Histopathological evidence that hippocampal atrophy following status epilepticus is a result of neuronal necrosis

Kumar, Gogi; Mittal, Sandeep; Moudgil, Shyam S.; Kupsky, William J.; Shah, Aashit

doi:10.1016/j.jns.2013.08.016

Cited by 25 publications

(25 citation statements)

References 30 publications

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“…Magnetic resonance imaging (MRI) reveals an increase in the T 2 -weighted signal, whereas the diffusion-weighted imaging shows a higher apparent diffusion coefficient in sclerotic hippocampi, indicative of an increased water flow into the hippocampus, and accumulation of water in the brain parenchyma. In another human study, hippocampal edema and neuronal cell loss appear together (Kumar et al, 2013). Therefore, a significant increase in aquaporin-4 (AQP-4) was observed in sclerotic, but not in non-sclerotic, hippocampi obtained from patients with medically intractable temporal lobe epilepsy .…”

Section: Discussionmentioning

confidence: 93%

Reduced hippocampal manganese-enhanced MRI (MEMRI) signal during pilocarpine-induced status epilepticus: Edema or apoptosis?

et al. 2014

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Section: Discussionmentioning

confidence: 93%

Reduced hippocampal manganese-enhanced MRI (MEMRI) signal during pilocarpine-induced status epilepticus: Edema or apoptosis?

et al. 2014

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“…According to our results, P2X7R can modulate the mechanisms involved in edema since the reduction in the expression of these receptors by siRNA prevented the edema in hippocampal subareas as hilus, dentate gyrus suprapyramidal, CA1, and CA3 of rats underwent to pilocarpine-induced SE. Although the mechanisms are not elucidated, the edema processes have been associated with cell death, particularly neuronal death, and hippocampal atrophy [82,83]. A positive relationship between cerebral edema and the occurrence of spontaneous recurrent seizures has been shown in kainic acid model, strengthening the association of edema to epileptogenesis [65].…”

Section: Discussionmentioning

confidence: 99%

Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behavioral impact of pilocarpine-induced epilepsy

Amorim

Araújo

Valero

et al. 2017

Purinergic Signalling

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Cell signaling mediated by P2X7 receptors (P2X7R) has been suggested to be involved in epileptogenesis, via modulation of intracellular calcium levels, excitotoxicity, activation of inflammatory cascades, and cell death, among other mechanisms. These processes have been described to be involved in pilocarpine-induced status epilepticus (SE) and contribute to hyperexcitability, resulting in spontaneous and recurrent seizures. Here, we aimed to investigate the role of P2X7R in epileptogenesis in vivo using RNA interference (RNAi) to inhibit the expression of this receptor. Small interfering RNA (siRNA) targeting P2X7R mRNA was injected into the lateral ventricles (icv) 6 h after SE. Four groups were studied: SalineVehicle, Saline-siRNA, Pilo-Vehicle, and Pilo-siRNA. P2X7R was quantified by western blotting and neuronal death assessed by Fluoro-Jade B histochemistry. The hippocampal volume (edema) was determined 48 h following RNAi. Behavioral parameters as latency to the appearance of spontaneous seizures and the number of seizures were determined until 60 days after the SE onset. The Saline-siRNA and Pilo-siRNA groups showed a 43 and 37% reduction, respectively, in P2X7R protein levels compared to respective vehicle groups. Neuroprotection was observed in CA1 and CA3 of the PilosiRNA group compared to Pilo-Vehicle. P2X7R silencing in pilocarpine group reversed the increase in the edema detected in the hilus, suprapyramidal dentate gyrus, CA1, and CA3; reduced mortality rate following SE; increased the time to onset of spontaneous seizure; and reduced the number of seizures, when compared to the Pilo-Vehicle group. Therefore, our data highlights the potential of P2X7R as a therapeutic target for the adjunct treatment of epilepsy.

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“…Hippocampal sclerosis is commonly observed in patients with temporal lobe epilepsy (TLE). 12 Clasadonte et al 13 demonstrated in a mouse pilocarpine model of TLE that hyperfunction of NMDARs at the CA1 hippocampal synapses causes hippocampal sclerosis and that astrocytes play an important role in controlling NMDARs by releasing chemical transmitters in a process termed gliotransmission.…”

Section: Discussionmentioning

confidence: 99%

“…The hippocampus is an important brain region involved in neurological disorders such as AD, schizophrenia, and epilepsy. [10][11][12][13] Therefore, we need to develop an assay system that uses human hippocampal neurons so that we can obtain a detailed understanding of the molecular mechanisms underlying these diseases and discover novel drugs for treating them.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Human Hippocampal Neural Stem/Progenitor Cells and Their Application to Physiologically Relevant Assays for Multiple Ionotropic Glutamate Receptors

et al. 2014

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The hippocampus is an important brain region that is involved in neurological disorders such as Alzheimer disease, schizophrenia, and epilepsy. Ionotropic glutamate receptors-namely,N-methyl-D-aspartate (NMDA) receptors (NMDARs), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors (AMPARs), and kainic acid (KA) receptors (KARs)-are well known to be involved in these diseases by mediating long-term potentiation, excitotoxicity, or both. To predict the therapeutic efficacy and neuronal toxicity of drug candidates acting on these receptors, physiologically relevant systems for assaying brain region-specific human neural cells are necessary. Here, we characterized the functional differentiation of human fetal hippocampus-derived neural stem/progenitor cells-namely, HIP-009 cells. Calcium rise assay demonstrated that, after a 4-week differentiation, the cells responded to NMDA (EC50= 7.5 ± 0.4 µM; n= 4), AMPA (EC50= 2.5 ± 0.1 µM; n= 3), or KA (EC50= 33.5 ± 1.1 µM; n= 3) in a concentration-dependent manner. An AMPA-evoked calcium rise was observed in the absence of the desensitization inhibitor cyclothiazide. In addition, the calcium rise induced by these agonists was inhibited by antagonists for each receptor-namely, MK-801 for NMDA stimulation (IC50= 0.6 ± 0.1 µM; n= 4) and NBQX for AMPA and KA stimulation (IC50= 0.7 ± 0.1 and 0.7 ± 0.03 µM, respectively; n= 3). The gene expression profile of differentiated HIP-009 cells was distinct from that of undifferentiated cells and closely resembled that of the human adult hippocampus. Our results show that HIP-009 cells are a unique tool for obtaining human hippocampal neural cells and are applicable to systems for assay of ionotropic glutamate receptors as a physiologically relevant in vitro model.

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Histopathological evidence that hippocampal atrophy following status epilepticus is a result of neuronal necrosis

Cited by 25 publications

References 30 publications

Reduced hippocampal manganese-enhanced MRI (MEMRI) signal during pilocarpine-induced status epilepticus: Edema or apoptosis?

Reduced hippocampal manganese-enhanced MRI (MEMRI) signal during pilocarpine-induced status epilepticus: Edema or apoptosis?

Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behavioral impact of pilocarpine-induced epilepsy

Characterization of Human Hippocampal Neural Stem/Progenitor Cells and Their Application to Physiologically Relevant Assays for Multiple Ionotropic Glutamate Receptors

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