneous networks.

We show that, by inserting suitable finite networks at a site of a chain, it is possible to realize filters and high-pass/low-pass devices for solitons propagating along the chain. The results are presented in the framework of coupled optical waveguides; possible applications to different contexts, such as photonic lattices and Bose-Einstein condensates in optical networks are also discussed. Our results provide a first step in the control of the soliton dynamics through the network topology.

Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures.

Using immunocytochemistry and ELISA, we investigated the production of interleukin (IL)-1beta in the rat hippocampus after focal application of kainic acid inducing electroencephalographic (EEG) seizures and CA3 neuronal cell loss. Next, we studied whether EEG seizures per se induced IL-1beta and microglia changes in the hippocampus using bicuculline as a nonexcitotoxic convulsant agent. Finally, to address the functional role of this cytokine, we measured the effect of human recombinant (hr)IL-1beta on seizure activity as one marker of the response to kainate. Three and 24 hr after unilateral intrahippocampal application of 0.19 nmol of kainate, IL-1beta immunoreactivity was enhanced in glia in the injected and the contralateral hippocampi. At 24 hr, IL-1beta concentration increased by 16-fold (p < 0.01) in the injected hippocampus. Reactive microglia was enhanced with a pattern similar to IL-1beta immunoreactivity. Intrahippocampal application of 0.77 nmol of bicuculline methiodide, which induces EEG seizures but not cell loss, enhanced IL-1beta immunoreactivity and microglia, although to a less extent and for a shorter time compared with kainate. One nanogram of (hr)IL-1beta intrahippocampally injected 10 min before kainate enhanced by 226% the time spent in seizures (p < 0.01). This effect was blocked by coinjection of 1 microgram (hr)IL-1beta receptor antagonist or 0.1 ng of 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate, selective antagonists of IL-1beta and NMDA receptors, respectively. Thus, convulsant and/or excitotoxic stimuli increase the production of IL-1beta in microglia-like cells in the hippocampus. In addition, exogenous application of IL-1beta prolongs kainate-induced hippocampal EEG seizures by enhancing glutamatergic neurotransmission.

Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases.

Interleukin (IL)-1beta is a proinflammatory cytokine implicated in various pathophysiological conditions of the CNS involving NMDA receptor activation. Circumstantial evidence suggests that IL-1beta and NMDA receptors can functionally interact. Using primary cultures of rat hippocampal neurons, we investigated whether IL-1beta affects NMDA receptor function(s) by studying (1) NMDA receptor-induced [Ca2+]i increase and (2) NMDA-mediated neurotoxicity. IL1beta (0.01-0.1 ng/ml) dose-dependently enhances NMDA-induced [Ca2+]i increases with a maximal effect of approximately 45%. This effect occurred only when neurons were pretreated with IL-1beta, whereas it was absent if IL-1beta and NMDA were applied simultaneously, and it was abolished by IL-1 receptor antagonist (50 ng/ml). Facilitation of NMDA-induced [Ca2+]i increase by IL-1beta was prevented by both lavendustin (LAV) A (500 nm) and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) (1 microm), suggesting an involvement of tyrosine kinases. Increased tyrosine phosphorylation of NMDA receptor subunits 2A and 2B and coimmunoprecipitation of activated Src tyrosine kinase with these subunits was observed after exposure of hippocampal neurons to 0.05 ng/ml IL-1beta. Finally, 0.05 ng/ml IL-1beta increased by approximately 30% neuronal cell death induced by NMDA, and this effect was blocked by both lavendustin A and PP2. These data suggest that IL-1beta increases NMDA receptor function through activation of tyrosine kinases and subsequent NR2A/B subunit phosphorylation. These effects may contribute to glutamate-mediated neurodegeneration.

Altered expression of GABA(A) and GABA(B) receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus.

Epilepsy may result from altered transmission of the principal inhibitory transmitter GABA in the brain. Using in situ hybridization in two animal models of epileptogenesis, we investigated changes in the expression of nine major GABA(A) receptor subunits (alpha1, alpha2, alpha4, alpha5, beta1-beta3, gamma2 and delta) and of the GABA(B) receptor species GABA(B)R1a, GABA(B)R1b and GABA(B)R2 in 1) hippocampal kindling and 2) epilepsy following electrically-induced status epilepticus (SE). Hippocampal kindling triggers a decrease in seizure threshold without producing spontaneous seizures and hippocampal damage, whereas the SE model is characterized by spontaneous seizures and hippocampal damage. Changes in the expression of GABA(A) and GABA(B) receptor mRNAs were observed in both models, and compared with those seen in other models and in human temporal lobe epilepsy. The most prominent changes were a relatively fast (24 h after kindling and electrically-induced SE) and lasting (7 and 30 days after termination of kindling and SE, respectively) reduction of GABA(A) receptor subunit delta mRNA levels (by 43-78%) in dentate granule cells, accompanied by increases in mRNA levels of all three beta-subunits (by 8-79%) and subunit gamma2 (by 11-43%). Levels of the minor subunit alpha4 were increased by up to 60% in dentate granule cells in both animal models, whereas those of subunit alpha5 were decreased 24 h and 30 days after SE, but not after kindling. In cornu ammonis 3 pyramidal cells, downregulation of subunits alpha2, alpha4, alpha5, and beta1-3 was observed in the ventral hippocampus and of alpha2, alpha5, beta3 and gamma2 in its dorsal extension 24 h after SE. Similar but less pronounced changes were seen in sector cornu ammonis 1. Persistent decreases in subunit alpha2, alpha4 and beta2 transcript levels were presumably related to SE-induced cell loss. GABA(B) receptor expression was characterized by increases in GABA(B)R2 mRNA levels at all intervals after kindling and SE. The observed changes suggest substantial and cell specific rearrangement of GABA receptors. Lasting downregulation of subunits delta and alpha5 in granule cells and transient decreases in subunit alpha2 and beta1-3 mRNA levels in cornu ammonis 3 pyramidal cells are suggestive of impaired GABA(A) receptor-mediated inhibition. Persistent upregulation of subunits beta1-3 and gamma2 of the GABA(A) receptor and of GABA(B)R2 mRNA in granule cells, however, may result in activation of compensatory anticonvulsant mechanisms.

Neuropeptide Y Y5 receptors inhibit kindling acquisition in rats.

Neuropeptide Y inhibits neuronal excitability and seizures in various experimental models. This peptide delays kindling epileptogenesis but the receptors involved in this action are unknown. We have studied the role of Y5 receptors in kindling using the selective antagonist GW438014A (IC50=210 nM), a small heterocycle molecule that crosses the blood-brain barrier, and the selective peptide agonist Ala31Aib34 NPY (IC50=6.0 nM). Intraperitoneal injection of GW438014A (10 mg/kg), 30 min before the beginning of a rapid-kindling protocol, significantly accelerated the rate of kindling acquisition as compared to vehicle-injected rats. Thus, the number of electrical stimuli required to reach stages 3 and 4-5 of kindling were reduced by 50% and 25%, respectively. The average afterdischarge duration in the stimulated hippocampus was prolonged by 2-fold. Conversely, kindling rate was delayed by intracerebroventricular administration of 24 nmol Ala31Aib32 NPY. Thus, the number of stimuli necessary to reach stages 2 and 3 of kindling was increased by 3- and 4-fold, respectively. During the stimulation protocol (40 stimuli) none of the rats treated with the Y5 agonist showed stages 4-5 seizures. Twenty-four hours after the last kindling stimulation, thus during the re-test session, Y5 agonist- or antagonist-treated rats had stages 4-5 seizures as their controls. In rats treated with both the antagonist and the agonist, kindling rate was similar to vehicle-injected rats. These data indicate that Y5 receptors mediate inhibitory effects of NPY in kindling and display anticonvulsant rather then antiepileptogenic effects upon agonist stimulation.

Neurodegenerative Effects Induced by Chronic Infusion of Quinolinic Acid in Rat Striatum and Hippocampus.

In this study we examined whether the potency of quinolinic acid (Quin) in inducing neurodegeneration in vivo was dependent on the exposure time of the tissue to the excitotoxin. The effect of chronic infusion of Quin into rat striatum and hippocampus was examined at the light microscopic level and by cell count on 40 microm Cresyl violet stained brain sections. Continuous infusion was at a constant speed (0.5 microl/h) for various times (15 h - 2 weeks) by osmotic minipumps (Alzet 2002). No build up of [3H]Quin occurred in the tissue during infusion; this was assessed by measuring the radioactivity 3 - 14 days after minipump placement. Intrastriatal infusion of 6 and 10 nmol/h Quin, but not of nicotinic acid, for 1 week induced a dose-dependent neurodegeneration (70 and 90% loss of neurons, respectively, compared to the contralateral striatum) extending 1.2 - 2 mm from the centre of the injection. The onset of the neurotoxicity caused by 10 nmol/h Quin was >24 h. One week's infusion of 4 nmol/h Quin did not induce neurotoxicity, but a 40% drop of neurons, compared to the contralateral side, occurred after 2 weeks. One week's intrahippocampal infusion of 2.4 and 6 nmol/h Quin, but not of nicotinic acid, caused a dose-dependent neurodegeneration with a radius of approximately 1 - 1.5 mm around the injection track. The onset of the neurotoxicity induced by 2.4 nmol/h Quin was < 15 h. The pattern of nerve cell loss induced by 1.2 nmol/h Quin after 1 week (CA4 cells lost in 50% of the rats) did not differ from that observed after 2 weeks of infusion. Nerve cell loss caused by Quin in the striatum and in the hippocampus was restricted to the injected area and antagonized by coinfusion with d(-)-2-amino-7-phosphonoheptanoic and kynurenic acids in molar ratios of 1:0.1 and 1:3, respectively. These data show that Quin's potency in inducing neurodegeneration in the striatum, but not in the hippocampus, depends on the exposure time of the tissue to the excitotoxin. In addition, neurodegeneration is induced faster by Quin in the hippocampus than in the striatum. The usefulness of this model to study the sequelae of the neurotoxic process in vivo will be discussed.

A peptidase-resistant cyclic octapeptide analogue of somatostatin (SMS 201-995) modulates seizures induced by quinolinic and kainic acids differently in the rat hippocampus.

Electroencephalographic (EEG) seizures were measured in rats after intrahippocampal injection of 120 nmol quinolinic acid into the stratum radiatum CA1 or 0.19 nmol kainic acid in the dentate gyrus or in the stratum radiatum. Injection of 5 micrograms SMS 201-995, a peptidase-resistant cyclic octapeptide analogue of somatostatin, into the stratum radiatum, 15 min before quinolinic acid, did not significantly modify the number of seizures and the total time in seizures. Five micrograms SMS 201-995 injected into the stratum radiatum reduced the number of seizures induced by kainic acid in the same area and the total time spent in seizures by 58% and 75%, respectively (Student's t-test; P less than 0.01). In both instances the latency to the first ictal episode was not significantly modified. Lesions of the medial septum, which reduced the activity of choline-o-acetyl-transferase (CAT) in the dorsal hippocampus by greater than 90% after one week did not significantly affect seizures induced by quinolinic acid. In rats lesioned in the medial septum, 5 micrograms SMS 201-995 reduced the total time spent in seizures by 43%, without changing the number of ictal episodes and raised the latency to the first quinolinic acid-induced seizure by 53% (ANOVA 2 x 2, P less than 0.05) but had no effect on these measures in the corresponding sham-operated group.(ABSTRACT TRUNCATED AT 250 WORDS)