Hippocampal Sclerosis in Feline Epilepsy

Hippocampal sclerosis (HS) refers to loss of hippocampal neurons and astrogliosis. In temporal lobe epilepsy (TLE), HS is a key factor for pharmacoresistance, even though the mechanisms are not quite understood. While experimental TLE models are available, there is lack of models reflecting the natural HS development. Among domestic animals, cats may present with TLE‐like seizures in natural and experimental settings. With this study on the prevalence, segmental pattern and clinicopathological correlates of feline HS, we evaluated the translational value for human research. Evaluation schemes for human brains were applied to epileptic cats. The loss of neurons was morphometrically assessed and the degree of gliosis was recorded. Hippocampal changes resembling human HS were seen in about one third of epileptic cats. Most of these were associated with infiltrative diseases such as limbic encephalitis. Irrespective of the etiology and semiology of seizures, total hippocampal sclerosis was the most prevalent form seen in epileptic animals. Other HS types also occur at varying frequencies. Segmental differences to human HS can be explained by species‐specific synaptic connectivities and a different spectrum of etiologies. All these variables require consideration when translating results from feline studies regarding seizure‐associated changes of the temporal lobe and especially HS.     

Advanced glycation end product Nε‐carboxymethyllysine induces endothelial cell injury: the involvement of SHP‐1‐regulated VEGFR‐2 dephosphorylation

N^ε‐carboxymethyllysine (CML), a major advanced glycation end product, plays a crucial role in diabetes‐induced vascular injury. The roles of protein tyrosine phosphatases and vascular endothelial growth factor (VEGF) receptors in CML‐related endothelial cell injury are still unclear. Human umbilical vein endothelial cells (HUVECs) are a commonly used human EC type. Here, we tested the hypothesis that NADPH oxidase/reactive oxygen species (ROS)‐mediated SH2 domain‐containing tyrosine phosphatase‐1 (SHP‐1) activation by CML inhibits the VEGF receptor‐2 (VEGFR‐2, KDR/Flk‐1) activation, resulting in HUVEC injury. CML significantly inhibited cell proliferation and induced apoptosis and reduced VEGFR‐2 activation in parallel with the increased SHP‐1 protein expression and activity in HUVECs. Adding recombinant VEGF increased forward biological effects, which were attenuated by CML. The effects of CML on HUVECs were abolished by SHP‐1 siRNA transfection. Exposure of HUVECs to CML also remarkably escalated the integration of SHP‐1 with VEGFR‐2. Consistently, SHP‐1 siRNA transfection and pharmacological inhibitors could block this interaction and elevating [³H]thymidine incorporation. CML also markedly activated the NADPH oxidase and ROS production. The CML‐increased SHP‐1 activity in HUVECs was effectively attenuated by antioxidants. Moreover, the immunohistochemical staining of SHP‐1 and CML was increased, but phospho‐VEGFR‐2 staining was decreased in the aortic endothelium of streptozotocin‐induced and high‐fat diet‐induced diabetic mice. We conclude that a pathway of tyrosine phosphatase SHP‐1‐regulated VEGFR‐2 dephosphorylation through NADPH oxidase‐derived ROS is involved in the CML‐triggered endothelial cell dysfunction/injury. These findings suggest new insights into the development of therapeutic approaches to reduce diabetic vascular complications. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

In vivo MRS and histochemistry of status epilepticus‐induced hippocampal pathology in a juvenile model of temporal lobe epilepsy

Childhood status epilepticus (SE) initiates an epileptogenic process that leads to spontaneous seizures and hippocampal pathology characterized by neuronal loss, gliosis and an imbalance between excitatory and inhibitory neurotransmission. It remains unclear whether these changes are a cause or consequence of chronic epilepsy. In this study, in vivo MRS was used in a post‐SE juvenile rat model of temporal lobe epilepsy (TLE) to establish the temporal evolution of hippocampal injury and neurotransmitter imbalance. SE was induced in P21 rats by injection of lithium and pilocarpine. Four and eight weeks after SE, in vivo ¹H and γ‐aminobutyric acid (GABA)‐edited MRS of the hippocampus was performed in combination with dedicated ex vivo immunohistochemistry for the interpretation and validation of MRS findings. MRS showed a 12% decrease (p < 0.0001) in N‐acetylaspartate and a 15% increase (p = 0.0226) in choline‐containing compound concentrations, indicating neuronal death and gliosis, respectively. These results were confirmed by FluoroJade and vimentin staining. Furthermore, severe and progressive decreases in GABA (?41%, p < 0.001) and glutamate (Glu) (?17%, p < 0.001) were found. The specific severity of GABAergic cell death was confirmed by parvalbumin immunoreactivity (?68%, p < 0.001). Unexpectedly, we found changes in glutamine (Gln), the metabolic precursor of both GABA and Glu. Gln increased at 4 weeks (+36%, p < 0.001), but returned to control levels at 8 weeks. This decrease was consistent with the simultaneous decrease in glutamine synthase immunoreactivity (?32%, p = 0.037). In vivo MRS showed gliosis and (predominantly GABAergic) neuronal loss. In addition, an increase in Gln was detected, accompanied by a decrease in glutamine synthase immunoreactivity. This may reflect glutamine synthase downregulation in order to normalize Gln levels. These changes occurred before spontaneous recurrent seizures were present but, by creating a pre‐epileptic state, may play a role in epileptogenesis. MRS can be applied in a clinical setting and may be used as a noninvasive tool to monitor the development of TLE. Copyright © 2012 John Wiley & Sons, Ltd.     

Astrocytic expression of cannabinoid type 1 receptor in rat and human sclerotic hippocampi

Cannabinoid type 1 receptor (CB1R), which is traditionally located on axon terminals, plays an important role in the pathology of epilepsy and neurodegenerative diseases by modulating synaptic transmission. Using the pilocarpine model of chronic spontaneous recurrent seizures, which mimics the main features of mesial temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) in humans, we examined the expression of CB1R in hippocampal astrocytes of epileptic rats. Furthermore, we also examined the expression of astrocytic CB1R in the resected hippocampi from patients with medically refractory mesial TLE. Using immunofluorescent double labeling, we found increased expression of astrocytic CB1R in hippocampi of epileptic rats, whereas expression of astrocytic CB1R was not detectable in hippocampi of saline treated animals. Furthermore, CB1R was also found in some astrocytes in sclerotic hippocampi in a subset of patients with intractable mesial TLE. Detection with immune electron microscopy showed that the expression of CB1R was increased in astrocytes of epileptic rats and modest levels of CB1R were also found on the astrocytic membrane of sclerotic hippocampi. These results suggest that increased expression of astrocytic CB1R in sclerotic hippocampi might be involved in the cellular basis of the effects of cannabinoids on epilepsy.     

Excitatory amino acid transporters EAAT‐1 and EAAT‐2 in temporal lobe and hippocampus in intractable temporal lobe epilepsy

Intractable temporal lobe epilepsy (TLE) is an invalidating disease and many patients are resistant to medical treatment. Increased glutamate concentration has been found in epileptogenic foci and may induce local over‐excitation and cytotoxicity; one of the proposed mechanisms involves reduced extra‐cellular clearance of glutamate by excitatory amino acid transporters (EAAT‐1 to EAAT‐5). EAAT‐1 and EAAT‐2 are mainly expressed on astroglial cells for the reuptake of glutamate from the extra‐cellular space. We have studied the expression of EAAT‐1 and EAAT‐2 in the hippocampus and temporal lobe in 12 patients with TLE by immunhistochemistry and densitometry. The expression of EAAT‐1 and EAAT‐2 was reduced to approximately 40% and 25%, respectively, in CA1 of the hippocampus. In the same area, an increased expression of glial fibrillary acid protein (GFAP) at 90% reflected molecular rearrangements and upregulation of GFAP in the existing astrocytes as Ki‐67 staining failed to demonstrate any signs of astrocytic proliferation. The aetiology of the reduced expression of EAAT‐1 and EAAT‐2 remains unclear. The downregulation of EAAT‐1 and EAAT‐2 may be an adaptive response to neuronal death or it may be a causative event contributing to neuronal death. Further studies of the EAATs and their function are needed to clarify the mechanisms and significance of EAAT‐1 and EAAT‐2 disappearance in TLE.     

Quantitative analysis of parvalbumin-immunoreactive cells in the human epileptic hippocampus

Hippocampal sclerosis is the most frequent pathology encountered in mesial temporal structures resected from patients with intractable temporal lobe epilepsy and it mainly involves hippocampal neuronal loss and gliosis. These alterations are accompanied by changes in the expression of a variety of molecules in the surviving neurons, as well as axonal reorganization in both excitatory and inhibitory circuits. The alteration of a subpopulation of GABAergic interneurons that expresses the calcium binding protein parvalbumin (PV) is thought to be a key factor in the epileptogenic process. We investigated the distribution and density of parvalbumin-immunoreactive (PV-ir) neurons in surgically resected hippocampal tissue from epileptic patients with and without sclerosis. Using quantitative stereological methods, we show for the first time that there is no correlation between total neuronal loss and PV-ir neuronal loss in any of the hippocampal fields. We also observed higher values of the total neuronal density in the sclerotic subiculum, which is accompanied by a lower density of PV-ir when compared with non-sclerotic epileptic and autopsy hippocampi. These findings suggest that, the apparently normal subiculum from sclerotic patients also shows unexpected changes in the density and proportion of PV-ir neurons.     

氯碘羟喹对癫痫小鼠海马神经元凋亡和学习记忆功能的保护作用

目的 研究氯碘羟喹对癫痫小鼠海马神经元凋亡和学习记忆功能的保护作用。 方法 采用匹罗卡品癫痫小鼠模型。实验动物根据给药方式分3组：对照组（生理盐水）、癫痫组（匹罗卡品+生理盐水）、氯碘羟喹组（匹罗卡品+氯碘羟喹）。金属自显影技术观察海马锌的分布;尼氏染色观察海马神经元形态和数量;免疫印迹检测海马Bcl-2和Bax表达;ELISA检测海马Caspases-9和Caspases-3表达;动物行为学观察自发性癫痫发作次数、发作级别和发作持续时间;T迷宫和Y迷宫检测学习记忆能力。 结果 氯碘羟喹组小鼠海马锌显著减少;神经元损伤减轻,细胞数量增多;Bcl-2表达增多,Bax、Caspases-9和Caspases-3表达减少,Bcl-2/Bax值增大;癫痫发作次数减少,发作级别降低,发作持续时间缩短,学习记记能力增强（P<0.01）。 结论 氯碘羟喹能保护小鼠海马神经元,改善学习记忆功能。     

Vesicular glutamate transporter 1 immunostaining in the normal and epileptic human cerebral cortex

Glutamate is the main excitatory neurotransmitter in the brain where, due to the activity of specific vesicular glutamate transporters, it accumulates in synaptic vesicles. The vesicular glutamate transporter 1 is found in the majority of axon terminals that form asymmetrical (excitatory) synapses in the rat neocortex. However, since there is no information available regarding the distribution of vesicular glutamate transporter 1 in the human neocortex, we have used correlative light and electron microscopy to define its expression in this tissue. We found that the distribution of vesicular glutamate transporter 1-immunoreactivity is virtually identical to that found in the rat neocortex, both at the light and electron microscope levels. Therefore, we assessed whether vesicular glutamate transporter 1 immunostaining might be a useful tool to study the pathological alterations of glutamatergic transmission in the epileptic cerebral cortex. We analyzed the distribution of vesicular glutamate transporter 1 in the peritumoral neocortex of patients with epilepsy secondary to low-grade tumors. In these regions, we found alterations in the pattern of vesicular glutamate transporter 1-immunoreactivity that perfectly matched the neuronal loss and gliosis, as well as the decrease in the number of asymmetrical synapses identified by electron microscopy in this tissue. Thus, vesicular glutamate transporter 1 immunostaining appears to be a reliable and simple tool to study glutamatergic synapses in the normal and epileptic human cerebral cortex.     

Microtubule-associated protein 2 phosphorylation is decreased in the human epileptic temporal lobe cortex.

Microtubule-associated protein 2 (MAP2) is an abundant component of the neuronal cytoskeleton whose function is related to the outgrowth and stability of neuronal processes, to synaptic plasticity and neuronal cell death. We have sought to study whether abnormal patterns of neuronal activity which are characteristic of epileptic patients are associated to alterations of MAP2 phosphorylation. An antibody (305) that selectively recognizes a phosphorylated epitope in a proline-rich region of the MAP2 molecule has been used to analyze neocortical biopsy samples from temporal lobe epileptic patients, whose electrocorticogram activity had been previously monitored. Immunoblot analysis showed that samples with greater spiking activity displayed significantly diminished MAP2 phosphorylation. Immunocytochemical analysis revealed the occurrence of discrete areas in the neocortex with highly decreased or no immunostaining for antibody 305, which showed a clear, although non-significant, tendency to appear more frequently in areas with greater spiking activity. To further support an association between epileptiform activity and MAP2 dephosphorylation an experimental model of epileptiform activity in cultures of rat hippocampal neurons was used. Neurons were cultured during 15 days in the presence of kynurenic acid, an antagonist of glutamate receptors. At this time, kynurenic acid was removed from the culture medium and neurons developed seizure-like activity. Using antibody 305, we found a decrease of MAP2 phosphorylation that was already visible after 15 min of kynurenic acid withdrawal.We therefore propose that MAP2 phosphorylation is decreased in the neocortex of epileptic patients and that this decrease is a likely consequence of seizure activity. Also, MAP2 dephosphorylation may lead to alterations of the neuronal cytoskeleton and eventually to neuronal damage and loss, which is typical of epileptic patients.     

Altered expression of CX3CL1 in patients with epilepsy and in a rat model

Chemokine C-X3-C motif ligand 1 (CX3CL1, alias fractalkine), is highly expressed in the central nervous system and participates in inflammatory responses. Recent studies indicated that inflammatory processes within the brain constitute a common and crucial mechanism in the pathophysiological characteristics of epilepsy. This study investigated the expression pattern of CX3CL1 in epilepsy and its relationship with neuronal loss. Double immunolabeling, IHC, and immunoblotting results showed that CX3CL1 expression was up-regulated in the temporal neocortex of patients with temporal lobe epilepsy. In a rat model of epilepsy, CX3CL1 up-regulation began 6 hours after epilepsy, with relatively high expression for 60 days. In addition, ELISA revealed that the concentrations of CX3CL1 in cerebrospinal fluid and serum were higher in epileptic patients than in patients with neurosis but lower than in patients with inflammatory neurological diseases. Moreover, H&E staining demonstrated significant neuronal loss in the brains of epileptic patients and in the rat model. Finally, the expression of tumor necrosis factor-related apoptosis-inducing ligand was significantly increased in both patients and the animal model, suggesting that tumor necrosis factor-related apoptosis-inducing ligand may play a role in CX3CL1-induced cell death. Thus, our results indicate that CX3CL1 may serve as a possible biomarker of brain inflammation in epileptic patients.     

Non-invasive detection of hippocampal sclerosis: correlation between metabolite alterations detected by (1)H-MRS and neuropathology

We assessed (1)H-MRS as a screening tool for detection of hippocampal sclerosis in patients with temporal lobe epilepsy (TLE). (1)H-MRS was carried out in the hippocampus of 23 patients with unilateral TLE. Metabolite alterations detected by (1)H-MRS correlated with degree of segmental neuronal cell loss and amount of astrogliosis. Positive correlation was found between total N-Acetylaspartate (tNAA) reduction and neuronal density in hippocampal CA1 (P < 0.001), CA3 (P = 0.015), and CA4 subfields (P = 0.031) and the dentate gyrus (P = 0.006). Neuronal cell loss in CA1 turned out to be the most predictive and only significant variable for tNAA reduction (P = 0.027). The association between myo-inositol (m-Ins) and astroglial glial fibrillary acidic protein (GFAP) expression revealed significantly increased m-Ins concentrations associated with diffuse astrogliosis (m-Ins = 6.4 +/- 1.1 institutional units) compared with gliosis restricted to isolated sectors of the hippocampus (i.e. hilus) (m-Ins = 5.2 +/- 1.2 institutional units) (P = 0.039). A negative correlation was found between m-Ins and neuronal loss in the CA4 subfield of the hippocampus (P = 0.028). Our results support (1)H-MRS as a suitable non-invasive method for preoperative identification of hippocampal sclerosis in patients with TLE. The extent of tNAA reduction correlates with hippocampal neuronal cell density. Furthermore, m-Ins is associated with the extent of hippocampal astrogliosis.     

Mitochondrial dysfunction and ultrastructural damage in the hippocampus of pilocarpine-induced epileptic rat

Mitochondrial dysfunction has been implicated as a contributing factor in epileptic seizures. Present studies were carried out to decipher seizure-dependent changes in mitochondrial function and ultrastructure in the chronic condition of temporal lobe epilepsy (TLE) induced by pilocarpine in rat hippocampus. Enzyme assay revealed significant depression of the activity of mitochondrial- and nuclear-encoded cytochrome oxidase (COX). Conversely, the activity of nuclear-encoded succinate dehydrogenase (SDH) remained unchanged. Discernible mitochondrial ultrastructural damage, varying from swelling to disruption of membrane, was observed in the hippocampus. Quantitative real-time PCR and Western blotting showed the expression of mitochondrial-encoded COX subunit III (COXIII) dropped significantly during the chronic seizure activity; the corresponding expression of COX subunit IV (COXIV) displayed no significant change. Most likely, our results suggest that dysfunction of mitochondrial COX respiratory enzyme and mitochondrial ultrastructural damage in the hippocampus are associated with prolonged seizure during experimental TLE and mitochondria are more vulnerable to epilepsy.     

Targeted loss of SHP1 in murine thymocytes dampens TCR signaling late in selection

SHP1 is a tyrosine phosphatase critical to proximal regulation of TCR signaling. Here, analysis of CD4‐Cre SHP1^fl/fl conditional knockout thymocytes using CD53, TCRβ, CD69, CD4, and CD8α expression demonstrates the importance of SHP1 in the survival of post selection (CD53⁺), single‐positive thymocytes. Using Ca²⁺ flux to assess the intensity of TCR signaling demonstrated that SHP1 dampens the signal strength of these same mature, postselection thymocytes. Consistent with its dampening effect, TCR signal strength was also probed functionally using peptides that can mediate selection of the OT‐I TCR, to reveal increased negative selection mediated by lower‐affinity ligand in the absence of SHP1. Our data show that SHP1 is required for the survival of mature thymocytes and the generation of the functional T‐cell repertoire, as its absence leads to a reduction in the numbers of CD4⁺ and CD8⁺ naïve T cells in the peripheral lymphoid compartments.     

Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation

Noonan syndrome is a developmental disorder with dysmorphic facies, short stature, cardiac defects, and skeletal anomalies, which can be caused by missense PTPN11 mutations. PTPN11 encodes Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2 or SHP-2), a protein tyrosine phosphatase that acts in signal transduction downstream to growth factor, hormone, and cytokine receptors. We compared the functional effects of three Noonan syndrome-causative PTPN11 mutations on SHP2's phosphatase activity, interaction with a binding partner, and signal transduction. All SHP2 mutants had significantly increased basal phosphatase activity compared to wild type, but that activity varied significantly between mutants and was further increased after epidermal growth factor stimulation. Cells expressing SHP2 mutants had prolonged extracellular signal-regulated kinase 2 activation, which was ligand-dependent. Binding of SHP2 mutants to Grb2-associated binder-1 was increased and sustained, and tyrosine phosphorylation of both proteins was prolonged. Coexpression of Grb2-associated binder-1-FF, which lacks SHP2 binding motifs, blocked the epidermal growth factor-mediated increase in SHP2's phosphatase activity and resulted in a dramatic reduction of extracellular signal-regulated kinase 2 activation. Taken together, these results document that Noonan syndrome-associated PTPN11 mutations increase SHP2's basal phosphatase activity, with greater activation when residues directly involved in binding at the interface between the N-terminal Src homology 2 and protein tyrosine phosphatase domains are altered. The SHP2 mutants prolonged signal flux through the RAS/mitogen-activated protein kinase (ERK2/MAPK1) pathway in a ligand-dependent manner that required docking through Grb2-associated binder-1 (GAB1), leading to increased cell proliferation.     

NG2+/Olig2+ Cells are the Major Cycle‐Related Cell Population of the Adult Human Normal Brain

A persistent cycling cell population in the normal adult human brain is well established. Neural stem cells or neural progenitors have been identified in the subventricular zone and the dentate gyrus subgranular layer (SGL), two areas of persistent neurogenesis. Cycling cells in other human normal brain areas, however, remains to be established. Here, we determined the distribution and identity of these cells in the cortex, the white matter and the hippocampal formation of adult patients with and without chronic temporal lobe epilepsy using immunohistochemistry for the cell cycle markers Ki‐67 (Mib‐1) and minichromosome maintenance protein 2. Rare proliferative neuronal precursors expressing the neuronal antigen neuronal nuclei were restricted to the SGL. In contrast, the oligodendrocyte progenitor cell markers Olig2 and the surface antigen NG2 were expressed by the vast majority of cycling cells scattered throughout the cortex and white matter of both control and epileptic patients. Most of these cycling cells were in early G1 phase, and were significantly more numerous in epileptic than in non‐epileptic patients. These results provide evidence for a persistent gliogenesis in the human cortex and white matter that is enhanced in an epileptic environment.     

Upregulation of inward rectifier K+ (Kir2) channels in dentate gyrus granule cells in temporal lobe epilepsy

In humans, temporal lobe epilepsy (TLE) is often associated with Ammon's horn sclerosis (AHS) characterized by hippocampal cell death, gliosis and granule cell dispersion (GCD) in the dentate gyrus. Granule cells surviving TLE have been proposed to be hyperexcitable and to play an important role in seizure generation. However, it is unclear whether this applies to conditions of AHS. We studied granule cells using the intrahippocampal kainate injection mouse model of TLE, brain slice patch-clamp recordings, morphological reconstructions and immunocytochemistry. With progressing AHS and GCD, 'epileptic' granule cells of the injected hippocampus displayed a decreased input resistance, a decreased membrane time constant and an increased rheobase. The resting leak conductance was doubled in epileptic granule cells and roughly 70–80% of this difference were sensitive to K⁺ replacement. Of the increased K⁺ leak, about 50% were sensitive to 1 m m Ba²⁺. Approximately 20–30% of the pathological leak was mediated by a bicuculline-sensitive GABA_A conductance. Epileptic granule cells had strongly enlarged inwardly rectifying currents with a low micromolar Ba²⁺ IC₅₀, reminiscent of classic inward rectifier K⁺ channels (Irk/Kir2). Indeed, protein expression of Kir2 subunits (Kir2.1, Kir2.2, Kir2.3, Kir2.4) was upregulated in epileptic granule cells. Immunolabelling for two-pore weak inward rectifier K⁺ channels (Twik1/K2P1.1, Twik2/K2P6.1) was also increased. We conclude that the excitability of granule cells in the sclerotic focus of TLE is reduced due to an increased resting conductance mainly due to upregulated K⁺ channel expression. These results point to a local adaptive mechanism that could counterbalance hyperexcitability in epilepsy.     

SHP1‐ing thymic selection

Thymocyte development and maintenance of peripheral T‐cell numbers and functions are critically dependent on T‐cell receptor (TCR) signal strength. SHP1 (Src homology region 2 domain‐containing phosphatase‐1), a tyrosine phosphatase, acts as a negative regulator of TCR signal strength. Moreover, germline SHP1 knockout mice have shown impaired thymic development. However, this has been recently questioned by an analysis of SHP1 conditional knockout mice, which reported normal thymic development of SHP1 deficient thymocytes. Using this SHP1 conditional knockout mice, in this issue of the European Journal of Immunology, Martinez et al. [Eur. J. Immunol. 2016. 46: 2103–2110] show that SHP1 indeed does have a role in the negative regulation of TCR signal strength in positively selected thymocytes, and in the final maturation of single positive thymocytes. They report that thymocyte development in such mice shows loss of mature, post‐selection cells. This is due to increased TCR signal transduction in thymocytes immediately post positive‐selection, and increased cell death in response to weak TCR ligands. Thus, SHP1‐deficiency shows strong similarities to deficiency in the T‐cell specific SHP1‐associated protein Themis.     

A role for astrocyte‐derived amyloid β peptides in the degeneration of neurons in an animal model of temporal lobe epilepsy

Kainic acid, an analogue of the excitatory neurotransmitter glutamate, can trigger seizures and neurotoxicity in the hippocampus and other limbic structures in a manner that mirrors the neuropathology of human temporal lobe epilepsy (TLE). However, the underlying mechanisms associated with the neurotoxicity remain unclear. Since amyloid‐β (Aβ) peptides, which are critical in the development of Alzheimer's disease, can mediate toxicity by activating glutamatergic NMDA receptors, it is likely that the enhanced glutamatergic transmission that renders hippocampal neurons vulnerable to kainic acid treatment may involve Aβ peptides. Thus, we seek to establish what role Aβ plays in kainic acid‐induced toxicity using in vivo and in vitro paradigms. Our results show that systemic injection of kainic acid to adult rats triggers seizures, gliosis and loss of hippocampal neurons, along with increased levels/processing of amyloid precursor protein (APP), resulting in the enhanced production of Aβ‐related peptides. The changes in APP levels/processing were evident primarily in activated astrocytes, implying a role for astrocytic Aβ in kainic acid‐induced toxicity. Accordingly, we showed that treating rat primary cultured astrocytes with kainic acid can lead to increased Aβ production/secretion without any compromise in cell viability. Additionally, we revealed that kainic acid reduces neuronal viability more in neuronal/astrocyte co‐cultures than in pure neuronal culture, and this is attenuated by precluding Aβ production. Collectively, these results indicate that increased production/secretion of Aβ‐related peptides from activated astrocytes can contribute to neurotoxicity in kainic acid‐treated rats. Since kainic acid administration can lead to neuropathological changes resembling TLE, it is likely that APP/Aβ peptides derived from astrocytes may have a role in TLE pathogenesis.