Madhuvika Murugan - Academia.edu (original) (raw)

Papers by Madhuvika Murugan

Glia, May 18, 2016

Epilepsy has remained a significant social concern and financial burden globally. Current therape... more 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 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 including epilepsy-induced alterations in basic microglial functions, neuro-microglial interactions during chronic epilepsy, and microglial contributions to developmental seizures. Studying the role of microglia in epilepsy could inform therapies to better alleviate the disease.

Additional file 2: Figure S2. Hv1−/− mice have distinct cytokines/chemokine expression pattern af... more Additional file 2: Figure S2. Hv1−/− mice have distinct cytokines/chemokine expression pattern after SCI. A. Schematic representation of the cytokine array. The array contains 40 different antibodies to mouse cytokines/chemokines, three positive controls (PC) and one negative control (NC), all in duplicates (upper right). The representative immunoblots of cytokines/chemokines in the spinal cord lysates (WT sham control, upper right; WT 3 d after SCI, bottom left; Hv1−/− 3 d after SCI, bottom right) are shown. B. Bar graph denotes optical density representing the expression level of cytokines/chemokines. Data is represented as mean ± SEM. (n = 3, * signifies comparison between Sham and WT 3 d after SCI. # signifies comparison between WT and Hv1−/− 3 d after SCI, *,#P < 0.05, **,##P < 0.01, ***, ###P < 0.001, Student's t-test).

Brain Communications

Sudden unexpected death in epilepsy is the leading cause of epilepsy related death. Currently, th... more Sudden unexpected death in epilepsy is the leading cause of epilepsy related death. Currently, there are no reliable methods for preventing sudden unexpected death in epilepsy. The precise pathophysiology of sudden unexpected death in epilepsy is unclear; however, convergent lines of evidence suggest that seizure-induced respiratory arrest plays a central role. It is generally agreed that sudden unexpected death in epilepsy could be averted if the patient could be rapidly ventilated following the seizure. The diaphragm is a muscle in the chest which contracts to draw air into the lungs. Diaphragmatic pacing is a surgical intervention which facilitates normal ventilation in situations, such as spinal cord injury and sleep apnoea, in which endogenous respiration would be inadequate or non-existent. In diaphragmatic pacing, electrodes are implanted directly onto diaphragm or adjacent to the phrenic nerves which innervate the diaphragm. These electrodes are then rhythmically stimulated,...

Ketogenic Diet and Metabolic Therapies, 2022

Approximately 60% of all epilepsy cases occur as a consequence of acute insults to the brain, suc... more Approximately 60% of all epilepsy cases occur as a consequence of acute insults to the brain, such as traumatic brain injury, cerebrovascular insult, or infections. After an insult, the brain enters a period during which progressive neurobiologic alterations convert a non-epileptic brain into a brain capable of generating spontaneous and recurrent seizures, which are defined as epilepsy. The series of events is known as epileptogenesis. Epigenetic (DNA methylation) changes may affect several genes thought to represent risk factors for epilepsy; epigenetic changes are potentially reversible and may constitute a novel target for therapeutic intervention. DNA hypermethylation related to adenosine deficiency results in a vicious cycle associated with the onset of epileptogenesis and leading to chronic pharmacoresistant epilepsy. DNA hypermethylation is restored by the ketogenic diet (KD) via adenosine augmentation, a shift in the S-adenosylhomocysteine and S-adenosylmethionine homeostas...

Additional file 1: Figure S1. Deficiency of Hv1 shows better motor recovery in both males and fem... more Additional file 1: Figure S1. Deficiency of Hv1 shows better motor recovery in both males and females. A. BMS sub-scores in WT and Hv1−/− mice (males and females combined) at different time points following SCI and sham controls (WT, n = 11; Hv1−/−, n = 18). B. Total BMS scores and C. BMS sub-scores in WT and Hv1−/− mice measured in males and females at different time points following SCI (WT: males, n = 8; females, n = 3; Hv1−/−: males, n = 13; females, n = 5). (*P < 0.05, **P < 0.01, ***P < 0.001, two-way ANOVA with repeated measures).

Frontiers in Neuroscience, 2021

Adenosine is an inhibitory modulator of neuronal excitability. Neuronal activity results in incre... more 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 antie...

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 17, 2017

Elevated levels of chemokine C-C motif ligand 2 (CCL2) and its receptor CCR2 have been reported i... more 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 1d after kainic acid (KA)-induced seizures. Taking advantage of CX3CR1(GFP/+):CCR2(RFP/+) double transgenic mice, we demonstrated that CCL2-CCR2 signaling participated 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 phosphorylation and IL-1β production, which are critical for promoting neuronal cell death after status epilepticus. Consistently, pharmacological...

eNeuro

Microglia, the resident immune cells of the brain, perform elaborate surveillance in which they p... more 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 in vivo and ex vivo, 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 def...

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 20, 2016

Clinical studies show that chronic pain is accompanied by memory deficits and reduction in hippoc... more 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 sciatic nerve induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn but impairs LTP in 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 significantly reduced 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-α (TNF-α) is up-regulated in bilateral hippocampus and in ipsilateral spinal dorsal horn, while brain derived neurotrophic fact...

Journal of neurochemistry, Oct 29, 2016

Microglia become activated during cerebral ischemia and exert pro-inflammatory or anti-inflammato... more 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 photot...

Cell reports, Jul 19, 2016

Peripheral nerve injury causes neuropathic pain accompanied by remarkable microgliosis in the spi... more 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 spi...

Molecular pain, 2016

Chronic pain is often accompanied by short-term memory deficit and depression. Currently, it is b... more 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. 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...

Brain, behavior, and immunity, Jul 11, 2015

Microglial cells are critical in the pathogenesis of neuropathic pain and several microglial rece... more 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 reve...

Journal of neurochemistry, Jan 14, 2015

NADPH oxidase (NOX)-dependent reactive oxygen species (ROS) production in inflammatory cells incl... more 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 MBP 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 phenotyp...

Frontiers in Clinical Drug Research- Central Nervous System, 2013

Journal of Insect Physiology, 2010

Circadian clocks provide adaptive advantage to their owners by timing their behavioural and physi... more Circadian clocks provide adaptive advantage to their owners by timing their behavioural and physiological processes in accordance with the external environment. Here we report the results of our study aimed at investigating the effect of the interaction between circadian timing system and environmental light/dark (LD) cycles on pre-adult development time of two sympatric species of Componotus ants, the night active Componotus compressus, and the day active C. paria-both species develop in dark underground nests, under fairly constant conditions of humidity and temperature. We estimated pre-adult developmental durations in these ants under three different LD cycles (T20 = 10 h of light and 10 h of darkness, T24 = 12 h of light and 12 h of darkness, and T28 = 14 h of light and 14 h of darkness). We find that both species exhibit significantly faster pre-adult development under T24 compared to T20 and T28. Given that faster development in insects is considered as an adaptive strategy these results can be taken to suggest that Camponotus ants accrue greater fitness advantage under T24 compared to T20 and T28 LD cycles, possibly due to ''circadian resonance'' between circadian timing system and environmental LD cycle. Thus our study reveals that boreal species of ants could serve as a case for the study of adaptive significance of circadian organization.

Glia, 2011

The present study was focused on identifying the expression of N-methyl D-aspartate receptor (NMD... more 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.

Nature communications, Jan 28, 2016

Microglia and peripheral monocytes contribute to hypersensitivity in rodent models of neuropathic... more 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.

Neuropharmacology, 2021

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in patients with refracto... more 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.