Differential regulation of mRNAs for neuropeptide Y and its receptor subtypes in widespread areas of the rat limbic system during kindling epileptogenesis.

Expression of mRNAs for neuropeptide Y (NPY) and its receptor subtypes Y1 (Y1-R), Y2 (Y2-R) and Y5 (Y5-R) was studied in adult rat brain using in situ hybridization after 40 rapidly recurring seizures induced with 5-min interval by hippocampal kindling stimulations. At 2-4 h post-seizure, NPY mRNA levels were markedly elevated in dentate granule cells, CA1 and CA3 pyramidal layers, amygdala and piriform and entorhinal cortices. Gene expression had returned to control level in the dentate granule cell layer at 48 h but remained high in the other areas, reaching baseline at 1 week. Transient decreases of Y1-R mRNA levels were detected at 2-4 h in hippocampal subregions, amygdala, piriform, entorhinal and somatosensory cortices. The Y2-R mRNA levels were reduced at 2-4 h in the CA3 region and piriform cortex, but exhibited marked increases at 48 h and 1 week post-seizure in the dentate gyrus, amygdala and piriform and entorhinal cortices. At 3 weeks, Y2-R mRNA expression had virtually returned to baseline. Elevated Y5-R mRNA levels were only detected at 2-4 h and confined to dentate granule cell layer and piriform and entorhinal cortices. These results demonstrate a cell- and region-specific, differential regulation of mRNA expression for NPY and Y1-R, Y2-R, and Y5-R in the limbic system following recurring seizures. Because the gene changes were transient, it seems unlikely that the presumed alterations of the corresponding proteins are involved in the maintenance of the epileptic syndrome, which develops up to 4 weeks post-seizure in the present model and is stable thereafter. Our data provide further support for the hypothesis that the changes of NPY and its receptors act to dampen seizure susceptibility, and suggest that the cascade of gene changes is orchestrated to optimize this anticonvulsant effect.     

FAST and SLOW amygdala kindling rat strains: comparison of amygdala, hippocampal, piriform and perirhinal cortex kindling.

In our companion paper, we selectively bred offspring of a Long Evans Hooded and Wistar rat cross for either fast or slow rates of amygdala kindling (Racine et al., 1999. Development of kindling-prone and kindling resistant rats: Selective breeding and electrophysiological studies, Epilepsy Res. 35, 183-195). Within 10 generations, there was no overlap in the distribution of kindling rates between these newly developed FAST and SLOW kindling strains. In the present report, we compared the local excitability, kindling rates, and convulsion profiles of kindling sites in either the amygdala, dorsal hippocampus, piriform cortex or perirhinal cortex in the two strains. Local excitability, measured as the local afterdischarge (AD) threshold and its duration, showed varied effects between structures and strains. Before kindling, the AD threshold was lower in the FAST than the SLOW rats in the hippocampus, piriform and perirhinal cortices, but not the amygdala (the selection structure). Also, the duration of the AD threshold duration was significantly longer in the FAST than in the SLOW rats in all structures, except the CA1 hippocampus. Most of these differences were maintained after kindling. Kindling itself was significantly faster in the FAST compared with the SLOW rats in all structures; however, the different structural kindling rates showed proportional differences between strains that were about five times different in the amygdala compared with only about two times different in the hippocampus. This suggested a selection bias for the amygdala and its networks. As in other rat strains, the fastest kindling rates were seen in the perirhinal cortex followed by the piriform cortex, amygdala and hippocampus in both FAST and SLOW rats. Other important differences between strains and structures occurred in the stage-5 convulsion profiles, including latency to forelimb clonus, clonus duration and duration of associated local afterdischarges. The differences in kindling profiles between strains and structures were discussed with respect to possible underlying mechanisms, significance for epileptogenesis, and impact on other normal behaviours.     

Central Nervous System IL-1β System and Neuropeptide Y mRNAs During IL-1β-induced Anorexia in Rats

Interleukin-1β (IL-1β) induces anorexia and neuropeptide Y (NPY) increases feeding by direct action in the central nervous system (CNS). IL-1β, depending on the dose, attenuates or blocks NPY-induced feeding. This suggests that IL-1β-NPY interactions may be involved in IL-1β-induced anorexia. Here, RNase protection assays were used to investigate the effects of the chronic intracerebroventricular (ICV) administration of IL-1β (at a dose that yields estimated pathophysiological concentrations in the cerebrospinal fluid) on mRNA levels of IL-1β system components and NPY in the cerebellum, parietofrontal cortex, hippocampus, hypothalamus, and midbrain. The results show that the chronic ICV administration of IL-1β (8.0 ng/24 h for 72 h) differentially induced IL-1β system components across brain regions in anorectic rats. IL-1β mRNA and IL-1 receptor antagonist (IL-1Ra) mRNA were induced similarly, exhibiting highest and lowest expression levels in the hypothalamus and hippocampus, respectively. IL-1 receptor type I (IL-1RI) mRNA and the soluble form of IL-1 receptor accessory protein (IL-1R AcP II) mRNA were also induced in the hypothalamus and cerebellum. NPY mRNA expression showed a small, but significant decrease in the hypothalamus. Heat-inactivated IL-1β (8.0 ng/24 h for 72 h) had no effect on the behavioral or molecular profiles. The results suggest that endogenous upregulation of IL-1β contributes to IL-1β-induced anorexia, and that modification of NPY mechanisms also may be involved.     

Pilocarpine-induced status epilepticus increases Homer1a and changes mGluR5 expression

Homer1a regulates expression of group I metabotropic glutamate receptors type I (mGluR1 and mGluR5) and is involved in neuronal plasticity. It has been reported that Homer1a expression is upregulated in the kindling model and hypothesized to act as an anticonvulsant. In the present work, we investigated whether pilocarpine-induced status epilepticus (SE) would alter Homer1a and mGluR5 expression in hippocampus. Adult rats were subjected to pilocarpine-model and analyzed at 2h, 8h, 24h and 7 d following SE. mRNA analysis showed the highest expression of Homer1a at 8h after SE onset, while immunohistochemistry demonstrated that Homer1a protein expression was significantly increased in hippocampus, amygdala and piriform and entorhinal cortices at 24h after SE onset when compared to control animals. The increased Homer1a expression coincided with a significant decrease of mGluR5 protein expression in amygdala and piriform and entorhinal cortices. The data suggest that during the critical periods of epileptogenesis, overexpression of Homer1a occurs to counteract hyperexcitability and thus Homer1a may be a molecular target in the treatment of epilepsy.     

Mapping of c-Fos expression in the rat brain during the evolution of pentylenetetrazol-kindled seizures

c-Fos protein immunocytochemistry was used to map the brain structures recruited during the evolution of seizures that follows repeated administration of a subconvulsive dose (35 mg/kg, ip) of pentylenetetrazol in rats. c-Fos appeared earliest in nucleus accumbens shell, piriform cortex, prefrontal cortex, and striatum (stages 1 and 2 of kindling in comparison to control, saline-treated animals). At the third stage of kindling, central amygdala nuclei, entorhinal cortex, and lateral septal nuclei had enhanced concentrations of c-Fos. At the fourth stage of kindling, c-Fos expression was increased in basolateral amygdala and CA1 area of the hippocampus. Finally, c-Fos labeling was enhanced in the dentate gyrus of the hippocampus only when tonic–clonic convulsions were fully developed. The most potent changes in c-Fos were observed in dentate gyrus, piriform cortex, CA1, lateral septal nuclei, basolateral amygdala, central amygdala nuclei, and prefrontal cortex. Piriform cortex, entorhinal cortex, prefrontal cortex, lateral septal nuclei, and CA3 area of the hippocampus appeared to be the brain structures selectively involved in the process of chemically induced kindling of seizures.     

Lipopolysaccharide (LPS)- and muramyl dipeptide (MDP)-induced anorexia during refeeding following acute fasting: characterization of brain cytokine and neuropeptide systems mRNAs

We investigated the effectiveness of lipopolysaccharide (LPS) and muramyl dipeptide (MDP) administered into the brain to induce anorexia in acutely fasted Wistar rats allowed to refeed. We also assayed for changes in mRNA levels of IL-1 system components, TNF-α, TGF-β1, glycoprotein 130 (gp 130), leptin receptor (OB-R), pro-opiomelanocortin (POMC), neuropeptide Y (NPY), glucocorticoid receptor (GR), and CRF receptor (CRF-R) in selected brain regions. The data show that LPS and MDP induced anorexia differentially during refeeding. LPS-induced anorexia was of a stronger magnitude and duration than that of MDP. RNase protection assays showed that LPS and MDP significantly increased the expression of IL-1β, IL-1 receptor type I, and TNF-α mRNAs in the cerebellum, hippocampus, and hypothalamus; LPS was more potent in all cases. MDP treatment, on the other hand, induced a stronger increase in hypothalamic levels of IL-1 receptor antagonist (IL-1Ra) and TGF-β1 mRNAs relative to LPS. In addition, competitive RT–PCR analysis showed that LPS induced an eleven-fold increase in IL-1α mRNA in the hypothalamus relative to vehicle. These findings suggest that LPS and MDP mediate anorexia through different cytokine mechanisms. A stronger up-regulation of anti-inflammatory cytokines (IL-1Ra and TGF-β1) mRNA expression by MDP may be involved in the weaker MDP-induced anorexia relative to LPS. No significant changes were observed in the peptide components examined except for an up-regulation in cerebellar gp 130 mRNA and down-regulation of hypothalamic GR mRNA expression in response to LPS or MDP. This study shows that LPS and MDP induce anorexia in fasted rats allowed to refeed, and suggests an important role for endogenous cytokine–cytokine interactions.     

Interleukin-1β System (Ligand, Receptor Type I, Receptor Accessory Protein and Receptor Antagonist), TNF-α, TGF-β1 and Neuropeptide Y mRNAs in Specific Brain Regions During Bacterial LPS-Induced Anorexia

Bacterial lipopolysaccharide (LPS) or endotoxin induces neurological manifestations including anorexia. It is proposed that LPS-induced cytokine production is involved in the generation of neurological manifestations and in neuroinflammatory/immunological responses during Gram-negative infections. For example, LPS-induced effects can be blocked or ameliorated by the interleukin-1 receptor antagonist (IL-1Ra). Here, sensitive and specific RNase protection assays were used to investigate the effects of the intracerebroventricular (i.c.v.) administration of LPS on mRNA levels of interleukin-1β (IL-1β) system components, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, and neuropeptide Y (NPY) in the cerebellum, hippocampus, and hypothalamus. The same brain region sample was analyzed with all of the antisense probes. The data show simultaneous local induction of multiple cytokine components messenger ribonucleic acids (mRNAs) within specific brain regions in anorectic rats responding to i.c.v. administered LPS (500 ng/rat). Interleukin-1β and IL-1Ra had a similar mRNA induction profile (hypothalamus > cerebellum > hippocampus). Interleukin-1 receptor type I (IL-1RI) mRNA also increased in all three brain regions examined, and the soluble form of IL-1 receptor accessory protein (IL-1R AcP II) mRNA was induced in the hypothalamus. Tumor necrosis factor-α mRNA levels increased in the hypothalamus > hippocampus > cerebellum. Levels of membrane bound IL-1R AcP, TGF-β1, and NPY mRNAs did not change significantly in any brain region. The results suggest that: (1) endogenous up-regulation of IL-1β and TNF-α in the hypothalamus contribute to LPS-induced anorexia; and (2) the ratio IL-1Ra/IL-1β, and IL-1β ↔ TNF-α interactions may have implications for Gram-negative infections associated with high levels of LPS in the brain-cerebrospinal fluid.     

HIV-1 Envelope Glycoprotein 120 Regulates Brain IL-1β System and TNF-α mRNAs In Vivo

Human immunodeficiency virus type I (HIV-1)-derived envelope glycoprotein 120 (gp120) is proposed to play an important role in HIV-1 neuropathology. Gp120 may act through mediators including proinflammatory cytokines. Here, we investigated the regulation of the IL-1β system [IL-1β, IL-1 receptor type I (IL-1RI), IL-1 receptor antagonist (IL-1Ra)], TNF-α and TGF-α mRNAs in the rat central nervous system (CNS) in response to the constant intracerebroventricular (ICV) microinfusion of HIV-1 gp120 for 72 h and 144 h. The results show that gp120: (1) increased IL-1β and IL-1Ra mRNAs levels in the same samples from the cerebellum, hypothalamus and midbrain, with the largest increase in the hypothalamus; (2) induced profiles of IL-1β mRNA and IL-1Ra mRNA that were highly intercorrelated; (3) increased the hypothalamic TNF-α mRNA levels; and (4) did not affect the IL-1RI mRNA and TGF-α mRNA levels in any brain region. A dysregulation in the IL-1β/IL-1Ra CNS balance and a mutual induction and synergistic activity of IL-1β and TNF-α could result in a deleterious amplification cycle of cellular activation and cytotoxicity with implications to HIV-1-associated encephalitis, encephalopathy, and neurological manifestations.     

Regulation of brain interleukin-1β (IL-1β) system mRNAs in response to pathophysiological concentrations of IL-1β in the cerebrospinal fluid

Interleukin-1β (IL-1β) is released during pathophysiological processes. IL-1β induces neurological manifestations when administered into the cerebrospinal fluid (CSF) at pathophysiological concentrations detected during central nervous system (CNS) infections and other neurological disorders. In the present study, we investigated the regulation of the IL-1β system in the CNS in response to the chronic intracerebroventricular (icv) microinfusion of IL-1β at estimated pathophysiological concentrations in the CSF. IL-1 receptor type I (IL-1RI), IL-1 receptor antagonist (IL-1Ra), and IL-1β mRNAs were determined by sensitive RNase protection assays in brain target regions for IL-1β (cerebellum, parieto-frontal cortex, hippocampus, and midbrain). The results show that chronic icv microinfusion of IL-1β induced significant anorexia, increased the cerebellar IL-1RI mRNA content, increased IL-1Ra and IL-1β mRNAs levels in the cerebellum > midbrain > cortex > hippocampus, and induced profiles of IL-1RI mRNA, IL-1Ra mRNA, and IL-1β mRNA that were highly intercorrelated. On the other hand, levels of rat glyceraldehyde 3-phosphate dehydrogenase mRNA and 18S rRNA were fairly constant, and heat-inactivated IL-1β had no effect on food intake or on IL-1RI, IL-1Ra, and IL-1β mRNAs levels in any brain region. The data suggest the operation of an IL-1β feedback system (IL-1β/IL-1Ra/IL-1RI) in brain regions. Dysregulation of the CNS IL-1β feedback system may have pathophysiological significance. This may be reflected, for example, in the pathogenicity and severity of neurological diseases, such as CNS infections.     

Autoregulation of the interleukin-1 system and cytokine-cytokine interactions in primary human astrocytoma cells

Cytokines are proposed to play important roles in brain tumor biology. Previous studies reported on interleukin-1beta (IL-1beta) production and IL-1 receptor type I (IL-1RI, signaling receptor) expression in human astrocytomas, and on IL-1beta action in astrocytoma cell lines. However, all studies that have tested the direct action of cytokines have used exclusively astrocytoma cell lines, which do not recapitulate the in situ astrocytoma. Here, we demonstrate that astrocytoma cells obtained shortly after tumor neurosurgical resection respond to the direct application of human IL-1beta with a significant upregulation of IL-1alpha, IL-1beta, IL-1RI, and tumor necrosis factor-alpha (TNF-alpha) mRNAs. IL-1 receptor antagonist (IL-1Ra, an endogenous inhibitor that blocks IL-1alpha and IL-1beta actions) mRNA was not upregulated. Application of heat-inactivated IL-1beta had no effect on any cytokine component examined, demonstrating specificity of action. On the other hand, IL-1beta application did not modulate any cytokine component in acutely resected and dissociated primitive neuroectodermal tumor cells. The data have implications for a positive autoregulatory IL-1beta feedback system and synergistic IL-1beta <=> TNF-alpha interactions, which can be involved in the growth of pilocytic astrocytomas. The results together with our previous studies also support the notion that IL-1Ra or a compound with similar cytokine inhibitory activity could be useful for brain immunotherapy of astrocytomas.     

Secondary generalization of hippocampal kindled seizures in rats: examining the role of the piriform cortex

A primary feature of epilepsy is the potential for focal seizures to recruit distant structures and generalize into convulsions. Key to understanding generalization is to identify critical structures facilitating the transition from focal to generalized seizures. In kindling, development of a primary site leads progressively to secondarily generalized convulsions. In addition, subsequent kindling of a secondary site results in rapid kindling from that site, presumably because of its facilitated access to the primary kindled network. Here, we investigated the role of the piriform cortex in convulsive generalization from a secondary site kindled in the hippocampus after primary site amygdala kindling. In a necessarily complicated design, rats initially experienced forebrain commissurotomy to lateralize the experiment to one hemisphere. Then the amygdala was kindled and, 3 weeks later, it was electrically-triggered into status epilepticus, which destroyed the ipsilateral piriform cortex. This experience occurred several days before secondary site kindling of the dorsal hippocampus. In rats with complete piriform cortex loss, there was no disruption in kindling or convulsive seizure expression from the hippocampus. However, when damage also involved parts of the perirhinal, insular and entorhinal cortices, convulsive expression was blocked. Although other evidence suggests that piriform lesions affect generalization of primary site kindling, the present study shows that they do not alter secondary site kindling in the dorsal hippocampus. The additional involvement of parahippocampal cortical areas in convulsive expression suggests an important functional association between these cortical regions and the hippocampus in seizure propagation and clinical expression.     

Neither acute nor chronic exposure to a naturalistic (predator) stressor influences the interleukin-1beta system, tumor necrosis factor-alpha, transforming growth factor-beta1, and neuropeptide mRNAs in specific brain regions

Physical (neurogenic) stressors may influence immune functioning and interleukin-1beta (IL-1beta) mRNA levels within several brain regions. The present study assessed the effects of an acute or repeated naturalistic, psychogenic stressor (predator exposure) on brain cytokine and neuropeptide mRNAs. Acute predator (ferret) exposure induced stress-like behavioral effects, including elicitation of a startle response and reduced exploratory behaviors; these responses diminished after 30 sessions. Moreover, acute and repeated predator exposure, like acute restraint stress, increased plasma corticosterone levels measured 5 min later, but not 2 h after stressor exposure. In contrast, none of the stressors used influenced IL-1beta, IL-1 receptor antagonist, IL-1 receptor type I, IL-1 receptor accessory proteins I and II, or tumor necrosis factor-alpha mRNA levels in the prefrontal cortex, amygdala, hippocampus, or hypothalamus. Likewise, there were no stressor effects on transforming growth factor-beta1, neuropeptide Y, glycoprotein 130, or leptin receptor mRNAs in brain regions. Thus, the naturalistic/psychogenic stressor used does not affect any of the brain cytokine component mRNAs studied. It is suggested that this type of stressor activates homeostatic mechanisms (e.g., glucocorticoid release), which act to preclude brain cytokine alterations that would otherwise favor neuroinflammatory/neuroimmunological responses and the consequent increase of brain sensitivity to neurotoxic and neurodegenerative processes.     

Amygdala kindling and c-fos protein(s)

c-fos protein was visualized immunohistochemically in the brains of rats after partial amygdala seizures and generalized amygdala-kindled seizures and in seizure-free amygdala-kindled rats. Four hours following partial amygdala seizures there was a massive induction of c-fos protein in the ipsilateral piriform cortex, entorhinal cortex, and amygdala. Following generalized amygdala-kindled seizures there was a massive bilateral induction of c-fos in the entire cerebral cortex, amygdala, piriform and entorhinal cortices, hippocampus, and dentate gyrus. However, there did not appear to be any change in the basal levels of c-fos in the brains of amygdala-kindled rats that had been seizure free for 7 days. These results show that kindled seizures induce c-fos in neurons, but that the permanence of kindling is not related to altered basal c-fos levels.     

Interleukin-1α (IL-1α), IL-1β, IL-1 receptor type I, IL-1 receptor antagonist, and TGF-β1 mRNAs in pediatric astrocytomas, ependymomas, and primitive neuroectodermal tumors

Interleukin-1α (IL-1α), IL-1β, interleukin-1 receptor type I (IL-1RI, signaling receptor), and IL-1 receptor antagonist (IL-1Ra, endogenous inhibitor) are pivotal components of the IL-1 system. IL-1 and other cytokines induced by IL-1, such as TGF-β1, may participate in the growth of various tumor cells. In children, primary nervous system tumors represent the most common solid malignancy. We investigated the levels of IL-1α, IL-1β, IL-1RI, IL-1Ra, and TGF-β1 mRNAs in pediatric astrocytomas (n=19), ependymomas (n=13), and primitive neuroectodermal tumors (n=22) using sensitive and specific RNase protection assays. The data show a significant distinct cytokine mRNA profile among brain tumor types. Pilocytic, nonpilocytic, and anaplastic astrocytomas have significant increased levels of IL-1β, IL-1RI, and TGF-β1 mRNAs, but low levels of IL-1Ra mRNA; this may have implications for an IL-1β feedback system and IL-1β?TGF-β1 interactions in astrocytomas. Ependymomas show increased levels of IL-1α and IL-1β mRNAs associated with low levels of IL-1Ra mRNA; primitive neuroectodermal tumors do not exhibit increased levels of any cytokine component examined. The data also suggest that a dysregulation of the balance between stimulatory and inhibitory cytokines may be involved in the growth and development of brain tumors via autocrine/paracrine mechanisms.     

Increased expression of mRNA encoding interleukin-1beta and caspase-1, and the secreted isoform of interleukin-1 receptor antagonist in the rat brain following systemic kainic acid administration

Kainic acid, an analogue of glutamate, injected systemically to rats evokes seizures that are accompanied by nerve cell damage primarily in the limbic system. In the present study, we have analyzed the temporal profile of the expression of the cytokines interleukin-1beta (IL-1beta) and IL-1 receptor antagonist (IL-1ra), and the related IL-1beta-converting enzyme (ICE/caspase-1), in different regions of the rat brain in response to peripheral kainic acid administration (10 mg/kg, i.p.). In situ hybridization histochemistry experiments revealed that IL-1beta mRNA-expressing cells, morphologically identified as microglial cells, were mainly localized to regions showing pronounced neuronal degeneration; hippocampus, thalamus, amygdala, and certain cortical regions. The strongest expression of IL-1beta mRNA was observed after 12 hr in these regions. A weak induction of the IL-1beta mRNA expression was observed already at 2 hr. Similar results were obtained by RT-PCR analysis, showing a significantly increased expression of IL-1beta mRNA in the hippocampus and amygdala after 12 hr. In addition, RT-PCR analysis revealed that IL-1ra mRNA, and specifically mRNA encoding the secreted isoform of IL-1ra (sIL-1ra), was strongly induced in the hippocampus and amygdala at 12 and 24 hr post-injection. RT-PCR analysis of mRNA encoding caspase-1 showed a significantly increased expression in the amygdala after 12 hr. In conclusion, in response to systemic kainic acid injection IL-1beta mRNA is rapidly induced and followed by induction of IL-1ra mRNA and caspase-1 mRNA, supporting a role of the IL-1 system in the inflammatory response during excitotoxic damage.     

Inhibition of kainic acid induced expression of interleukin-1 beta and interleukin-1 receptor antagonist mRNA in the rat brain by NMDA receptor antagonists

The cytokines interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1ra) are rapidly induced in response to excitotoxic and ischemic brain damage. The aim of the present study was to investigate the influence of a non-competitive (dizocilpine maleate, MK-801) and a competitive ((R)-CPP) NMDA receptor antagonist on the transient cytokine expression in the rat brain induced by systemic kainic acid administration. Peripheral administration of kainic acid (10 mg/kg, i.p.) results in a transient expression of IL-1 beta and IL-1ra mRNA, mainly in microglia, in regions showing neurodegeneration such as the hippocampus, thalamus, amygdala, and certain cortical regions. In addition, a few neurons expressing IL-1ra mRNA were observed in the piriform cortex and amygdala following kainic acid injection. Administration of MK-801 (i.p.) 1 h prior to kainic acid injection reduced cytokine expression in all of these regions. MK-801 at 3.0 mg/kg decreased the IL-1 beta mRNA expression, blocked or decreased the IL-1ra mRNA expression, depending on the brain region. MK-801 at 5.0 mg/kg abolished IL-1ra mRNA expression in all of the regions, whereas the IL-1 beta mRNA expression was decreased or blocked, depending on the brain region, or the time point investigated. Peripheral administration of (R)-CPP (15 mg/kg, i.p.) 15 min prior to the kainic acid injection abolished the IL-1 beta mRNA expression. The IL-1ra mRNA expression was abolished in all regions except for a few neurons in the piriform cortex. The finding that NMDA receptor antagonists inhibit the IL-1 beta and IL-1ra mRNA synthesis induced by kainic acid suggests that NMDA receptor activation may be involved in triggering cytokine synthesis following excitotoxic brain damage.