Role of p38 and p44/42 mitogen‐activated protein kinases in microglia

Koistinaho, Milla; Koistinaho, Jari

doi:10.1002/glia.10151

Cited by 260 publications

(202 citation statements)

References 109 publications

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“…Such activation of MAPK cascades is consistent with inflammatory activation of microglia [69]. Ibrahim and coworkers also used IHC staining with retinal microglia marker antibody and with an antibody to Almadori-glycated albumin (AGA) to show that both were localized in the ganglion cell layer [68].…”

Section: Microglial Activation In Diabetic Retinopathymentioning

confidence: 79%

Neural inflammation and the microglial response in diabetic retinopathy

Abcouwer

2011

j ocul biol dis inform

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Section: Microglial Activation In Diabetic Retinopathymentioning

confidence: 79%

Neural inflammation and the microglial response in diabetic retinopathy

Abcouwer

2011

j ocul biol dis inform

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“…In microglia, many proinflammatory stimuli cause phosphorylation (activation) of the mitogenactivated protein kinase p38 MAPK and consequent production of cytotoxic molecules, including nitric oxide (Jeohn et al, 2002;Koistinaho and Koistinaho, 2002). Similar p38 MAPK activation occurs in numerous acute and chronic brain disorders, including stroke, spinal cord injury, Alzheimer's disease, and Parkinson's disease (Koistinaho and Koistinaho, 2002), and there is increasing evidence that p38 MAPK inhibitors can protect against microglia-induced neurotoxicity in vivo (Barone et al, 2001;Koistinaho and Koistinaho, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of p38 MAP kinase in microglia is an important upstream regulator of production of numerous potential neurotoxins, including proinflammatory cytokines and reactive nitrogen species (Jeohn et al, 2002;Koistinaho and Koistinaho, 2002). Hence, we assessed whether the neuroprotective effect of Kv1.3 channel blockers is through interference with p38 MAPK phosphorylation and consequent activation.…”

Section: P38 Mapk Activation and Microglia-mediated Neuron Killingmentioning

confidence: 99%

Microglia Kv1.3 Channels Contribute to Their Ability to Kill Neurons

Fordyce¹,

Jagasia²,

Zhu³

et al. 2005

J. Neurosci.

187

189

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Many CNS disorders involve an inflammatory response that is orchestrated by cells of the innate immune system: macrophages, neutrophils, and microglia (the endogenous CNS immune cell). Hence, there is considerable interest in anti-inflammatory strategies that target these cells. Microglia express Kv1.3 (KCNA3) channels, which we showed previously are important for their proliferation and the NADPH-mediated respiratory burst. Here, we demonstrate the potential for targeting Kv1.3 channels to control CNS inflammation. Rat microglia express Kv1.2, Kv1.3, and Kv1.5 transcripts and protein, but only a Kv1.3 current was detected. When microglia were activated with lipopolysaccharide or a phorbol ester, only the Kv1.3 transcript (but not protein) expression changed. Using a Transwell cell-culture system that allows separate drug treatment of microglia or neurons, we found that activated microglia killed postnatal hippocampal neurons through a process that requires Kv1.3 channel activity in microglia but not in neurons. A major neurotoxic molecule in this model was peroxynitrite, which is formed from superoxide and nitric oxide; thus, it is significant that Kv1.3 channel blockers reduced the respiratory burst, but not nitric oxide production, by the activated microglia. In addressing the biochemical pathway affected by Kv1.3 channel activity, we found that Kv1.3 acts via a different cellular mechanism from the broad-spectrum drug minocycline, which is often used in animal models of neuroinflammation. That is, the dose-dependent reduction in neuron killing by minocycline corresponded with a reduction in p38 mitogen-activated protein kinase activation in microglia; however, none of the Kv1.3 blockers affected p38 activation.

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“…The p38 inhibitor SB203580 does not inhibit the phosphorylation of p38 but rather binds to the ATP pocket in the enzyme, thereby inhibiting its activity (Koistinaho and Koistinaho, 2002). On the other hand, FR167653 was first discovered as a potent inhibitor of tumor necrosis factor (TNF)-␣ and interleukin-1␤ production (Yamamoto et al, 1996(Yamamoto et al, , 1997.…”

Section: Inhibition Of P38 Activation Attenuates L5 Snl-induced Thermmentioning

confidence: 99%

Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation

Obata¹,

Yamanaka²,

Kobayashi³

et al. 2004

J. Neurosci.

290

208

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To investigate whether activation of mitogen-activated protein kinase (MAPK) in damaged and/or undamaged primary afferents participates in neuropathic pain after partial nerve injury, we examined the phosphorylation of extracellular signal-regulated protein kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) in the L4 and L5 dorsal root ganglion (DRG) in the L5 spinal nerve ligation (SNL) model. We first confirmed, using activating transcription factor 3 and neuropeptide Y immunoreactivity, that virtually all L4 DRG neurons are spared from axotomy in this model. In the injured L5 DRG, the L5 SNL induced the activation of ERK, p38, and JNK in different populations of DRG neurons. In contrast, in the uninjured L4 DRG, the L5 SNL induced only p38 activation in tyrosine kinase A-expressing small-to medium-diameter neurons. Intrathecal ERK, p38, and JNK inhibitor infusions reversed SNL-induced mechanical allodynia, whereas only p38 inhibitor application attenuated SNL-induced thermal hyperalgesia. Furthermore, the L5 dorsal rhizotomy did not prevent SNL-induced thermal hyperalgesia. We therefore hypothesized that p38 activation in the uninjured L4 DRG might be involved in the development of heat hypersensitivity in the L5 SNL model. In fact, the treatment of the p38 inhibitor and also anti-nerve growth factor reduced SNL-induced upregulation of brain-derived neurotrophic factor and transient receptor potential vanilloid type 1 expression in the L4 DRG. Together, our results demonstrate that the L5 SNL induces differential activation of MAPK in injured and uninjured DRG neurons and, furthermore, that MAPK activation in the primary afferents may participate in generating pain hypersensitivity after partial nerve injury.

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Role of p38 and p44/42 mitogen‐activated protein kinases in microglia

Cited by 260 publications

References 109 publications

Neural inflammation and the microglial response in diabetic retinopathy

Neural inflammation and the microglial response in diabetic retinopathy

Microglia Kv1.3 Channels Contribute to Their Ability to Kill Neurons

Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation

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