Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca<sup>2+</sup> signalling in hippocampal neurons

Gonzalez, Jose; Egea, Javier; Godino, María del Carmen; Fernandez-Gomez, Francisco-José; Sánchez‐Prieto, José; Gandı́a, Luis; Garcı́a, Antonio G.; Jordán, Joaquı́n; Hernández‐Guijo, Jesús M.

doi:10.1111/j.1460-9568.2007.05873.x

Cited by 99 publications

(74 citation statements)

References 44 publications

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“…2A). This result is consistent with our previous findings that minocycline decreases the amplitude and the number of excitatory postsynaptic currents with EC 50 between 42 and 64 M, indicating that glutamatergic synaptic transmission is drastically affected by neuroprotective concentrations of minocycline (30 M or higher [35]). …”

Section: Minocycline and Calcium Signalssupporting

confidence: 93%

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Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

García-Martínez

Sanz-Blasco

Karachitos

et al. 2010

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Garcia-Martinez EM et al., 2 AbstractMinocycline, an antibiotic of the tetracycline family, has attracted considerable interest for its theoretical therapeutic applications in neurodegenerative diseases. However, the mechanism of action underlying its effect remains elusive. Here we have studied the effect of minocycline under excitotoxic conditions. Fluorescence and bioluminescence imaging studies in rat cerebellar granular neuron cultures using fura-2/AM and mitochondria-targeted aequorin revealed that minocycline, at concentrations higher than those shown to block inflammation and inflammation-induced neuronal death, inhibited NMDA-induced cytosolic and mitochondrial rises in Ca 2+ concentrations in a reversible manner. Moreover, minocycline added in the course of NMDA stimulation decreased Ca 2+ intracellular levels, but not when induced by depolarization with a high K + medium. We also found that minocycline, at the same concentrations, partially depolarized mitochondria by about 5-30 mV, prevented mitochondrial Ca 2+ uptake under conditions of environmental stress, and abrogated NMDAinduced reactive oxygen species (ROS) formation. Consistently, minocycline also abrogates the rise in ROS induced by 75 M Ca 2+ in isolated brain mitochondria. In search for the mechanism of mitochondrial depolarization, we found that minocycline markedly inhibited state 3 respiration of rat brain mitochondria, although distinctly increased oxygen uptake in state 4. Minocycline inhibited NADH-cytochrome c reductase and cytochrome c oxidase activities, whereas the activity of succinate-cytochrome c reductase was not modified, suggesting selective inhibition of complex I and IV. Finally, minocycline affected activity of voltage-dependent anion channel (VDAC) as determined in the reconstituted system. Taken together, our results indicate that mitochondria are a critical factor in minocycline-mediated neuroprotection.

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Section: Minocycline and Calcium Signalssupporting

confidence: 93%

“…The present data, built upon our group's previous work [22,35,43], posits the intricate involvement of mitochondria in minocycline-mediated cytoprotection for neuronal cells.…”

Section: Discussionmentioning

confidence: 61%

Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

García-Martínez

Sanz-Blasco

Karachitos

et al. 2010

Biochemical Pharmacology

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“…Minocycline has been shown to exert neuroprotective effects by either reducing microglial activation (Yrjanheikki et al, 1999) or acting directly on neurons (Lin et al, 2001;Alano et al, 2006;González et al, 2007). Induction of ATF3 is triggered by signals that also induce cellular damage (Chen et al, 1996).…”

Section: Cytokines Neuronal and Glial Markers In Sensory Gangliamentioning

confidence: 99%

Differential Implication of Proinflammatory Cytokine Interleukin-6 in the Development of Cephalic versus Extracephalic Neuropathic Pain in Rats

et al. 2008

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Responses resulting from injury to the trigeminal nerve exhibit differences compared with those caused by lesion of other peripheral nerves. With the aim of elucidating the physiopathological mechanisms underlying cephalic versus extracephalic neuropathic pain, we determined the time course expression of proinflammatory cytokines interleukin-6 (IL-6) and IL-1␤, neuronal injury (ATF3), macrophage/microglial (OX-42), and satellite cells/astrocyte (GFAP) markers in central and ganglion tissues in rats that underwent unilateral chronic constriction injury (CCI) to either infraorbital nerve (IoN) (cephalic area) or sciatic nerve (SN) (extracephalic area). Whereas CCI induced microglial activation in both models, we observed a concomitant upregulation of IL-6 and ATF3 in the ipsilateral dorsal horn of the lumbar cord in SN-CCI rats but not in the ipsilateral spinal nucleus of the trigeminal nerve (Sp5c) in IoN-CCI rats. Preemptive treatment with minocycline (daily administration of 20 mg/kg, i.p., for 2 weeks) partially prevented pain behavior and microglial activation in SN-CCI rats but was ineffective in IoN-CCI rats. We show that IL-6 can upregulate OX-42 and ATF3 expression in cultured microglia and neurons from spinal cord, respectively, as well as in the dorsal horn after acute intrathecal administration of the cytokine. We propose that IL-6 could be one of the promoters of the signaling cascade leading to abnormal pain behavior in SN-CCI but not IoN-CCI rats. Our data further support the idea that different pathophysiological mechanisms contribute to the development of cephalic versus extracephalic neuropathic pain.

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“…Systemic or regionspecific injections of glial modulators prevent morphineinduced elevations of CD11b or GFAP, although the precise mechanisms whereby ibudilast or minocycline suppress glial activity remain unclear. It is important to consider that both ibudilast and minocycline are known to affect the functional properties of other cells, so the mechanism of action for these pharmacological agents may not be exclusive to glia (González et al, 2007).…”

Section: Opioids Glia and Neuroimmune Signalingmentioning

confidence: 99%

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Lacagnina

Rivera

Bilbo

2016

Neuropsychopharmacol

223

170

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Drugs of abuse cause persistent alterations in synaptic plasticity that may underlie addiction behaviors. Evidence suggests glial cells have an essential and underappreciated role in the development and maintenance of drug abuse by influencing neuronal and synaptic functions in multifaceted ways. Microglia and astrocytes perform critical functions in synapse formation and refinement in the developing brain, and there is growing evidence that disruptions in glial function may be implicated in numerous neurological disorders throughout the lifespan. Linking evidence of function in health and under pathological conditions, this review will outline the glial and neuroimmune mechanisms that may contribute to drug-abuse liability, exploring evidence from opioids, alcohol, and psychostimulants. Drugs of abuse can activate microglia and astrocytes through signaling at innate immune receptors, which in turn influence neuronal function not only through secretion of soluble factors (eg, cytokines and chemokines) but also potentially through direct remodeling of the synapses. In sum, this review will argue that neural-glial interactions represent an important avenue for advancing our understanding of substance abuse disorders.

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Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca²⁺ signalling in hippocampal neurons

Cited by 99 publications

References 44 publications

Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

Differential Implication of Proinflammatory Cytokine Interleukin-6 in the Development of Cephalic versus Extracephalic Neuropathic Pain in Rats

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

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Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca2+ signalling in hippocampal neurons

Cited by 99 publications

References 44 publications

Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

Differential Implication of Proinflammatory Cytokine Interleukin-6 in the Development of Cephalic versus Extracephalic Neuropathic Pain in Rats

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

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Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca²⁺ signalling in hippocampal neurons