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Focal brain ischemia in mice does not cause electrophysiological signs of critical illness neuropathy.

ABSTRACT: OBJECTIVE:Critical illness polyneuropathy (CIP) is a common complication of severe systemic illness treated in intensive care medicine. Ischemic stroke leads to an acute critical injury of the brain with hemiparesis, immunosuppression and subsequent infections, all of which require extended medical treatment. Stroke-induced sarcopenia further contributes to poor rehabilitation and is characterized by muscle wasting and denervation in the paralytic, but also the unaffected limbs. Therefore, we asked whether stroke leads to an additional CIP-like neurodegeneration. RESULTS:Focal brain ischemia was induced in adult mice by 60-min middle cerebral artery occlusion (MCAo) following reperfusion and led to functional deficits and marked hemispheric brain atrophy. Nerve conduction function and muscle potentials were measured in the ipsilateral sciatic nerve and gastrocnemius and quadriceps muscle with electroneurography/-myography on days 10, 22, 44 after stroke. An additional crush-injury to the sciatic nerve was included in two sham mice as positive control (sham?+). We found no differences in nerve conduction function nor spontaneous electromyographic activity between MCAo and sham animals. Sham?+?mice developed marked reduction of the motor action potential amplitudes and conduction velocities with pathologic spontaneous activity. In conclusion, we found no peripheral nerve dysfunction/degeneration as signs of a CIP-like phenotype after MCAo.

SUBMITTER: Huehnchen P

PROVIDER: S-EPMC7488231 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Focal brain ischemia in mice does not cause electrophysiological signs of critical illness neuropathy.

Huehnchen Petra P Toyka Klaus Viktor KV Gertz Karen K Endres Matthias M Boehmerle Wolfgang W

BMC research notes 20200910 1

<h4>Objective</h4>Critical illness polyneuropathy (CIP) is a common complication of severe systemic illness treated in intensive care medicine. Ischemic stroke leads to an acute critical injury of the brain with hemiparesis, immunosuppression and subsequent infections, all of which require extended medical treatment. Stroke-induced sarcopenia further contributes to poor rehabilitation and is characterized by muscle wasting and denervation in the paralytic, but also the unaffected limbs. Therefor ...[more]

PMID: 32912287

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Project description:BACKGROUND:Lysophosphatidic acid receptor 1 (LPA1) is in the spotlight because its synthetic antagonist has been under clinical trials for lung fibrosis and psoriasis. Targeting LPA1 might also be a therapeutic strategy for cerebral ischemia because LPA1 triggers microglial activation, a core pathogenesis in cerebral ischemia. Here, we addressed this possibility using a mouse model of transient middle cerebral artery occlusion (tMCAO). METHODS:To address the role of LPA1 in the ischemic brain damage, we used AM095, a selective LPA1 antagonist, as a pharmacological tool and lentivirus bearing a specific LPA1 shRNA as a genetic tool. Brain injury after tMCAO challenge was accessed by determining brain infarction and neurological deficit score. Role of LPA1 in tMCAO-induced microglial activation was ascertained by immunohistochemical analysis. Proinflammatory responses in the ischemic brain were determined by qRT-PCR and immunohistochemical analyses, which were validated in vitro using mouse primary microglia. Activation of MAPKs and PI3K/Akt was determined by Western blot analysis. RESULTS:AM095 administration immediately after reperfusion attenuated brain damage such as brain infarction and neurological deficit at 1?day after tMCAO, which was reaffirmed by LPA1 shRNA lentivirus. AM095 administration also attenuated brain infarction and neurological deficit at 3?days after tMCAO. LPA1 antagonism attenuated microglial activation; it reduced numbers and soma size of activated microglia, reversed their morphology into less toxic one, and reduced microglial proliferation. Additionally, LPA1 antagonism reduced mRNA expression levels of proinflammatory cytokines and suppressed NF-?B activation, demonstrating its regulatory role of proinflammatory responses in the ischemic brain. Particularly, these LPA1-driven proinflammatory responses appeared to occur in activated microglia because NF-?B activation occurred mainly in activated microglia in the ischemic brain. Regulatory role of LPA1 in proinflammatory responses of microglia was further supported by in vitro findings using lipopolysaccharide-stimulated cultured microglia, showing that suppressing LPA1 activity reduced mRNA expression levels of proinflammatory cytokines. In the ischemic brain, LPA1 influenced PI3K/Akt and MAPKs; suppressing LPA1 activity decreased MAPK activation and increased Akt phosphorylation. CONCLUSION:This study demonstrates that LPA1 is a new etiological factor for cerebral ischemia, strongly indicating that its modulation can be a potential strategy to reduce ischemic brain damage.

Project description:One of the major players in the pathophysiology of cerebral ischemia is disrupted homeostasis of glutamatergic neurotransmission, resulting in elevated extracellular glutamate (Glu) concentrations and excitotoxicity-related cell death. In the brain, Glu concentrations are regulated by Glu transporters, including Glu transporter-1 (GLT-1) and cystine/Glu antiporter (system xc-). Modulation of these transporters by administration of ceftriaxone (CEF, 200 mg/kg, i.p.) or N-acetylcysteine (NAC, 150 mg/kg, i.p.) for 5 days before focal cerebral ischemia may induce brain tolerance to ischemia by significantly limiting stroke-related damage and normalizing Glu concentrations. In the present study, focal cerebral ischemia was induced by 90-minute middle cerebral artery occlusion (MCAO). We compared the effects of CEF and NAC pretreatment on Glu concentrations in extracellular fluid and cellular-specific expression of GLT-1 and xCT with the effects of two reference preconditioning methods, namely, ischemic preconditioning and chemical preconditioning in rats. Both CEF and NAC significantly reduced Glu levels in the frontal cortex and hippocampus during focal cerebral ischemia, and this decrease was comparable with the Glu level achieved with the reference preconditioning strategies. The results of immunofluorescence staining of GLT-1 and xCT on astrocytes, neurons and microglia accounted for the observed changes in extracellular Glu levels to a certain extent. Briefly, after MCAO, the expression of GLT-1 on astrocytes decreased, but pretreatment with CEF seemed to prevent this downregulation. In addition, every intervention used in this study seemed to reduce xCT expression on astrocytes and neurons. The results of this study indicate that modulation of Glu transporter expression may restore Glu homeostasis. Moreover, our results suggest that CEF and NAC may induce brain tolerance to ischemia by influencing GLT-1 and system xc- expression levels. These transporters are presumably good targets for the development of novel therapies for brain ischemia.

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Focal brain ischemia in mice does not cause electrophysiological signs of critical illness neuropathy.

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Focal brain ischemia in mice does not cause electrophysiological signs of critical illness neuropathy.

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