Naloxone Inhibition of Lipopolysaccharide-Induced Activation of Retinal Microglia is Partly Mediated via the p38 Mitogen Activated Protein Kinase Signalling Pathway

Yf, Xu; Ll, Fu; Ch, Jiang; Yw, Qin; Yq, Ni; Jw, Fan

doi:10.1177/147323001204000422

Cited by 14 publications

(8 citation statements)

References 55 publications

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“…Current researches suggest that various signaling pathways are involved in microglia activation such as TSPO, 31 ionotropic (P2X), metabotropic (P2Y) purinergic receptors, 32 and so forth, among which four pathways, namely Jak‐Stat, 33 NF‐κB, 34 ERK 1/2, 35 and p38 MAPK, 36 are acknowledged to be the most closely related. Therefore, we screened these four signaling pathways to determine whether OPN can regulate retinal microglia activation through any of them.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin activates retinal microglia causing retinal ganglion cells loss via p38 MAPK signaling pathway in glaucoma

Huang

et al. 2021

FASEB j.

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Microglia activation and release of pro‐inflammatory cytokines have been closely linked to glaucoma. However, the mechanisms that initiate these pathways remain unclear. Here, we investigated the role of a pro‐inflammatory cytokine––osteopontin (OPN), in retinal microglia activation process along with the underlying mechanisms in glaucoma. A rat chronic ocular hypertension (COH) model was established presenting an increase in retinal OPN level and activation of microglia. Primary microglia cells were isolated and cultured under a pressure culture system showing heightened expressions of microglia‐derived OPN with changes in inflammatory factors (TNF‐α, IL‐1β, and IL‐6). OPN and OPN neutralizing antibody (Anti‐OPN) interventions were both applied systems for comparison, and cross‐referenced with OPN knockdown in vitro. JAK/STAT, NF‐κB, ERK1/2, and p38 MAPK, recognized as the primary signaling pathways related to microglia activation, were then screened on whether they can facilitate OPN to act on microglia and their impact on specific inhibitors. Thereafter, retrograde labeling of retinal ganglion cells (RGCs) and flash visual evoked potentials (F‐VEP) were used to investigate neuron protection in context of each blockade. Results suggest that OPN is able to enhance the proliferation and activation of retinal microglia in experimental glaucoma which may play a role in the glaucomatous optic neuropathy, and contribute to the eventual RGCs loss and vision function impairment. Such effect may be mediated through the regulation of p38 MAPK signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Osteopontin activates retinal microglia causing retinal ganglion cells loss via p38 MAPK signaling pathway in glaucoma

Huang

et al. 2021

FASEB j.

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“…Taken together, these findings demonstrate the functional similarity between macrophages and RMG with regard to the involvement of AR in regulating cytokine production. It has been shown that TNF-a, as one of the major cytokines secreted by activated RMG, 31,46 may be involved in neurodegeneration 39 and uveitis. 47 Therefore, inhibition of TNF-a through pharmacologic inhibition of AR in microglia may hold promise as a potential new strategy against ocular inflammation.…”

Section: Discussionmentioning

confidence: 99%

Aldose Reductase Inhibition Prevents Endotoxin-Induced Inflammatory Responses in Retinal Microglia

Chang

Ponder

LaBarbera

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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“…Hence a sizable literature on blockade of LPS effects by naloxone and naltrexone makes no mention of TLR4, as it had not yet been discovered. The evidence of naloxone/naltrexone blockade of LPS effects is now quite far-reaching including excitatory post-synaptic potentials [22], seizures [23, 24], microglial activation [25–27], proinflammatory cytokines [25, 28], nitric oxide and superoxide [29, 30], neurotoxicity and neurodegeneration [31–34], hepatitis [35], septic shock [36, 37], hormone release [38], fever [39], pain [40], reduction in morphine analgesia [41, 42], and so on. Even when (+)-isomers of naloxone and naltrexone are employed to prevent possible influence of opioid receptors, there is suppression of LPS-induced proinflammatory responses [34, 43], LPS-induced excitotoxic death of dopamine neurons [33, 34]; suppression of neuropathic pain [12, 44]; potentiation of opioid analgesia [10, 45]); and decreased opioid-induced withdrawal, tolerance, hyperalgesia and constipation [2, 7, 10, 40].…”

Section: How Did a Focus On Tlr4 Arise?mentioning

confidence: 99%

Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4

Bachtell

Hutchinson²,

Wang³

et al. 2015

CNSNDDT

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There is growing recognition that glial proinflammatory activation importantly contributes to the rewarding and reinforcing effects of a variety of drugs of abuse, including cocaine, methamphetamine, opioids, and alcohol. It has recently been proposed that glia are recognizing, and becoming activated by, such drugs as a CNS immunological response to these agents being xenobiotics; that is, substances foreign to the brain. Activation of glia, primarily microglia, by various drugs of abuse occurs via toll like receptor 4 (TLR4). The detection of such xenobiotics by TLR4 results in the release of glial neuroexcitatory and neurotoxic substances. These glial products of TLR4 activation enhance neuronal excitability within brain reward circuitry, thereby enhancing their rewarding and reinforcing effects. Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. These include: conditioned place preference, self-administration, drug-primed reinstatement, incubation of craving, and elevations of nucleus accumbens shell dopamine. Notably, TLR4 blockade fails to alter self-administration of food, indicative of a selective effect on drugs of abuse. Genetic disruption of TLR4 signaling recapitulates the effects of pharmacological TLR4 blockade, providing converging lines of evidence of a central importance of TLR4. Taken together, multiple lines of evidence converge to raise TLR4 as a promising therapeutic target for drug abuse.

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Naloxone Inhibition of Lipopolysaccharide-Induced Activation of Retinal Microglia is Partly Mediated via the p38 Mitogen Activated Protein Kinase Signalling Pathway

Abstract: Naloxone suppressed LPS-induced activation of cultured retinal microglia and this suppression appeared to occur partly through the p38 MAPK signalling pathway. Naloxone may have therapeutic potential in neuro degenerative diseases characterized by the activation of microglia.

Cited by 14 publications

References 55 publications

Osteopontin activates retinal microglia causing retinal ganglion cells loss via p38 MAPK signaling pathway in glaucoma

Osteopontin activates retinal microglia causing retinal ganglion cells loss via p38 MAPK signaling pathway in glaucoma

Aldose Reductase Inhibition Prevents Endotoxin-Induced Inflammatory Responses in Retinal Microglia

Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4

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