Chronic inflammation, cognitive impairment, and distal brain region alteration following intracerebral hemorrhage

Shi, Elaine; Shi, Kaibin; Qiu, Shenfeng; Sheth, Kevin N; Lawton, Michael T.; Ducruet, Andrew F.

doi:10.1096/fj.201900257r

Cited by 57 publications

(24 citation statements)

References 39 publications

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“…In agreement with our ndings, Cope and colleagues recently found that microglial activation plays an active role in obesity-associated cognitive decline since blocking microglial activation by minocycline prevented loss of dendritic spine and cognitive decline in obese mice [45]. Depletion of microglia by CSF1R inhibitors, such as PLX3397 and PLX5622, was also associated improved cognitive performance in experimental mouse models of AD [46], intracerebral hemorrhage [47] and irradiation-induced memory de cits [48].…”

Section: Discussionsupporting

confidence: 89%

Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Zhang

Hou

et al. 2020

Preprint

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BackgroundCognitive decline occurs frequently in Parkinson’s disease (PD), which greatly decreases the life quality of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by over-activated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using rotenone-induced mouse PD model. Methods: To evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by morris water maze, objective recognition and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation and apoptosis were determined by immunohistochemistry, Western blot or immunofluorescence staining. The gene expressions of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively. ResultsRotenone dose-dependently induced cognitive deficits in mice by showing decreased abilities of novel objective recognition, passive avoidance, as well as morris water maze performance compared with vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. Time course study revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 or minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in combined PLX3397 or minocycline and rotenone-treated mice compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis. ConclusionsTaken together, our findings suggested that microglial activation contributed to cognitive impairments in rotenone-induced mouse PD model via neuroinflammation, oxidative stress and apoptosis, providing novel insight for the immunopathogensis of cognitive deficits in PD.

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Section: Discussionsupporting

confidence: 89%

Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Zhang

Hou

et al. 2020

Preprint

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“…This is consistent with brain injury in cardiac arrest rats being attenuated by blocking HMGB1 activity [91]. These associations of biomarkers and mediators in AD and PD are consistent with the therapeutic implications of recent detailed analyses of global inflammation in experimental stroke [94], intracerebral hemorrhage [95], and TBI [96]…”

Section: Changes In Triggering Receptor Expressed Onsupporting

confidence: 77%

Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches

Clark

Vissel

2021

JAD

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Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post-traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer’s disease and Parkinson’s disease sufferers. In contrast, Alzheimer’s disease and Parkinson’s disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.

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“…Other studies [31,32] confirmed that cortical infarction can lead to hippocampal atrophy, metabolic dysfunction, and memory decline. Recently, Shi et al detected significant cognitive impairment after basal ganglia hemorrhage, accompanied by reduced spine density on ipsilateral hippocampus neurons [33]. In the present study, we found that cognitive function is diminished as early as week 1 after ICH, and whole brain-based analysis of DTI data showed a decline in FA values in the ipsilateral hippocampus.…”

Section: Agingsupporting

confidence: 70%

Secondary injury to distal regions after intracerebral hemorrhage influence neurological functional outcome

Song

Liu

Zheng

et al. 2020

Aging

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Although many studies have focused on functional impairment after intracerebral hemorrhage, little is known about the relationship between secondary injuries to distal regions and neurological function. Our study aimed to evaluate the secondary injuries after intracerebral hemorrhage and explore their relationship to neurological functional outcome. Twenty-one patients with hemorrhages in supratentorial, deep locations and 10 healthy subjects were recruited. Longitudinal examinations of diffusion tensor imaging, hydrogen proton magnetic resonance spectroscopy imaging and neuropsychological assessment were performed after weeks 1 and 12 to elucidate the relationship between magnetic resonance imaging parameters and neurologic outcomes. By week 12, motor function had significantly improved, but cognitive function had deteriorated compared to week 1. Fractional anisotropy values for the ipsilateral cerebral peduncle correlated with motor function at week 1. No significant correlation between fractional anisotropy for the ipsilateral cerebral peduncle and the Fugl-Meyer Motor Scale was found at week 12. Fractional anisotropy values for the ipsilateral hippocampus were related to the Montreal Cognitive Assessment and Mini-Mental State Examination at weeks 1 and 12. Deep supratentorial hemorrhage may result in injury to distal regions, which correlate with impaired motor and cognitive function.

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Chronic inflammation, cognitive impairment, and distal brain region alteration following intracerebral hemorrhage

Cited by 57 publications

References 39 publications

Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches

Secondary injury to distal regions after intracerebral hemorrhage influence neurological functional outcome

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