Tumor necrosis factor reduces the amplitude of rat cortical spreading depression <i>in vivo</i>

Richter, Frank; Lütz, Wibke; Eitner, Annett; Leuchtweis, Johannes; Lehmenkühler, A.; Schaible, Hans‐Georg

doi:10.1002/ana.24176

Cited by 29 publications

(31 citation statements)

References 46 publications

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“…Although pharmacologically decreased SD amplitude is often interpreted as a sign of protection (Richter et al, 2014), the lack of a clear-cut association between SD amplitude and histological or neurological damage imposed creates persistent controversies. On the other hand, the number of rSDs, the cumulative duration of SDs, and the inability of the tissue to recover from SD (i.e., long SD duration) have been shown to correlate with or be a sign of injury progression (Dijkhuizen et al, 1999;Dreier et al, 2006;Nedergaard, 1996).…”

Section: Discussionmentioning

confidence: 99%

The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization

Szabó

Tóth

Török

et al. 2019

British J Pharmacology

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Background and Purpose: A new class of dihydropyridine derivatives, which act as co-inducers of heat shock protein but are devoid of calcium channel antagonist and vasodilator effects, has recently been developed with the purpose of selectively targeting neurodegeneration. Here, we evaluated the action of one of these novel compounds LA1011 on neurovascular coupling in the ischaemic rat cerebral cortex.As a reference, we applied nimodipine, a vasodilator dihydropyridine and wellknown calcium channel antagonist.Experimental Approach: Rats were treated with LA1011 or nimodipine, either by chronic, systemic (LA1011), or acute, local administration (LA1011 and nimodipine).In the latter treatment group, global forebrain ischaemia was induced in half of the animals by bilateral common carotid artery occlusion under isoflurane anaesthesia.Functional hyperaemia in the somatosensory cortex was created by mechanical stimulation of the contralateral whisker pad under α-chloralose anaesthesia. Spreading depolarization (SD) events were elicited subsequently by 1 M KCl. Local field potential and cerebral blood flow (CBF) in the parietal somatosensory cortex were monitored by electrophysiology and laser Doppler flowmetry.Key Results: LA1011 did not alter CBF, but intensified SD, presumably indicating the co-induction of heat shock proteins, and, perhaps an anti-inflammatory effect.Nimodipine attenuated evoked potentials and SD. In addition to the elevation of baseline CBF, nimodipine augmented hyperaemia in response to both somatosensory stimulation and SD, particularly under ischaemia. Conclusions and implications:In contrast to the CBF improvement achieved with nimodipine, LA1011 seems not to have discernible cerebrovascular effects but may up-regulate the stress response.Abbreviations: 2VO, permanent, bilateral occlusion of the common carotid arteries ("two-vessel occlusion"); CBF, cerebral blood flow; DC, direct current; EFP, evoked field potential; eNOS, endothelial NOS; Hsp, heat shock protein; LDF, laser Doppler flowmetry; LFP, local field potential; MABP, mean arterial BP; rSD, recurrent spreading depolarization; SD, spreading depolarization; SD1, the first spreading depolarization in a train of events

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Section: Discussionmentioning

confidence: 99%

The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization

Szabó

Tóth

Török

et al. 2019

British J Pharmacology

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“…A recent study indicated that multiple CSD caused a marked enlargement of microglia [5] and release of microglia cytokine, such as IL-1β and TNF-α. These cytokines also affected the threshold and amplitude of CSD [25–27]. In addition, Cui Y and colleagues also found in a PET study that microglia were activated in the rat brain as a consequence of CSD stimulation [28].…”

Section: Discussionmentioning

confidence: 99%

Microglia P2X4 receptor contributes to central sensitization following recurrent nitroglycerin stimulation

Long

Pan

et al. 2018

J Neuroinflammation

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BackgroundThe mechanism underlying migraine chronification remains unclear. Central sensitization may account for this progression. The microglia P2X4 receptor (P2X4R) plays a pivotal role in the central sensitization of inflammatory and neuropathic pain, but there is no information about P2X4R in migraine. Therefore, the aim of this study was to identify the precise role of microglia P2X4R in chronic migraine (CM).MethodsWe used an animal model with recurrent intermittent administration of nitroglycerin (NTG), which closely mimics CM. NTG-induced basal and acute mechanical hypersensitivity were evaluated using the von Frey filament test. Then, we detected Iba1 immunoreactivity (Iba1-IR) and P2X4R expression in the trigeminal nucleus caudalis (TNC). To understand the effect of microglia and P2X4R on central sensitization of CM, we examined whether minocycline, an inhibitor of microglia activation, and 5-BDBD, a P2X4R antagonist, altered NTG-induced mechanical hyperalgesia. In addition, we also evaluated the effect of 5-BDBD on c-Fos and calcitonin gene-related peptide (CGRP) expression within the TNC.ResultsChronic intermittent administration of NTG resulted in acute and chronic basal mechanical hyperalgesia, accompanied with microglia activation and upregulation of P2X4R expression. Minocycline significantly decreased basal pain hypersensitivity but did not alter acute NTG-induced hyperalgesia. Minocycline also reduced microglia activation. 5-BDBD completely blocked the basal and acute hyperalgesia induced by NTG. This effect was associated with a significant inhibition of the NTG-induced increase in c-Fos protein and CGRP release in the TNC.ConclusionsOur results indicate that blocking microglia activation may have an effect on the prevention of migraine chronification. Moreover, we speculate that the P2X4R may be implicated in the microglia-neuronal signal in the TNC, which contributes to the central sensitization of CM.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1285-3) contains supplementary material, which is available to authorized users.

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“…35,37 On the other hand, TNFα has been shown to reduce CSD amplitudes in a dose-dependent manner. 58 Hence, this proinflammarory cytokine seems to exert complex actions on CSD. In addition, IL-1β is also known to attenuate CSD amplitudes via the GABA A receptor activity at lower concentrations.…”

Section: Effects Of Csd On Microglial Functionmentioning

confidence: 99%

Exploring the role of microglia in cortical spreading depression in neurological disease

Shibata

Suzuki

2017

J Cereb Blood Flow Metab

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Microglia play a pivotal role in innate immunity in the brain. During development, they mature from myeloerythroid progenitor cells in the yolk sac and colonize the brain to establish a resident population of tissue macrophages. In the postnatal brain, they exert phagocytosis and induce inflammatory response against invading pathogens. Microglia also act as guardians of brain homeostasis by surveying the microenvironment using motile processes. Cortical spreading depression (CSD) is a slowly propagating (2–5 mm/min) wave of rapid, near-complete depolarization of neurons and astrocytes followed by a period of electrical suppression of a distinct population of cortical neurons. Not only has CSD been implicated in brain migraine aura, but CSD-like events have also been detected in stroke and traumatic injury. CSD causes a considerable perturbation of the ionic environment in the brain, which may be readily detected by microglia. Although CSD is known to activate microglia, the role of microglial activation in CSD-related neurological disorders remains poorly understood. In this article, we first provide an overview of microglial development and the multiple functions of microglia. Then, we review existing data on the relationship between microglia and CSD and discuss the relevance of CSD-induced microglial activation in neurological disease.

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Tumor necrosis factor reduces the amplitude of rat cortical spreading depression in vivo

Abstract: We identified a functional link between TNF and CSD. TNF activates TNFR2 in cortical inhibitory interneurons. The resulting release of GABA reduces CSD amplitudes. In this manner, TNF might be neuroprotective in pathological conditions.

Cited by 29 publications

References 46 publications

The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization

The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization

Microglia P2X4 receptor contributes to central sensitization following recurrent nitroglycerin stimulation

Exploring the role of microglia in cortical spreading depression in neurological disease

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