A Prosaposin-Derived Peptide Alleviates Kainic Acid-Induced Brain Injury

Nabeka, Hiroaki; Shimokawa, Tetsuya; Doihara, Takuya; Saito, Shouichiro; Wakisaka, Hiroyuki; Hamada, Fumihiko; Kobayashi, Naoto; Matsuda, Seiji

doi:10.1371/journal.pone.0126856

Cited by 14 publications

(18 citation statements)

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“…Previous studies suggest that KA-induced microglia activation can cause hippocampal neuron apoptosis [ 44 – 46 ]. Therefore, preventing microglia activation protects hippocampus against neuron apoptosis caused by KA-induced seizures [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor SAHA attenuates post-seizure hippocampal microglia TLR4/MYD88 signaling and inhibits TLR4 gene expression via histone acetylation

Mao

2016

BMC Neurosci

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BackgroundEpilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. Seizure-induced TLR4/MYD88 signaling plays a critical role in activating microglia and triggering neuron apoptosis. SAHA is a histone deacetylase inhibitor that regulates gene expression by increasing chromatin histone acetylation. In this study, we investigated the role of SAHA in TLR4/MYD88 signaling in a rat seizure model.ResultsSprague–Dawley rats with kainic acid (KA)-induced seizures were treated with SAHA. The expression of TLR4, MYD88, NF-κB P65 and IL-1β in hippocampus was detected at hour 2 and 6 and day 1, 2, and 3 post seizure. SAHA pretreatment increased seizure latency and decreased seizure scores. The expression levels of TLR4, MYD88, NF-κB and IL-1β increased significantly in both activated microglia and apoptotic neurons after KA treatment. The effects were attenuated by SAHA. Chromatin immunoprecipitation assays indicated that the H3 histone acetylation levels significantly decreased while H3K9 levels significantly increased in the KA treatment group. The H3 and H3K9 acetylation levels returned to control levels after SAHA (50 mg/kg) pretreatment. There was a positive correlation between the expression of TLR4 and the acetylation levels of H3K9.ConclusionsHistone deacetylase inhibitor SAHA can suppress seizure-induced TLR4/MYD88 signaling and inhibit TLR4 gene expression through histone acetylation regulation. This suggests that SAHA may protect against seizure-induced brain damage.

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Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor SAHA attenuates post-seizure hippocampal microglia TLR4/MYD88 signaling and inhibits TLR4 gene expression via histone acetylation

Mao

2016

BMC Neurosci

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“…In a previous study, we established a rat model using systemic injection of KA, and investigated the expression and function of PSAP in the brain ( Nabeka et al., 2014 , Nabeka et al., 2015 ). However, we did not determine what happened to the cerebellum using this model.…”

Section: Introductionmentioning

confidence: 99%

Expression of prosaposin and its receptors in the rat cerebellum after kainic acid injection

Nabeka

Saito

et al. 2017

IBRO Reports

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Prosaposin (PSAP), a highly conserved glycoprotein, is a precursor of saposins A–D. Accumulating evidence suggests that PSAP is a neurotrophic factor that induces differentiation and prevents death in a variety of neuronal cells through the active region within the saposin C domain both in vivo and in vitro. Recently, GPR37 and GPR37L1 were recognized as PSAP receptors. In this study, we examined the alteration in expression of PSAP and its receptors in the cerebellum using rats injected with kainic acid (KA). The results show that PSAP was strongly expressed in the cytoplasm of Purkinje cells and interneurons in the molecular layer, and that PSAP expression in both types of neurons was markedly enhanced following KA treatment. Immunoblotting revealed that the expression of GPR37 was diminished significantly three days after KA injection compared with control rats; however, no changes were observed through immunostaining. No discernable changes were found in GPR37L1. These findings may help us to understand the role of PSAP and the GPR37 and GPR37L1 receptors in alleviating the neural damage caused by KA.

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“…The nature of neuronal degeneration caused by systemic KA injection resembles some forms of ischemia [79]. The degree of KA-induced neuronal injury is influenced by temperature, anesthesia, and anticonvulsant drugs [80,81].…”

Section: Ka and Kainate Acid Receptor (Kar)mentioning

confidence: 99%

Effects of Excitotoxic Lesion with Inhaled Anesthetics on Nervous System Cells of Rodents

Quiroz‐Padilla

Guillazo-Blanch

Sanchez

et al. 2018

CPD

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Different anesthesia methods can variably influence excitotoxic lesion effects on the brain. The main purpose of this review is to identify potential differences in the toxicity to nervous system cells of two common inhalation anesthesia methods, isoflurane and sevoflurane, used in combination with an excitotoxic lesion procedure in rodents. The use of bioassays in animal models has provided the opportunity to examine the role of specific molecules and cellular interactions that underlie important aspects of neurotoxic effects relating to calcium homeostasis and apoptosis activation. Processes induced by NMDA antagonist drugs involve translocation of Bax protein to mitochondrial membranes, allowing extra-mitochondrial leakage of cytochrome C, followed by sequence of changes that ending in activation of CASP-3. The literature demonstrates that the use of these anesthetics in excitotoxic surgery increases neuroinflammation activity facilitating the effects of apoptosis and necrosis on nervous system cells, depending on the concentration and exposure duration of the anesthetic. High numbers of microglia and astrocytes and high levels of proinflammatory cytokines and caspase activation possibly mediate these inflammatory responses. However, it is necessary to continue studies in rodents to understand the effect of the use of inhaled anesthetics with excitotoxic lesions in different developmental stages, including newborns, juveniles and adults. Understanding the mechanisms of regulation of cell death during development can potentially provide tools to promote neuroprotection and eventually achieve the repair of the nervous system in pathological conditions.

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A Prosaposin-Derived Peptide Alleviates Kainic Acid-Induced Brain Injury

Cited by 14 publications

References 50 publications

Histone deacetylase inhibitor SAHA attenuates post-seizure hippocampal microglia TLR4/MYD88 signaling and inhibits TLR4 gene expression via histone acetylation

Histone deacetylase inhibitor SAHA attenuates post-seizure hippocampal microglia TLR4/MYD88 signaling and inhibits TLR4 gene expression via histone acetylation

Expression of prosaposin and its receptors in the rat cerebellum after kainic acid injection

Effects of Excitotoxic Lesion with Inhaled Anesthetics on Nervous System Cells of Rodents

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