Publications by authors named "Madhuvika Murugan"

32 Publications

The Good, the Bad, and the Deadly: Adenosinergic Mechanisms Underlying Sudden Unexpected Death in Epilepsy.

Front Neurosci 2021 12;15:708304. Epub 2021 Jul 12.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States.

Adenosine is an inhibitory modulator of neuronal excitability. Neuronal activity results in increased adenosine release, thereby constraining excessive excitation. The exceptionally high neuronal activity of a seizure results in a surge in extracellular adenosine to concentrations many-fold higher than would be observed under normal conditions. In this review, we discuss the multifarious effects of adenosine signaling in the context of epilepsy, with emphasis on sudden unexpected death in epilepsy (SUDEP). We describe and categorize the beneficial, detrimental, and potentially deadly aspects of adenosine signaling. The good or beneficial characteristics of adenosine signaling in the context of seizures include: (1) its direct effect on seizure termination and the prevention of status epilepticus; (2) the vasodilatory effect of adenosine, potentially counteracting postictal vasoconstriction; (3) its neuroprotective effects under hypoxic conditions; and (4) its disease modifying antiepileptogenic effect. The bad or detrimental effects of adenosine signaling include: (1) its capacity to suppress breathing and contribute to peri-ictal respiratory dysfunction; (2) its contribution to postictal generalized EEG suppression (PGES); (3) the prolonged increase in extracellular adenosine following spreading depolarization waves may contribute to postictal neuronal dysfunction; (4) the excitatory effects of A receptor activation is thought to exacerbate seizures in some instances; and (5) its potential contributions to sleep alterations in epilepsy. Finally, the adverse effects of adenosine signaling may potentiate a deadly outcome in the form of SUDEP by suppressing breathing and arousal in the postictal period. Evidence from animal models suggests that excessive postictal adenosine signaling contributes to the pathophysiology of SUDEP. The goal of this review is to discuss the beneficial, harmful, and potentially deadly roles that adenosine plays in the context of epilepsy and to identify crucial gaps in knowledge where further investigation is necessary. By better understanding adenosine dynamics, we may gain insights into the treatment of epilepsy and the prevention of SUDEP.
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http://dx.doi.org/10.3389/fnins.2021.708304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311182PMC
July 2021

Adenosine kinase: An epigenetic modulator in development and disease.

Neurochem Int 2021 Jul 5;147:105054. Epub 2021 May 5.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA; Department of Neurosurgery, New Jersey Medical School, Rutgers University, Newark, NJ 07102, USA; Brain Health Institute, Rutgers University, Piscataway, NJ 08854, USA. Electronic address:

Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5'-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). The two isoforms are developmentally regulated and are differentially expressed in distinct subcellular compartments with ADK-L localized in the nucleus and ADK-S localized in the cytoplasm. The nuclear localization of ADK-L and its biochemical link to the transmethylation pathway suggest a specific role for gene regulation via epigenetic mechanisms. Recent evidence reveals an adenosine receptor-independent role of ADK in determining the global methylation status of DNA and thereby contributing to epigenomic regulation. Here we summarize recent progress in understanding the biochemical interactions between adenosine metabolism by ADK-L and epigenetic modifications linked to transmethylation reactions. This review will provide a comprehensive overview of ADK-associated changes in DNA methylation in developmental, as well as in pathological conditions including brain injury, epilepsy, vascular diseases, cancer, and diabetes. Challenges in investigating the epigenetic role of ADK for therapeutic gains are briefly discussed.
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http://dx.doi.org/10.1016/j.neuint.2021.105054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178237PMC
July 2021

Possible Role of Adenosine in COVID-19 Pathogenesis and Therapeutic Opportunities.

Front Pharmacol 2020 26;11:594487. Epub 2020 Nov 26.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States.

The outbreak of the novel coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) requires urgent clinical interventions. Crucial clinical needs are: 1) prevention of infection and spread of the virus within lung epithelia and between people, 2) attenuation of excessive lung injury in Advanced Respiratory Distress Syndrome, which develops during the end stage of the disease, and 3) prevention of thrombosis associated with SARS-CoV-2 infection. Adenosine and the key adenosine regulators adenosine deaminase (ADA), adenosine kinase (ADK), and equilibrative nucleoside transporter 1 may play a role in COVID-19 pathogenesis. Here, we highlight 1) the non-enzymatic role of ADA by which it might out-compete the virus (SARS-CoV-2) for binding to the CD26 receptor, 2) the enzymatic roles of ADK and ADA to increase adenosine levels and ameliorate Advanced Respiratory Distress Syndrome, and 3) inhibition of adenosine transporters to reduce platelet activation, thrombosis and improve COVID-19 outcomes. Depending on the stage of exposure to and infection by SARS-CoV-2, enhancing adenosine levels by targeting key adenosine regulators such as ADA, ADK and equilibrative nucleoside transporter 1 might find therapeutic use against COVID-19 and warrants further investigation.
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http://dx.doi.org/10.3389/fphar.2020.594487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726428PMC
November 2020

Suppression of phrenic nerve activity as a potential predictor of imminent sudden unexpected death in epilepsy (SUDEP).

Neuropharmacology 2021 02 16;184:108405. Epub 2020 Nov 16.

Department of Neurosurgery, Robert Wood Johnson and New Jersey Medical Schools, Rutgers University, Piscataway, NJ, 08854, USA; Brain Health Institute, Rutgers University, Piscataway, NJ, 08854, USA; Rutgers Neurosurgery H.O.P.E. Center, Department of Neurosurgery, Rutgers University, New Brunswick, NJ, 08901, USA. Electronic address:

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in patients with refractory epilepsy. Centrally-mediated respiratory dysfunction has been identified as one of the principal mechanisms responsible for SUDEP. Seizures generate a surge in adenosine release. Elevated adenosine levels suppress breathing. Insufficient metabolic clearance of a seizure-induced adenosine surge might be a precipitating factor in SUDEP. In order to deliver targeted therapies to prevent SUDEP, reliable biomarkers must be identified to enable prompt intervention. Because of the integral role of the phrenic nerve in breathing, we hypothesized that suppression of phrenic nerve activity could be utilized as predictive biomarker for imminent SUDEP. We used a rat model of kainic acid-induced seizures in combination with pharmacological suppression of metabolic adenosine clearance to trigger seizure-induced death in tracheostomized rats. Recordings of EEG, blood pressure, and phrenic nerve activity were made concomitant to the seizure. We found suppression of phrenic nerve burst frequency to 58.9% of baseline (p < 0.001, one-way ANOVA) which preceded seizure-induced death; importantly, irregularities of phrenic nerve activity were partly reversible by the adenosine receptor antagonist caffeine. Suppression of phrenic nerve activity may be a useful biomarker for imminent SUDEP. The ability to reliably detect the onset of SUDEP may be instrumental in the timely administration of potentially lifesaving interventions.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199795PMC
February 2021

The voltage-gated proton channel Hv1 contributes to neuronal injury and motor deficits in a mouse model of spinal cord injury.

Mol Brain 2020 10 20;13(1):143. Epub 2020 Oct 20.

Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.

Traumatic injury to the spinal cord initiates a series of pathological cellular processes that exacerbate tissue damage at and beyond the original site of injury. This secondary damage includes oxidative stress and inflammatory cascades that can lead to further neuronal loss and motor deficits. Microglial activation is an essential component of these secondary signaling cascades. The voltage-gated proton channel, Hv1, functionally expressed in microglia has been implicated in microglia polarization and oxidative stress in ischemic stroke. Here, we investigate whether Hv1 mediates microglial/macrophage activation and aggravates secondary damage following spinal cord injury (SCI). Following contusion SCI, wild-type (WT) mice showed significant tissue damage, white matter damage and impaired motor recovery. However, mice lacking Hv1 (Hv1) showed significant white matter sparing and improved motor recovery. The improved motor recovery in Hv1 mice was associated with decreased interleukin-1β, reactive oxygen/ nitrogen species production and reduced neuronal loss. Further, deficiency of Hv1 directly influenced microglia activation as noted by decrease in microglia numbers, soma size and reduced outward rectifier K current density in Hv1 mice compared to WT mice at 7 d following SCI. Our results therefore implicate that Hv1 may be a promising potential therapeutic target to alleviate secondary damage following SCI caused by microglia/macrophage activation.
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http://dx.doi.org/10.1186/s13041-020-00682-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574559PMC
October 2020

Ketogenic diet, neuroprotection, and antiepileptogenesis.

Epilepsy Res 2020 11 19;167:106444. Epub 2020 Aug 19.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, United States; Department of Neurosurgery, New Jersey Medical School, Rutgers University, Newark, NJ 07102, United States; Rutgers Neurosurgery H.O.P.E. Center, Department of Neurosurgery, Rutgers University, New Brunswick, NJ 08901, United States. Electronic address:

High fat, low carbohydrate ketogenic diets (KD) have been in use for the treatment of epilepsy for almost a hundred years. Remarkably, seizures that are resistant to conventional anti-seizure drugs can in many cases be controlled by the KD therapy, and it has been shown that many patients with epilepsy become seizure free even after discontinuation of the diet. These findings suggest that KD combine anti-seizure effects with disease modifying effects. In addition to the treatment of epilepsy, KDs are now widely used for the treatment of a wide range of conditions including weight reduction, diabetes, and cancer. The reason for the success of metabolic therapies is based on the synergism of at least a dozen different mechanisms through which KDs provide beneficial activities. Among the newest findings are epigenetic mechanisms (DNA methylation and histone acetylation) through which KD exerts long-lasting disease modifying effects. Here we review mechanisms through which KD can affect neuroprotection in the brain, and how a combination of those mechanisms with epigenetic alterations can attenuate and possibly reverse the development of epilepsy.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655615PMC
November 2020

Chemokine signaling mediated monocyte infiltration affects anxiety-like behavior following blast injury.

Brain Behav Immun 2020 08 30;88:340-352. Epub 2020 Mar 30.

Department of Biomedical Engineering, Center for Injury Biomechanics Materials and Medicine, New Jersey Institute of Technology, Newark, NJ 07102, United States. Electronic address:

The activation of resident microglia and infiltrated monocytes are known potent mediators of chronic neuroinflammation following traumatic brain injury (TBI). In this study, we use a mouse model of blast-induced TBI (bTBI) to investigate whether microglia and monocytes contribute to the neuroinflammatory and behavioral consequences of bTBI. Eight-ten week old mice were subject to moderate TBI (180 kPa) in a shock tube. Using double transgenic CCR2 CX3CR1 mice, we were able to note that in addition to resident Cx3CR1+ microglia, infiltrating CCR2+ monocytes also contributed to the expanding macrophage population that was observed after bTBI. The microglia activation and monocyte infiltration occurred as early as 4 h and lasted up to 30d after blast exposure, suggesting chronic inflammation. The infiltration of monocytes may be partly mediated by chemokine CCL2-CCR2 signaling axis and compromised blood brain barrier permeability. Hence, bTBI-induced infiltration of monocytes and production of IL-1β were prevented in mice lacking CCR2 (CCR2 KO). Finally, this study showed that interference of monocyte infiltration using CCR2 KO, ameliorated the chronic effects of bTBI such as anxiety-like behavior and short-term memory decline. Taken together, these data suggest that bTBI leads to activation of both resident microglia and infiltrated monocytes. The infiltration of monocytes was partly mediated by CCL2-CCR2 signaling, which in turn contributes to increased production of IL-1β leading to behavioral deficits after bTBI. Furthermore, bTBI induced behavioral outcomes were reduced by targeting CCL2-CCR2 signaling, highlighting the significance of this signaling axis in bTBI pathology.
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http://dx.doi.org/10.1016/j.bbi.2020.03.029DOI Listing
August 2020

Microglia Are Indispensable for Synaptic Plasticity in the Spinal Dorsal Horn and Chronic Pain.

Cell Rep 2019 06;27(13):3844-3859.e6

Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

Spinal long-term potentiation (LTP) at C-fiber synapses is hypothesized to underlie chronic pain. However, a causal link between spinal LTP and chronic pain is still lacking. Here, we report that high-frequency stimulation (HFS; 100 Hz, 10 V) of the mouse sciatic nerve reliably induces spinal LTP without causing nerve injury. LTP-inducible stimulation triggers chronic pain lasting for more than 35 days and increases the number of calcitonin gene-related peptide (CGRP) terminals in the spinal dorsal horn. The behavioral and morphological changes can be prevented by blocking NMDA receptors, ablating spinal microglia, or conditionally deleting microglial brain-derived neurotrophic factor (BDNF). HFS-induced spinal LTP, microglial activation, and upregulation of BDNF are inhibited by antibodies against colony-stimulating factor 1 (CSF-1). Together, our results show that microglial CSF1 and BDNF signaling are indispensable for spinal LTP and chronic pain. The microglia-dependent transition of synaptic potentiation to structural alterations in pain pathways may underlie pain chronicity.
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http://dx.doi.org/10.1016/j.celrep.2019.05.087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060767PMC
June 2019

Microglial proliferation and monocyte infiltration contribute to microgliosis following status epilepticus.

Glia 2019 08 5;67(8):1434-1448. Epub 2019 Apr 5.

Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers University, Piscataway, New Jersey.

Microglial activation has been recognized as a major contributor to inflammation of the epileptic brain. Seizures are commonly accompanied by remarkable microgliosis and loss of neurons. In this study, we utilize the CX3CR1 CCR2 genetic mouse model, in which CX3CR1 resident microglia and CCR2 monocytes are labeled with GFP and RFP, respectively. Using a combination of time-lapse two-photon imaging and whole-cell patch clamp recording, we determined the distinct morphological, dynamic, and electrophysiological characteristics of infiltrated monocytes and resident microglia, and the evolution of their behavior at different time points following kainic acid-induced seizures. Seizure activated microglia presented enlarged somas with less ramified processes, whereas, infiltrated monocytes were smaller, highly motile cells that lacked processes. Moreover, resident microglia, but not infiltrated monocytes, proliferate locally in the hippocampus after seizure. Microglial proliferation was dependent on the colony-stimulating factor 1 receptor (CSF-1R) pathway. Pharmacological inhibition of CSF-1R reduced seizure-induced microglial proliferation, which correlated with attenuation of neuronal death without altering acute seizure behaviors. Taken together, we demonstrated that proliferation of activated resident microglia contributes to neuronal death in the hippocampus via CSF-1R after status epilepticus, providing potential therapeutic targets for neuroprotection in epilepsy.
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http://dx.doi.org/10.1002/glia.23616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559368PMC
August 2019

Microglia Receptors in Animal Models of Traumatic Brain Injury.

Mol Neurobiol 2019 Jul 16;56(7):5202-5228. Epub 2018 Dec 16.

Department of Bioengineering, New Jersey Institute of Technology, 111 Lock Street, Room105 CHEN bldg, Newark, NJ, 07102, USA.

Microglia have been implicated as a key mediator of chronic inflammation following traumatic brain injury (TBI). The animal models of TBI vary significantly based on the type of brain injury (focal versus diffuse). This has made it extremely difficult to assess the role of microglia and the window of microglia activation. Hence, the focus of this review is to summarize the time course of microglia activation in various animal models of TBI. The review explores the repertoire of secondary injury mechanisms such as aberrant neurotransmitter release, oxidative stress, blood-brain barrier disruption, and production of pro-inflammatory cytokines that follow microglia activation. Since receptors act as sensors for activation, we highlight certain microglia receptors that have been implicated in TBI pathology, including fractalkine receptor (CX3CR1), purinergic receptor (P2Y12R), Toll-like receptor (TLR4), scavenger receptors, tumor necrosis factor receptor (TNF-1R), interleukin receptor (IL-1R), complement receptors, and peroxisome proliferator-activated receptor (PPAR). In addition to describing their downstream signaling pathways in TBI, we describe the functional consequences of their activation and the implication in behavioral outcomes. Taken together, this review will provide a holistic view of the role of microglia and its receptors in TBI based on animal studies.
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http://dx.doi.org/10.1007/s12035-018-1428-7DOI Listing
July 2019

P2Y12R-Dependent Translocation Mechanisms Gate the Changing Microglial Landscape.

Cell Rep 2018 04;23(4):959-966

Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA; Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address:

Microglia are an exquisitely tiled and self-contained population in the CNS that do not receive contributions from circulating monocytes in the periphery. While microglia are long-lived cells, the extent to which their cell bodies are fixed and the molecular mechanisms by which the microglial landscape is regulated have not been determined. Using chronic in vivo two-photon imaging to follow the microglial population in young adult mice, we document a daily rearrangement of the microglial landscape. Furthermore, we show that the microglial landscape can be modulated by severe seizures, acute injury, and sensory deprivation. Finally, we demonstrate a critical role for microglial P2Y12Rs in regulating the microglial landscape through cellular translocation independent of proliferation. These findings suggest that microglial patrol the CNS through both process motility and soma translocation.
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http://dx.doi.org/10.1016/j.celrep.2018.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965271PMC
April 2018

The GluN2A Subunit Regulates Neuronal NMDA receptor-Induced Microglia-Neuron Physical Interactions.

Sci Rep 2018 01 16;8(1):828. Epub 2018 Jan 16.

Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.

Microglia are known to engage in physical interactions with neurons. However, our understanding of the detailed mechanistic regulation of microglia-neuron interactions is incomplete. Here, using high resolution two photon imaging, we investigated the regulation of NMDA receptor-induced microglia-neuron physical interactions. We found that the GluN2A inhibitor NVPAAM007, but not the GluN2B inhibitor ifenprodil, blocked the occurrence of these interactions. Consistent with the well-known developmental regulation of the GluN2A subunit, these interactions are absent in neonatal tissues. Furthermore, consistent with a preferential synaptic localization of GluN2A subunits, there is a differential sensitivity of their occurrence between denser (stratum radiatum) and less dense (stratum pyramidale) synaptic sub-regions of the CA1. Finally, consistent with differentially expressed GluN2A subunits in the CA1 and DG areas of the hippocampus, these interactions could not be elicited in the DG despite robust microglial chemotactic capabilities. Together, these results enhance our understanding of the mechanistic regulation of NMDA receptor-dependent microglia-neuronal physical interactions phenomena by the GluN2A subunit that may be relevant in the mammalian brain during heightened glutamatergic neurotransmission such as epilepsy and ischemic stroke.
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http://dx.doi.org/10.1038/s41598-018-19205-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770428PMC
January 2018

Microglial interactions with the neurovascular system in physiology and pathology.

Dev Neurobiol 2018 06 1;78(6):604-617. Epub 2018 Feb 1.

Department of Neurology, Mayo Clinic, Rochester, Minnesota.

Microglia as immune cells of the central nervous system (CNS) play significant roles not only in pathology but also in physiology, such as shaping of the CNS during development and its proper maintenance in maturity. Emerging research is showing a close association between microglia and the neurovasculature that is critical for brain energy supply. In this review, we summarize the current literature on microglial interaction with the vascular system in the normal and diseased brain. First, we highlight data that indicate interesting potential involvement of microglia in developmental angiogenesis. Then we discuss the evidence for microglial participation with the vasculature in neuropathologies from brain tumors to acute injuries such as ischemic stroke to chronic neurodegenerative conditions. We conclude by suggesting future areas of research to advance the field in light of current technical progress and outstanding questions. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 604-617, 2018.
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http://dx.doi.org/10.1002/dneu.22576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980686PMC
June 2018

Fingolimod Protects Against Ischemic White Matter Damage by Modulating Microglia Toward M2 Polarization via STAT3 Pathway.

Stroke 2017 12 7;48(12):3336-3346. Epub 2017 Nov 7.

From the Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (C.Q., W.-H.F., Q.L., K.S., W.W., D.-S.T.); Department of Neurology, General Hospital of the Yangtze River Shipping, Wuhan, China (W.-H.F.); Department of Neurology, Mayo Clinic, Rochester, MN (M.M., L.-J.W.); and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (M.M., L.-J.W.).

Background And Purpose: White matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of demyelination after WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model.

Methods: Chronic WM ischemic injury model was induced by bilateral carotid artery stenosis. Cognitive function, WM integrity, microglial activation, and potential pathway involved in microglial polarization were assessed after bilateral carotid artery stenosis.

Results: Disruption of WM integrity was characterized by demyelination in the corpus callosum and disorganization of Ranvier nodes using Luxol fast blue staining, immunofluorescence staining, and electron microscopy. In addition, radial maze test demonstrated that working memory performance was decreased at 1-month post-bilateral carotid artery stenosis-induced injury. Interestingly, FTY720 could reduce cognitive decline and ameliorate the disruption of WM integrity. Mechanistically, cerebral hypoperfusion induced microglial activation, production of associated proinflammatory cytokines, and priming of microglial polarization toward the M1 phenotype, whereas FTY720 attenuated microglia-mediated neuroinflammation after WM ischemia and promoted oligodendrocytogenesis by shifting microglia toward M2 polarization. FTY720's effect on microglial M2 polarization was largely suppressed by selective signal transducer and activator of transcription 3 (STAT3) blockade in vitro, revealing that FTY720-enabled shift of microglia from M1 to M2 polarization state was possibly mediated by STAT3 signaling.

Conclusions: Our study suggested that FTY720 might be a potential therapeutic drug targeting brain inflammation by skewing microglia toward M2 polarization after chronic cerebral hypoperfusion.
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http://dx.doi.org/10.1161/STROKEAHA.117.018505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728178PMC
December 2017

Chemokine CCL2-CCR2 Signaling Induces Neuronal Cell Death via STAT3 Activation and IL-1β Production after Status Epilepticus.

J Neurosci 2017 08 17;37(33):7878-7892. Epub 2017 Jul 17.

Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers University, Piscataway, New Jersey 08854, and

Elevated levels of chemokine C-C motif ligand 2 (CCL2) and its receptor CCR2 have been reported in patients with temporal lobe epilepsy and in experimental seizures. However, the functional significance and molecular mechanism underlying CCL2-CCR2 signaling in epileptic brain remains largely unknown. In this study, we found that the upregulated CCL2 was mainly expressed in hippocampal neurons and activated microglia from mice 1 d after kainic acid (KA)-induced seizures. Taking advantage of double-transgenic mice, we demonstrated that CCL2-CCR2 signaling has a role in resident microglial activation and blood-derived monocyte infiltration. Moreover, seizure-induced degeneration of neurons in the hippocampal CA3 region was attenuated in mice lacking CCL2 or CCR2. We further showed that CCR2 activation induced STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL-1β production, which are critical for promoting neuronal cell death after status epilepticus. Consistently, pharmacological inhibition of STAT3 by WP1066 reduced seizure-induced IL-1β production and subsequent neuronal death. Two weeks after KA-induced seizures, CCR2 deficiency not only reduced neuronal loss, but also attenuated seizure-induced behavioral impairments, including anxiety, memory decline, and recurrent seizure severity. Together, we demonstrated that CCL2-CCR2 signaling contributes to neurodegeneration via STAT3 activation and IL-1β production after status epilepticus, providing potential therapeutic targets for the treatment of epilepsy. Epilepsy is a global concern and epileptic seizures occur in many neurological conditions. Neuroinflammation associated with microglial activation and monocyte infiltration are characteristic of epileptic brains. However, molecular mechanisms underlying neuroinflammation in neuronal death following epilepsy remain to be elucidated. Here we demonstrate that CCL2-CCR2 signaling is required for monocyte infiltration, which in turn contributes to kainic acid (KA)-induced neuronal cell death. The downstream of CCR2 activation involves STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL-1β production. Two weeks after KA-induced seizures, CCR2 deficiency not only reduced neuronal loss, but also attenuated seizure-induced behavioral impairments, including anxiety, memory decline, and recurrent seizure severity. The current study provides a novel insight on the function and mechanisms of CCL2-CCR2 signaling in KA-induced neurodegeneration and behavioral deficits.
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http://dx.doi.org/10.1523/JNEUROSCI.0315-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559763PMC
August 2017

TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury.

J Neurosci 2017 01;37(4):871-881

Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China,

Clinical studies show that chronic pain is accompanied by memory deficits and reduction in hippocampal volume. Experimental studies show that spared nerve injury (SNI) of the sciatic nerve induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn, but impairs LTP in the hippocampus. The opposite changes may contribute to neuropathic pain and memory deficits, respectively. However, the cellular and molecular mechanisms underlying the functional synaptic changes are unclear. Here, we show that the dendrite lengths and spine densities are reduced significantly in hippocampal CA1 pyramidal neurons, but increased in spinal neurokinin-1-positive neurons in mice after SNI, indicating that the excitatory synaptic connectivity is reduced in hippocampus but enhanced in spinal dorsal horn in this neuropathic pain model. Mechanistically, tumor necrosis factor-alpha (TNF-α) is upregulated in bilateral hippocampus and in ipsilateral spinal dorsal horn, whereas brain-derived neurotrophic factor (BDNF) is decreased in the hippocampus but increased in the ipsilateral spinal dorsal horn after SNI. Importantly, the SNI-induced opposite changes in synaptic connectivity and BDNF expression are prevented by genetic deletion of TNF receptor 1 in vivo and are mimicked by TNF-α in cultured slices. Furthermore, SNI activated microglia in both spinal dorsal horn and hippocampus; pharmacological inhibition or genetic ablation of microglia prevented the region-dependent synaptic changes, neuropathic pain, and memory deficits induced by SNI. The data suggest that neuropathic pain involves different structural synaptic alterations in spinal and hippocampal neurons that are mediated by overproduction of TNF-α and microglial activation and may underlie chronic pain and memory deficits.

Significance Statement: Chronic pain is often accompanied by memory deficits. Previous studies have shown that peripheral nerve injury produces both neuropathic pain and memory deficits and induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn (SDH) but inhibits LTP in hippocampus. The opposite changes in synaptic plasticity may contribute to chronic pain and memory deficits, respectively. However, the structural and molecular bases of these alterations of synaptic plasticity are unclear. Here, we show that the complexity of excitatory synaptic connectivity and brain-derived neurotrophic factor (BDNF) expression are enhanced in SDH but reduced in the hippocampus in neuropathic pain and the opposite changes depend on tumor necrosis factor-alpha/tumor necrosis factor receptor 1 signaling and microglial activation. The region-dependent synaptic alterations may underlie chronic neuropathic pain and memory deficits induced by peripheral nerve injury.
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http://dx.doi.org/10.1523/JNEUROSCI.2235-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296781PMC
January 2017

Regulation of Physical Microglia-Neuron Interactions by Fractalkine Signaling after Status Epilepticus.

eNeuro 2016 Nov-Dec;3(6). Epub 2017 Jan 16.

Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854; Department of Neurology, Mayo Clinic, Rochester, MN 55905.

Microglia, the resident immune cells of the brain, perform elaborate surveillance in which they physically interact with neuronal elements. A novel form of microglia-neuron interaction named microglial process convergence (MPC) toward neuronal axons and dendrites has recently been described. However, the molecular regulators and pathological relevance of MPC have not been explored. Here, using high-resolution two-photon imaging and , we observed a dramatic increase in MPCs after kainic acid- or pilocarpine-induced experimental seizures that was reconstituted after glutamate treatment in slices from mice. Interestingly, a deficiency of the fractalkine receptor (CX3CR1) decreased MPCs, whereas fractalkine (CX3CL1) treatment increased MPCs, suggesting that fractalkine signaling is a critical regulator of these microglia-neuron interactions. Furthermore, we found that interleukin-1β was necessary and sufficient to trigger CX3CR1-dependent MPCs. Finally, we show that a deficiency in fractalkine signaling corresponds with increased seizure phenotypes. Together, our results identify the neuroglial CX3CL1-CX3CR1 communication axis as a modulator of potentially neuroprotective microglia-neuron physical interactions during conditions of neuronal hyperactivity.
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http://dx.doi.org/10.1523/ENEURO.0209-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237828PMC
October 2017

Deficiency in the voltage-gated proton channel Hv1 increases M2 polarization of microglia and attenuates brain damage from photothrombotic ischemic stroke.

J Neurochem 2016 10 9;139(1):96-105. Epub 2016 Sep 9.

Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Microglia become activated during cerebral ischemia and exert pro-inflammatory or anti-inflammatory role dependent of microglial polarization. NADPH oxidase (NOX)-dependent reactive oxygen species (ROS) production in microglia plays an important role in neuronal damage after ischemic stroke. Recently, NOX and ROS are consistently reported to participate in the microglial activation and polarization; NOX2 inhibition or suppression of ROS production are shown to shift the microglial polarization from M1 toward M2 state after stroke. The voltage-gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX-dependent ROS generation in the brain. However, the effect of Hv1 proton channel on microglial M1/M2 polarization state after cerebral ischemia remains unknown. In this study, we investigated the role of microglial Hv1 proton channel in modulating microglial M1/M2 polarization during the pathogenesis of ischemic cerebral injury using a mouse model of photothrombosis. Following photothrombotic ischemic stroke, wild-type mice presented obvious brain infarct, neuronal damage, and impaired motor coordination. However, mice lacking Hv1 (Hv1(-/-)) were partially protected from brain damage and motor deficits compared to wild-type mice. These rescued phenotypes in Hv1(-/-) mice in ischemic stroke is accompanied by reduced ROS production, shifted the microglial polarization from M1 to M2 state. Hv1 deficiency was also found to shift the M1/M2 polarization in primary cultured microglia. Our study suggests that the microglial Hv1 proton channel is a unique target for modulation of microglial M1/M2 polarization in the pathogenesis of ischemic stroke. The voltage-gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX-dependent generation of reactive oxygen species (ROS) in the brain. ROS participate in microglial activation and polarization. However, the effect of Hv1 on microglial M1/M2 polarization state after cerebral ischemia remains unknown. Hv1 deficiency was found to shift the microglial polarization from M1 to M2 state in ischemic stroke accompanied by reduced ROS production. Our study suggests that the microglial Hv1 proton channel is a unique target for modulation of microglial M1/M2 polarization in the pathogenesis of ischemic stroke.
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http://dx.doi.org/10.1111/jnc.13751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037018PMC
October 2016

Spinal Microgliosis Due to Resident Microglial Proliferation Is Required for Pain Hypersensitivity after Peripheral Nerve Injury.

Cell Rep 2016 07 30;16(3):605-14. Epub 2016 Jun 30.

Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA. Electronic address:

Peripheral nerve injury causes neuropathic pain accompanied by remarkable microgliosis in the spinal cord dorsal horn. However, it is still debated whether infiltrated monocytes contribute to injury-induced expansion of the microglial population. Here, we found that spinal microgliosis predominantly results from local proliferation of resident microglia but not from infiltrating monocytes after spinal nerve transection (SNT) by using two genetic mouse models (CCR2(RFP/+):CX3CR1(GFP/+) and CX3CR1(creER/+):R26(tdTomato/+) mice) as well as specific staining of microglia and macrophages. Pharmacological inhibition of SNT-induced microglial proliferation correlated with attenuated neuropathic pain hypersensitivities. Microglial proliferation is partially controlled by purinergic and fractalkine signaling, as CX3CR1(-/-) and P2Y12(-/-) mice show reduced spinal microglial proliferation and neuropathic pain. These results suggest that local microglial proliferation is the sole source of spinal microgliosis, which represents a potential therapeutic target for neuropathic pain management.
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http://dx.doi.org/10.1016/j.celrep.2016.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956495PMC
July 2016

Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury.

Nat Commun 2016 06 28;7:12029. Epub 2016 Jun 28.

Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, USA.

Microglia and peripheral monocytes contribute to hypersensitivity in rodent models of neuropathic pain. However, the precise respective function of microglia and peripheral monocytes has not been investigated in these models. To address this question, here we combined transgenic mice and pharmacological tools to specifically and temporally control the depletion of microglia and monocytes in a mouse model of spinal nerve transection (SNT). We found that although microglia and monocytes are required during the initiation of mechanical allodynia or thermal hyperalgesia, these cells may not be as important for the maintenance of hypersensitivity. Moreover, we demonstrated that either resident microglia or peripheral monocytes are sufficient in gating neuropathic pain after SNT. We propose that resident microglia and peripheral monocytes act synergistically to initiate hypersensitivity and promote the transition from acute to chronic pain after peripheral nerve injury.
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http://dx.doi.org/10.1038/ncomms12029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931235PMC
June 2016

Microglia-Neuron Communication in Epilepsy.

Glia 2017 01 18;65(1):5-18. Epub 2016 May 18.

Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey.

Epilepsy has remained a significant social concern and financial burden globally. Current therapeutic strategies are based primarily on neurocentric mechanisms that have not proven successful in at least a third of patients, raising the need for novel alternative and complementary approaches. Recent evidence implicates glial cells and neuroinflammation in the pathogenesis of epilepsy with the promise of targeting these cells to complement existing strategies. Specifically, microglial involvement, as a major inflammatory cell in the epileptic brain, has been poorly studied. In this review, we highlight microglial reaction to experimental seizures, discuss microglial control of neuronal activities, and propose the functions of microglia during acute epileptic phenotypes, delayed neurodegeneration, and aberrant neurogenesis. Future research that would help fill in the current gaps in our knowledge includes epilepsy-induced alterations in basic microglial functions, neuro-microglial interactions during chronic epilepsy, and microglial contribution to developmental seizures. Studying the role of microglia in epilepsy could inform therapies to better alleviate the disease. GLIA 2016;65:5-18.
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http://dx.doi.org/10.1002/glia.23006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116010PMC
January 2017

Interleukin-1β overproduction is a common cause for neuropathic pain, memory deficit, and depression following peripheral nerve injury in rodents.

Mol Pain 2016 12;12. Epub 2016 May 12.

Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, China

Background: Chronic pain is often accompanied by short-term memory deficit and depression. Currently, it is believed that short-term memory deficit and depression are consequences of chronic pain. Here, we test the hypothesis that the symptoms might be caused by overproduction of interleukin-1beta (IL-1β) in the injured nerve independent of neuropathic pain following spared nerve injury in rats and mice.

Results: Mechanical allodynia, a behavioral sign of neuropathic pain, was not correlated with short-term memory deficit and depressive behavior in spared nerve injury rats. Spared nerve injury upregulated IL-1β in the injured sciatic nerve, plasma, and the regions in central nervous system closely associated with pain, memory and emotion, including spinal dorsal horn, hippocampus, prefrontal cortex, nucleus accumbens, and amygdala. Importantly, the spared nerve injury-induced memory deficits, depressive, and pain behaviors were substantially prevented by peri-sciatic administration of IL-1β neutralizing antibody in rats or deletion of IL-1 receptor type 1 in mice. Furthermore, the behavioral abnormalities induced by spared nerve injury were mimicked in naïve rats by repetitive intravenous injection of re combinant rat IL-1β (rrIL-1β) at a pathological concentration as determined from spared nerve injury rats. In addition, microglia were activated by both spared nerve injury and intravenous injection of rrIL-1β and the effect of spared nerve injury was substantially reversed by peri-sciatic administration of anti-IL-1β.

Conclusions: Neuropathic pain was not necessary for the development of cognitive and emotional disorders, while the overproduction of IL-1β in the injured sciatic nerve following peripheral nerve injury may be a common mechanism underlying the generation of neuropathic pain, memory deficit, and depression.
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http://dx.doi.org/10.1177/1744806916646784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956151PMC
December 2016

Facilitating Mitochondrial Calcium Uptake Improves Activation-Induced Cerebral Blood Flow and Behavior after mTBI.

Front Syst Neurosci 2016 8;10:19. Epub 2016 Mar 8.

Department of Radiology, Rutgers New Jersey Medical School Newark, NJ, USA.

Mild to moderate traumatic brain injury (mTBI) leads to secondary neuronal loss via excitotoxic mechanisms, including mitochondrial Ca(2+) overload. However, in the surviving cellular population, mitochondrial Ca(2+) influx, and oxidative metabolism are diminished leading to suboptimal neuronal circuit activity and poor prognosis. Hence we tested the impact of boosting neuronal electrical activity and oxidative metabolism by facilitating mitochondrial Ca(2+) uptake in a rat model of mTBI. In developing rats (P25-P26) sustaining an mTBI, we demonstrate post-traumatic changes in cerebral blood flow (CBF) in the sensorimotor cortex in response to whisker stimulation compared to sham using functional Laser Doppler Imaging (fLDI) at adulthood (P67-P73). Compared to sham, whisker stimulation-evoked positive CBF responses decreased while negative CBF responses increased in the mTBI animals. The spatiotemporal CBF changes representing underlying neuronal activity suggested profound changes to neurovascular activity after mTBI. Behavioral assessment of the same cohort of animals prior to fLDI showed that mTBI resulted in persistent contralateral sensorimotor behavioral deficit along with ipsilateral neuronal loss compared to sham. Treating mTBI rats with Kaempferol, a dietary flavonol compound that enhanced mitochondrial Ca(2+) uptake, eliminated the inter-hemispheric asymmetry in the whisker stimulation-induced positive CBF responses and the ipsilateral negative CBF responses otherwise observed in the untreated and vehicle-treated mTBI animals in adulthood. Kaempferol also improved somatosensory behavioral measures compared to untreated and vehicle treated mTBI animals without augmenting post-injury neuronal loss. The results indicate that reduced mitochondrial Ca(2+) uptake in the surviving populations affect post-traumatic neural activation leading to persistent behavioral deficits. Improvement in sensorimotor behavior and spatiotemporal neurovascular activity following kaempferol treatment suggests that facilitation of mitochondrial Ca(2+) uptake in the early window after injury may sustain optimal neural activity and metabolism and contribute to improved function of the surviving cellular populations after mTBI.
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http://dx.doi.org/10.3389/fnsys.2016.00019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782040PMC
March 2016

Microglial P2Y12 receptors regulate microglial activation and surveillance during neuropathic pain.

Brain Behav Immun 2016 07 11;55:82-92. Epub 2015 Nov 11.

Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA. Electronic address:

Microglial cells are critical in the pathogenesis of neuropathic pain and several microglial receptors have been proposed to mediate this process. Of these receptors, the P2Y12 receptor is a unique purinergic receptor that is exclusively expressed by microglia in the central nervous system (CNS). In this study, we set forth to investigate the role of P2Y12 receptors in microglial electrophysiological and morphological (static and dynamic) activation during spinal nerve transection (SNT)-induced neuropathic pain in mice. First, we found that a genetic deficiency of the P2Y12 receptor (P2Y12(-/-) mice) ameliorated pain hypersensitivities during the initiation phase of neuropathic pain. Next, we characterised both the electrophysiological and morphological properties of microglia in the superficial spinal cord dorsal horn following SNT injury. We show dramatic alterations including a peak at 3days post injury in microglial electrophysiology while high resolution two-photon imaging revealed significant changes of both static and dynamic microglial morphological properties by 7days post injury. Finally, in P2Y12(-/-) mice, these electrophysiological and morphological changes were ameliorated suggesting roles for P2Y12 receptors in SNT-induced microglial activation. Our results therefore indicate that P2Y12 receptors regulate microglial electrophysiological as well as static and dynamic microglial properties after peripheral nerve injury, suggesting that the microglial P2Y12 receptor could be a potential therapeutic target for the treatment of neuropathic pain.
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http://dx.doi.org/10.1016/j.bbi.2015.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864135PMC
July 2016

Hypoxia-Induced Iron Accumulation in Oligodendrocytes Mediates Apoptosis by Eliciting Endoplasmic Reticulum Stress.

Mol Neurobiol 2016 09 29;53(7):4713-27. Epub 2015 Aug 29.

Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Blk MD10, 4 Medical Drive, Singapore, Singapore, 117594.

This study was aimed at evaluating the role of increased iron accumulation in oligodendrocytes and its role in their apoptosis in the periventricular white matter damage (PWMD) following a hypoxic injury to the neonatal brain. In response to hypoxia, in the PWM, there was increased expression of proteins involved in iron acquisition, such as iron regulatory proteins (IRP1, IRP2) and transferrin receptor in oligodendrocytes. Consistent with this, following a hypoxic exposure, there was increased accumulation of iron in primary cultured oligodendrocytes. The increased concentration of iron within hypoxic oligodendrocytes was found to elicit ryanodine receptor (RyR) expression, and the expression of endoplasmic reticulum (ER) stress markers such as binding-immunoglobulin protein (BiP) and inositol-requiring enzyme (IRE)-1α. Associated with ER stress, there was reduced adenosine triphosphate (ATP) levels within hypoxic oligodendrocytes. However, treatment with deferoxamine reduced the increased expression of RyR, BiP, and IRE-1α and increased ATP levels in hypoxic oligodendrocytes. Parallel to ER stress there was enhanced reactive oxygen species production within mitochondria of hypoxic oligodendrocytes, which was attenuated when these cells were treated with deferoxamine. At the ultrastructural level, hypoxic oligodendrocytes frequently showed dilated ER and disrupted mitochondria, which became less evident in those treated with deferoxamine. Associated with these subcellular changes, the apoptosis of hypoxic oligodendrocytes was evident with an increase in p53 and caspase-3 expression, which was attenuated when these cells were treated with deferoxamine. Thus, the present study emphasizes that the excess iron accumulated within oligodendrocytes in hypoxic PWM could result in their death by eliciting ER stress and mitochondrial disruption.
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http://dx.doi.org/10.1007/s12035-015-9389-6DOI Listing
September 2016

Microglial Hv1 proton channel promotes cuprizone-induced demyelination through oxidative damage.

J Neurochem 2015 Oct 11;135(2):347-56. Epub 2015 Aug 11.

Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

NADPH oxidase (NOX)-dependent reactive oxygen species (ROS) production in inflammatory cells including microglia plays an important role in demyelination and free radical-mediated tissue injury in multiple sclerosis (MS). However, the mechanism underlying microglial ROS production and demyelination remains largely unknown. The voltage-gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX-dependent ROS generation in the brain. In the present study, we sought to determine the role of microglial Hv1 proton channels in a mouse model of cuprizone-induced demyelination, a model for MS. Following cuprizone exposure, wild-type mice presented obvious demyelination, decreased myelin basic protein expression, loss of mature oligodendrocytes, and impaired motor coordination in comparison to mice on a normal chow diet. However, mice lacking Hv1 (Hv1(-/-) ) are partially protected from demyelination and motor deficits compared with those in wild-type mice. These rescued phenotypes in Hv1(-/-) mice in cuprizone-induced demyelination is accompanied by reduced ROS production, ameliorated microglial activation, increased oligodendrocyte progenitor cell (NG2) proliferation, and increased number of mature oligodendrocytes. These results demonstrate that the Hv1 proton channel is required for cuprizone-induced microglial oxidative damage and subsequent demyelination. Our study suggests that the microglial Hv1 proton channel is a unique target for controlling NOX-dependent ROS production in the pathogenesis of MS.
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http://dx.doi.org/10.1111/jnc.13242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721248PMC
October 2015

Extracellular ATP enhances radiation-induced brain injury through microglial activation and paracrine signaling via P2X7 receptor.

Brain Behav Immun 2015 Nov 27;50:87-100. Epub 2015 Jun 27.

Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. Electronic address:

Activation of purinergic receptors by extracellular ATP (eATP) released from injured cells has been implicated in the pathogenesis of many neuronal disorders. The P2X7 receptor (P2X7R), an ion-selective purinergic receptor, is associated with microglial activation and paracrine signaling. However, whether ATP and P2X7R are involved in radiation-induced brain injury (RBI) remains to be determined. Here, we found that the eATP level was elevated in the cerebrospinal fluid (CSF) of RBI patients and was associated with the clinical severity of the disorder. In our experimental model, radiation treatment increased the level of eATP in the supernatant of primary cultures of neurons and glial cells and in the CSF of irradiated mice. In addition, ATP administration activated microglia, induced the release of the inflammatory mediators such as cyclooxygenase-2, tumor necrosis factor α and interleukin 6, and promoted neuronal apoptosis. Furthermore, blockade of ATP-P2X7R interaction using P2X7 antagonist Brilliant Blue G or P2X7 knockdown suppressed radiation-induced microglial activation and proliferation in the hippocampus, and restored the spatial memory of irradiated mice. Finally, we found that the PI3K/AKT and nuclear factor κB mediated pathways were downstream of ATP-P2X7R signaling in RBI. Taken together, our results unveiled the critical role of ATP-P2X7R in brain damage in RBI, suggesting that inhibition of ATP-P2X7R axis might be a potential strategy for the treatment of patients with RBI.
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http://dx.doi.org/10.1016/j.bbi.2015.06.020DOI Listing
November 2015

Glutamate receptors in microglia.

CNS Neurol Disord Drug Targets 2013 Sep;12(6):773-84

Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.

Expression of functional glutamate receptors (GluR) on glial cells in the developing and mature brain has been recently established. Over the last decade there has been physiological, molecular and biochemical evidence suggesting the presence of GluR on microglia. However, the significance of GluR activation in microglia remains largely unknown. In this review, we discuss the expression of GluR on microglia and the effect of GluR activation on microglial function. Microglia are the resident immune cells of the central nervous system, and activation of GluR in them has been shown to regulate their immunological response which may be either neuroprotective or neurotoxic. Microglial activation is known to initiate a myriad of molecular events such as nitric oxide production, free radicals generation, disruption of calcium regulation and release of proinflammatory cytokines, proteases, neurotransmitters, and excitatory amino acids, primarily glutamate. Since microglial activation has been implicated in several neuropathologies, an understanding of the pathway coupled to the various microglial GluR will help to develop therapeutic interventions for ameliorating microglia-mediated damage.
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http://dx.doi.org/10.2174/18715273113126660174DOI Listing
September 2013

Dysregulated glutamate uptake by astrocytes causes oligodendroglia death in hypoxic perventricular white matter damage.

Mol Cell Neurosci 2013 Sep 13;56:342-54. Epub 2013 Jul 13.

Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.

Excess glutamate mediates damage to oligodendroglia, resulting in myelination disturbances characteristic of hypoxic periventricular white matter (PWM) damage. We sought to examine if hypoxia altered the expression of astroglial excitatory amino acid transporters (EAAT1, EAAT2 and EAAT3) in the PWM, and, if so, whether it activated astroglial N-methyl D-aspartate receptors (NMDAR) which might lead to apoptosis of oligodendroglia. EAAT expression in the PWM of neonatal rats was measured at different time points after hypoxic exposure; it was attenuated at 7 and 14 d following hypoxia. Hypoxia prevented the uptake of glutamate by astroglial EAATs causing increased levels of extracellular glutamate. Excess glutamate augmented the expression of functional astroglial NMDAR. Following hypoxia, an increase in gap junction proteins between astroglia and oligodendroglia aided in the spreading of NMDAR-mediated excitotoxic calcium signals into the latter cell type triggering its apoptosis. Hence, dysregulated glutamate homeostasis is believed to contribute to hypoxia-induced death of oligodendroglia leading to neonatal PWM damage.
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http://dx.doi.org/10.1016/j.mcn.2013.07.005DOI Listing
September 2013

Expression of N-methyl D-aspartate receptor subunits in amoeboid microglia mediates production of nitric oxide via NF-κB signaling pathway and oligodendrocyte cell death in hypoxic postnatal rats.

Glia 2011 Apr 6;59(4):521-39. Epub 2011 Jan 6.

Department of Anatomy, Yong Loo Lin School of Medicine, Blk MD10, 4 Medical Drive, National University of Singapore, Singapore.

The present study was focused on identifying the expression of N-methyl D-aspartate receptor (NMDAR) subunits on activated microglia and to determine their role in the pathogenesis of periventricular white matter damage (PWMD) in neonatal rats following hypoxia. One day old wistar rats were subjected to hypoxia (5% O(2) ; 95% N(2) ) and the mRNA and protein expression of NMDAR subunits (NR1, NR2A-D, and NR3A) in the periventricular white matter (PWM) was determined at different time points (3,24 h, 3, 7, and 14 days) following hypoxic exposure. Immunoexpression of NR1 and NR2A-D was localized in amoeboid microglial cells (AMC) suggesting the presence of functional NMDARs in them. The expression of NMDAR in primary microglial cultures was ascertained by RT-PCR analysis and double immunofluorescence studies. The functionality of the microglial NMDAR in cultured microglial cells was examined by monitoring calcium movements in cells with fura-2. In primary microglial cultures, hypoxia induced the nuclear translocation of NF-κB which was suppressed by administration of MK801, an NMDAR antagonist. MK801 also down regulated the hypoxia-induced expression of tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase (iNOS), and nitric oxide (NO) production by microglia which may be mediated by the NF-κB signaling pathway. NO produced by microglia is known to cause death of oligodendrocytes in the developing PWM. In this connection, pharmacological agents such as MK801, BAY (NF-κB inhibitor), and 1400w (iNOS inhibitor) proved to be beneficial since they reduced the hypoxia-induced iNOS expression, NO production, and a corresponding reduction in the death of oligodendrocytes following hypoxia.
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http://dx.doi.org/10.1002/glia.21121DOI Listing
April 2011
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