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23 pages, 5300 KiB

Open AccessArticle

The Transient Receptor Potential Melastatin 7 (TRPM7) Inhibitors Suppress Seizure-Induced Neuron Death by Inhibiting Zinc Neurotoxicity

by Jeong Hyun Jeong, Song Hee Lee, A Ra Kho, Dae Ki Hong, Dong Hyeon Kang, Beom Seok Kang, Min Kyu Park, Bo Young Choi, Hui Chul Choi, Man-Sup Lim and Sang Won Suh

Int. J. Mol. Sci. 2020, 21(21), 7897; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217897 - 24 Oct 2020

Cited by 17 | Viewed by 3119

Abstract

Transient receptor potential melastatin 7 (TRPM7) is an ion channel that mediates monovalent cations out of cells, as well as the entry of divalent cations, such as zinc, magnesium, and calcium, into the cell. It has been reported that inhibitors of TRPM7 are [...] Read more.

Transient receptor potential melastatin 7 (TRPM7) is an ion channel that mediates monovalent cations out of cells, as well as the entry of divalent cations, such as zinc, magnesium, and calcium, into the cell. It has been reported that inhibitors of TRPM7 are neuroprotective in various neurological diseases. Previous studies in our lab suggested that seizure-induced neuronal death may be caused by the excessive release of vesicular zinc and the subsequent accumulation of zinc in the neurons. However, no studies have evaluated the effects of carvacrol and 2-aminoethoxydiphenyl borate (2-APB), both inhibitors of TRPM7, on the accumulation of intracellular zinc in dying neurons following seizure. Here, we investigated the therapeutic efficacy of carvacrol and 2-APB against pilocarpine-induced seizure. Carvacrol (50 mg/kg) was injected once per day for 3 or 7 days after seizure. 2-APB (2 mg/kg) was also injected once per day for 3 days after seizure. We found that inhibitors of TRPM7 reduced seizure-induced TRPM7 overexpression, intracellular zinc accumulation, and reactive oxygen species production. Moreover, there was a suppression of oxidative stress, glial activation, and the blood–brain barrier breakdown. In addition, inhibitors of TRPM7 remarkably decreased apoptotic neuron death following seizure. Taken together, the present study demonstrates that TRPM7-mediated zinc translocation is involved in neuron death after seizure. The present study suggests that inhibitors of TRPM7 may have high therapeutic potential to reduce seizure-induced neuron death. Full article

(This article belongs to the Special Issue Neuronal, Glial, and Immune Changes in Models of Epilepsy and Epileptogenesis)

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13 pages, 2507 KiB

Open AccessArticle

Antagonism of Macrophage Migration Inhibitory Factory (MIF) after Traumatic Brain Injury Ameliorates Astrocytosis and Peripheral Lymphocyte Activation and Expansion

by M. Karen Newell-Rogers, Susannah K. Rogers, Richard P. Tobin, Sanjib Mukherjee and Lee A. Shapiro

Int. J. Mol. Sci. 2020, 21(20), 7448; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207448 - 09 Oct 2020

Cited by 12 | Viewed by 2487

Abstract

Traumatic brain injury (TBI) precedes the onset of epilepsy in up to 15–20% of symptomatic epilepsies and up to 5% of all epilepsy. Treatment of acquired epilepsies, including post-traumatic epilepsy (PTE), presents clinical challenges, including frequent resistance to anti-epileptic therapies. Considering that over [...] Read more.

Traumatic brain injury (TBI) precedes the onset of epilepsy in up to 15–20% of symptomatic epilepsies and up to 5% of all epilepsy. Treatment of acquired epilepsies, including post-traumatic epilepsy (PTE), presents clinical challenges, including frequent resistance to anti-epileptic therapies. Considering that over 1.6 million Americans present with a TBI each year, PTE is an urgent clinical problem. Neuroinflammation is thought to play a major causative role in many of the post-traumatic syndromes, including PTE. Increasing evidence suggests that neuroinflammation facilitates and potentially contributes to seizure induction and propagation. The inflammatory cytokine, macrophage migration inhibitory factor (MIF), is elevated after TBI and higher levels of MIF correlate with worse post-traumatic outcomes. MIF was recently demonstrated to directly alter the firing dynamics of CA1 pyramidal neurons in the hippocampus, a structure critically involved in many types of seizures. We hypothesized that antagonizing MIF after TBI would be anti-inflammatory, anti-neuroinflammatory and neuroprotective. The results show that administering the MIF antagonist ISO1 at 30 min after TBI prevented astrocytosis but was not neuroprotective in the peri-lesion cortex. The results also show that ISO1 inhibited the TBI-induced increase in γδT cells in the gut, and the percent of B cells infiltrating into the brain. The ISO1 treatment also increased this population of B cells in the spleen. These findings are discussed with an eye towards their therapeutic potential for post-traumatic syndromes, including PTE. Full article

(This article belongs to the Special Issue Neuronal, Glial, and Immune Changes in Models of Epilepsy and Epileptogenesis)

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19 pages, 4826 KiB

Open AccessArticle

Development of a Rat Model for Glioma-Related Epilepsy

by Charlotte Bouckaert, Charlotte Germonpré, Jeroen Verhoeven, Seon-Ah Chong, Lucas Jacquin, Georges Mairet-Coello, Véronique Marie André, Karine Leclercq, Christian Vanhove, Filip De Vos, Caroline Van den Broecke, Ingeborg Goethals, Benedicte Descamps, Sam Donche, Evelien Carrette, Wytse Wadman, Paul Boon, Kristl Vonck and Robrecht Raedt

Int. J. Mol. Sci. 2020, 21(19), 6999; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21196999 - 23 Sep 2020

Cited by 7 | Viewed by 3152

Abstract

Seizures are common in patients with high-grade gliomas (30–60%) and approximately 15–30% of glioblastoma (GB) patients develop drug-resistant epilepsy. Reliable animal models are needed to develop adequate treatments for glioma-related epilepsy. Therefore, fifteen rats were inoculated with F98 GB cells (GB group) and [...] Read more.

Seizures are common in patients with high-grade gliomas (30–60%) and approximately 15–30% of glioblastoma (GB) patients develop drug-resistant epilepsy. Reliable animal models are needed to develop adequate treatments for glioma-related epilepsy. Therefore, fifteen rats were inoculated with F98 GB cells (GB group) and four rats with vehicle only (control group) in the right entorhinal cortex. MRI was performed to visualize tumor presence. A subset of seven GB and two control rats were implanted with recording electrodes to determine the occurrence of epileptic seizures with video-EEG recording over multiple days. In a subset of rats, tumor size and expression of tumor markers were investigated with histology or mRNA in situ hybridization. Tumors were visible on MRI six days post-inoculation. Time-dependent changes in tumor morphology and size were visible on MRI. Epileptic seizures were detected in all GB rats monitored with video-EEG. Twenty-one days after inoculation, rats were euthanized based on signs of discomfort and pain. This study describes, for the first time, reproducible tumor growth and spontaneous seizures upon inoculation of F98 cells in the rat entorhinal cortex. The development of this new model of GB-related epilepsy may be valuable to design new therapies against tumor growth and associated epileptic seizures. Full article

(This article belongs to the Special Issue Neuronal, Glial, and Immune Changes in Models of Epilepsy and Epileptogenesis)

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14 pages, 7382 KiB

Open AccessArticle

Mice Lacking Connective Tissue Growth Factor in the Forebrain Exhibit Delayed Seizure Response, Reduced C-Fos Expression and Different Microglial Phenotype Following Acute PTZ Injection

by Pei-Fen Siow, Chih-Yu Tsao, Ho-Ching Chang, Chwen-Yu Chen, I-Shing Yu, Kuang-Yung Lee and Li-Jen Lee

Int. J. Mol. Sci. 2020, 21(14), 4921; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144921 - 12 Jul 2020

Cited by 5 | Viewed by 3410

Abstract

Connective tissue growth factor (CTGF) plays important roles in the development and regeneration of the connective tissue, yet its function in the nervous system is still not clear. CTGF is expressed in some distinct regions of the brain, including the dorsal endopiriform nucleus [...] Read more.

Connective tissue growth factor (CTGF) plays important roles in the development and regeneration of the connective tissue, yet its function in the nervous system is still not clear. CTGF is expressed in some distinct regions of the brain, including the dorsal endopiriform nucleus (DEPN) which has been recognized as an epileptogenic zone. We generated a forebrain-specific Ctgf knockout (FbCtgf KO) mouse line in which the expression of Ctgf in the DEPN is eliminated. In this study, we adopted a pentylenetetrazole (PTZ)-induced seizure model and found similar severity and latencies to death between FbCtgf KO and WT mice. Interestingly, there was a delay in the seizure reactions in the mutant mice. We further observed reduced c-fos expression subsequent to PTZ treatment in the KO mice, especially in the hippocampus. While the densities of astrocytes and microglia in the hippocampus were kept constant after acute PTZ treatment, microglial morphology was different between genotypes. Our present study demonstrated that in the FbCtgf KO mice, PTZ failed to increase neuronal activity and microglial response in the hippocampus. Our results suggested that inhibition of Ctgf function may have a therapeutic potential in preventing the pathophysiology of epilepsy. Full article

(This article belongs to the Special Issue Neuronal, Glial, and Immune Changes in Models of Epilepsy and Epileptogenesis)

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13 pages, 1813 KiB

Open AccessCommunication

Macrophage Migration Inhibitory Factor Alters Functional Properties of CA1 Hippocampal Neurons in Mouse Brain Slices

by Eric Bancroft, Rahul Srinivasan and Lee A. Shapiro

Int. J. Mol. Sci. 2020, 21(1), 276; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010276 - 31 Dec 2019

Cited by 5 | Viewed by 3268

Abstract

Neuroinflammation is implicated in a host of neurological insults, such as traumatic brain injury (TBI), ischemic stroke, Alzheimer’s disease, Parkinson’s disease, and epilepsy. The immune response to central nervous system (CNS) injury involves sequelae including the release of numerous cytokines and chemokines. Macrophage [...] Read more.

Neuroinflammation is implicated in a host of neurological insults, such as traumatic brain injury (TBI), ischemic stroke, Alzheimer’s disease, Parkinson’s disease, and epilepsy. The immune response to central nervous system (CNS) injury involves sequelae including the release of numerous cytokines and chemokines. Macrophage migration inhibitory factor (MIF), is one such cytokine that is elevated following CNS injury, and is associated with the prognosis of TBI, and ischemic stroke. MIF has been identified in astrocytes and neurons, and some of the trophic actions of MIF have been related to its direct and indirect actions on astrocytes. However, the potential modulation of CNS neuronal function by MIF has not yet been explored. This study tests the hypothesis that MIF can directly influence hippocampal neuronal function. MIF was microinjected into the hippocampus and the genetically encoded calcium indicator, GCaMP6f, was used to measure Ca²⁺ events in acute adult mouse brain hippocampal slices. Results demonstrated that a single injection of 200 ng MIF into the hippocampus significantly increased baseline calcium signals in CA1 pyramidal neuron somata, and altered calcium responses to N-methyl-d-aspartate (NMDA) + D-serine in pyramidal cell apical dendrites located in the stratum radiatum. These data are the first to show direct effects of MIF on hippocampal neurons and on NMDA receptor function. Considering that MIF is elevated after brain insults such as TBI, the data suggest that, in addition to the previously described role of MIF in astrocyte reactivity, elevated MIF can have significant effects on neuronal function in the hippocampus. Full article

(This article belongs to the Special Issue Neuronal, Glial, and Immune Changes in Models of Epilepsy and Epileptogenesis)

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15 pages, 4633 KiB

Open AccessArticle

Intranasally Administered Human MSC-Derived Extracellular Vesicles Pervasively Incorporate into Neurons and Microglia in both Intact and Status Epilepticus Injured Forebrain

by Maheedhar Kodali, Olagide W. Castro, Dong-Ki Kim, Alicia Thomas, Bing Shuai, Sahithi Attaluri, Raghavendra Upadhya, Daniel Gitai, Leelavathi N. Madhu, Darwin J. Prockop and Ashok K. Shetty

Int. J. Mol. Sci. 2020, 21(1), 181; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010181 - 26 Dec 2019

Cited by 69 | Viewed by 6672

Abstract

Extracellular vesicles (EVs) derived from human bone marrow mesenchymal stem cells (hMSCs) have great promise as biologics to treat neurological and neurodegenerative conditions due to their robust antiinflammatory and neuroprotective properties. Besides, intranasal (IN) administration of EVs has caught much attention because the [...] Read more.

Extracellular vesicles (EVs) derived from human bone marrow mesenchymal stem cells (hMSCs) have great promise as biologics to treat neurological and neurodegenerative conditions due to their robust antiinflammatory and neuroprotective properties. Besides, intranasal (IN) administration of EVs has caught much attention because the procedure is noninvasive, amenable for repetitive dispensation, and leads to a quick penetration of EVs into multiple regions of the forebrain. Nonetheless, it is unknown whether brain injury-induced signals are essential for the entry of IN-administered EVs into different brain regions. Therefore, in this study, we investigated the distribution of IN-administered hMSC-derived EVs into neurons and microglia in the intact and status epilepticus (SE) injured rat forebrain. Ten billion EVs labeled with PKH26 were dispensed unilaterally into the left nostril of naïve rats, and rats that experienced two hours of kainate-induced SE. Six hours later, PKH26 + EVs were quantified from multiple forebrain regions using serial brain sections processed for different neural cell markers and confocal microscopy. Remarkably, EVs were seen bilaterally in virtually all regions of intact and SE-injured forebrain. The percentage of neurons incorporating EVs were comparable for most forebrain regions. However, in animals that underwent SE, a higher percentage of neurons incorporated EVs in the hippocampal CA1 subfield and the entorhinal cortex, the regions that typically display neurodegeneration after SE. In contrast, the incorporation of EVs by microglia was highly comparable in every region of the forebrain measured. Thus, unilateral IN administration of EVs is efficient for delivering EVs bilaterally into neurons and microglia in multiple regions in the intact or injured forebrain. Furthermore, incorporation of EVs by neurons is higher in areas of brain injury, implying that injury-related signals likely play a role in targeting of EVs into neurons, which may be beneficial for EV therapy in various neurodegenerative conditions including traumatic brain injury, stroke, multiple sclerosis, and Alzheimer’s disease. Full article

(This article belongs to the Special Issue Neuronal, Glial, and Immune Changes in Models of Epilepsy and Epileptogenesis)

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Review

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13 pages, 909 KiB

Open AccessReview

Unravelling the Role of Glycogen Synthase Kinase-3 in Alzheimer’s Disease-Related Epileptic Seizures

by Runxuan Lin, Nigel Charles Jones and Patrick Kwan

Int. J. Mol. Sci. 2020, 21(10), 3676; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103676 - 23 May 2020

Cited by 14 | Viewed by 2589

Abstract

Alzheimer’s disease (AD) is the most common form of dementia. An increasing body of evidence describes an elevated incidence of epilepsy in patients with AD, and many transgenic animal models of AD also exhibit seizures and susceptibility to epilepsy. However, the biological mechanisms [...] Read more.

Alzheimer’s disease (AD) is the most common form of dementia. An increasing body of evidence describes an elevated incidence of epilepsy in patients with AD, and many transgenic animal models of AD also exhibit seizures and susceptibility to epilepsy. However, the biological mechanisms that underlie the occurrence of seizure or increased susceptibility to seizures in AD is unknown. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates various cellular signaling pathways, and plays a crucial role in the pathogenesis of AD. It has been suggested that GSK-3 might be a key factor that drives epileptogenesis in AD by interacting with the pathological hallmarks of AD, amyloid precursor protein (APP) and tau. Furthermore, seizures may also contribute to the progression of AD through GSK-3. In this way, GSK-3 might be involved in initiating a vicious cycle between AD and seizures. This review aims to summarise the possible role of GSK-3 in the link between AD and seizures. Understanding the role of GSK-3 in AD-associated seizures and epilepsy may help researchers develop new therapeutic approach that can manage seizure and epilepsy in AD patients as well as decelerate the progression of AD. Full article

(This article belongs to the Special Issue Neuronal, Glial, and Immune Changes in Models of Epilepsy and Epileptogenesis)

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19 pages, 1519 KiB

Open AccessReview

Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

by Wolfgang Löscher and Alon Friedman

Int. J. Mol. Sci. 2020, 21(2), 591; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020591 - 16 Jan 2020

Cited by 121 | Viewed by 8973

Abstract

The blood-brain barrier (BBB) is a dynamic, highly selective barrier primarily formed by endothelial cells connected by tight junctions that separate the circulating blood from the brain extracellular fluid. The endothelial cells lining the brain microvessels are under the inductive influence of neighboring [...] Read more.

The blood-brain barrier (BBB) is a dynamic, highly selective barrier primarily formed by endothelial cells connected by tight junctions that separate the circulating blood from the brain extracellular fluid. The endothelial cells lining the brain microvessels are under the inductive influence of neighboring cell types, including astrocytes and pericytes. In addition to the anatomical characteristics of the BBB, various specific transport systems, enzymes and receptors regulate molecular and cellular traffic across the BBB. While the intact BBB prevents many macromolecules and immune cells from entering the brain, following epileptogenic brain insults the BBB changes its properties. Among BBB alterations, albumin extravasation and diapedesis of leucocytes from blood into brain parenchyma occur, inducing or contributing to epileptogenesis. Furthermore, seizures themselves may modulate BBB functions, permitting albumin extravasation, leading to activation of astrocytes and the innate immune system, and eventually modifications of neuronal networks. BBB alterations following seizures are not necessarily associated with enhanced drug penetration into the brain. Increased expression of multidrug efflux transporters such as P-glycoprotein likely act as a ‘second line defense’ mechanism to protect the brain from toxins. A better understanding of the complex alterations in BBB structure and function following seizures and in epilepsy may lead to novel therapeutic interventions allowing the prevention and treatment of epilepsy as well as other detrimental neuro-psychiatric sequelae of brain injury. Full article

(This article belongs to the Special Issue Neuronal, Glial, and Immune Changes in Models of Epilepsy and Epileptogenesis)

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