Microglia as target for anti-inflammatory approaches to prevent secondary brain injury after subarachnoid hemorrhage (SAH)

Abstract Background Microglia-driven cerebral spreading inflammation is a key contributor to secondary brain injury after SAH. Genetic depletion or deactivation of microglia has been shown to ameliorate neuronal cell death. Therefore, clinically feasible anti-inflammatory approaches counteracting microglia accumulation or activation are interesting targets for SAH treatment. Here, we tested two different methods of interference with microglia-driven cerebral inflammation in a murine SAH model: (i) inflammatory preconditioning and (ii) pharmacological deactivation. Methods 7T-MRI-controlled SAH was induced by endovascular perforation in four groups of C57Bl/6 mice: (i) Sham-operation, (ii) SAH naïve, (iii) SAH followed by inflammatory preconditioning (LPS intraperitoneally), and (iv) SAH followed by pharmacological microglia deactivation (colony-stimulating factor-1 receptor-antagonist PLX3397 intraperitoneally). Microglia accumulation and neuronal cell death (immuno-fluorescence), as well as activation status (RT-PCR for inflammation-associated molecules from isolated microglia) were recorded at day 4 and 14. Toll-like receptor4 (TLR4) status was analyzed using FACS. Results Following SAH, significant cerebral spreading inflammation occurred. Microglia accumulation and pro-inflammatory gene expression were accompanied by neuronal cell death with a maximum on day 14 after SAH. Inflammatory preconditioning as well as PLX3397-treatment resulted in significantly reduced microglia accumulation and activation as well as neuronal cell death. TLR4 surface expression in preconditioned animals was diminished as a sign for receptor activation and internalization. Conclusions Microglia-driven cerebral spreading inflammation following SAH contributes to secondary brain injury. Two microglia-focused treatment strategies, (i) inflammatory preconditioning with LPS and (ii) pharmacological deactivation with PLX3397, led to significant reduction of neuronal cell death. Increased internalization of inflammation-driving TLR4 after preconditioning leaves less receptor molecules on the cell surface, providing a probable explanation for significantly reduced microglia activation. Our findings support microglia-focused treatment strategies to overcome secondary brain injury after SAH. Delayed inflammation onset provides a valuable clinical window of opportunity.

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Effects of S-2474, a novel nonsteroidal anti-inflammatory drug, on amyloid β protein-induced neuronal cell death

British Journal of Pharmacology ◽

10.1038/sj.bjp.0704261 ◽

2001 ◽

Vol 134 (3) ◽

pp. 673-681 ◽

Cited By ~ 39

Author(s):

Tatsurou Yagami ◽

Keiichi Ueda ◽

Kenji Asakura ◽

Toshiyuki Sakaeda ◽

Takayuki Kuroda ◽

...

Keyword(s):

Cell Death ◽

Neuronal Cell Death ◽

Amyloid Β ◽

Neuronal Cell ◽

Amyloid Β Protein ◽

Inflammatory Drug ◽

Β Protein ◽

Anti Inflammatory

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p53-mediated neuronal cell death in ischemic brain injury

Neuroscience Bulletin ◽

10.1007/s12264-010-1111-0 ◽

2010 ◽

Vol 26 (3) ◽

pp. 232-240 ◽

Cited By ~ 54

Author(s):

Li-Zhi Hong ◽

Xiao-Yuan Zhao ◽

Hui-Ling Zhang

Keyword(s):

Cell Death ◽

Brain Injury ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ischemic Brain Injury ◽

Ischemic Brain

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Mesenchymal Stem Cells (MSCs) Coculture Protects [Ca2+]i Orchestrated Oxidant Mediated Damage in Differentiated Neurons In Vitro

Cells ◽

10.3390/cells7120250 ◽

2018 ◽

Vol 7 (12) ◽

pp. 250 ◽

Cited By ~ 9

Author(s):

Adel Alhazzani ◽

Prasanna Rajagopalan ◽

Zaher Albarqi ◽

Anantharam Devaraj ◽

Mohamed Hessian Mohamed ◽

...

Keyword(s):

Cell Death ◽

Transforming Growth Factor ◽

Neuronal Cells ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Apoptotic Cells ◽

Sequence Of Events ◽

Cox 2 ◽

Anti Inflammatory

Cell-therapy modalities using mesenchymal stem (MSCs) in experimental strokes are being investigated due to the role of MSCs in neuroprotection and regeneration. It is necessary to know the sequence of events that occur during stress and how MSCs complement the rescue of neuronal cell death mediated by [Ca2+]i and reactive oxygen species (ROS). In the current study, SH-SY5Y-differentiated neuronal cells were subjected to in vitro cerebral ischemia-like stress and were experimentally rescued from cell death using an MSCs/neuronal cell coculture model. Neuronal cell death was characterized by the induction of proinflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-1β and -12, up to 35-fold with corresponding downregulation of anti-inflammatory cytokine transforming growth factor (TGF)-β, IL-6 and -10 by approximately 1 to 7 fold. Increased intracellular calcium [Ca2+]i and ROS clearly reaffirmed oxidative stress-mediated apoptosis, while upregulation of nuclear factor NF-B and cyclo-oxygenase (COX)-2 expressions, along with ~41% accumulation of early and late phase apoptotic cells, confirmed ischemic stress-mediated cell death. Stressed neuronal cells were rescued from death when cocultured with MSCs via increased expression of anti-inflammatory cytokines (TGF-β, 17%; IL-6, 4%; and IL-10, 13%), significantly downregulated NF-B and proinflammatory COX-2 expression. Further accumulation of early and late apoptotic cells was diminished to 23%, while corresponding cell death decreased from 40% to 17%. Low superoxide dismutase 1 (SOD1) expression at the mRNA level was rescued by MSCs coculture, while no significant changes were observed with catalase (CAT) and glutathione peroxidase (GPx). Interestingly, increased serotonin release into the culture supernatant was proportionate to the elevated [Ca2+]i and corresponding ROS, which were later rescued by the MSCs coculture to near normalcy. Taken together, all of these results primarily support MSCs-mediated modulation of stressed neuronal cell survival in vitro.

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Peroxisome Proliferator-Activated Receptors: “Key” Regulators of Neuroinflammation after Traumatic Brain Injury

PPAR Research ◽

10.1155/2008/538141 ◽

2008 ◽

Vol 2008 ◽

pp. 1-7 ◽

Cited By ~ 27

Author(s):

Philip F. Stahel ◽

Wade R. Smith ◽

Jay Bruchis ◽

Craig H. Rabb

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Neuronal Cell Death ◽

Synthetic Cannabinoids ◽

Experimental Studies ◽

Neuronal Cell ◽

Peroxisome Proliferator ◽

Therapeutic Concept ◽

Anti Inflammatory ◽

Peroxisome Proliferator Activated Receptors

Traumatic brain injury is characterized by neuroinflammatory pathological sequelae which contribute to brain edema and delayed neuronal cell death. Until present, no specific pharmacological compound has been found, which attenuates these pathophysiological events and improves the outcome after head injury. Recent experimental studies suggest that targeting peroxisome proliferator-activated receptors (PPARs) may represent a new anti-inflammatory therapeutic concept for traumatic brain injury. PPARs are “key” transcription factors which inhibit NFκBactivity and downstream transcription products, such as proinflammatory and proapoptotic cytokines. The present review outlines our current understanding of PPAR-mediated neuroprotective mechanisms in the injured brain and discusses potential future anti-inflammatory strategies for head-injured patients, with an emphasis on the putative beneficial combination therapy of synthetic cannabinoids (e.g., dexanabinol) with PPARαagonists (e.g., fenofibrate).

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Disruption of Bax Protein Prevents Neuronal Cell Death but Produces Cognitive Impairment in Mice following Traumatic Brain Injury

Journal of Neurotrauma ◽

10.1089/neu.2007.0441 ◽

2008 ◽

Vol 25 (7) ◽

pp. 755-767 ◽

Cited By ~ 39

Author(s):

Roya Tehranian ◽

Marie E. Rose ◽

Vincent Vagni ◽

Alicia M. Pickrell ◽

Raymond P. Griffith ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Cognitive Impairment ◽

Brain Injury ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Bax Protein

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Reverse glial glutamate uptake triggers neuronal cell death through extrasynaptic NMDA receptor activation

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2009.01.002 ◽

2009 ◽

Vol 40 (4) ◽

pp. 463-473 ◽

Cited By ~ 47

Author(s):

E. Gouix ◽

F. Léveillé ◽

O. Nicole ◽

C. Melon ◽

L. Had-Aissouni ◽

...

Keyword(s):

Cell Death ◽

Nmda Receptor ◽

Glutamate Uptake ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Receptor Activation ◽

Nmda Receptor Activation

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UPEI-400, a Conjugate of Lipoic Acid and Scopoletin, Mediates Neuroprotection in a Rat Model of Ischemia/Reperfusion

10.20944/preprints201610.0083.v1 ◽

2016 ◽

Author(s):

Barry J. Connell ◽

Monique C. Saleh ◽

Desikan Rajagopal ◽

Tarek M. Saleh

Keyword(s):

Cell Death ◽

Lipoic Acid ◽

Ischemia Reperfusion ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Covalent Bond ◽

Male Rats ◽

In Vivo Model ◽

Naturally Occurring ◽

Anti Inflammatory

Background: Previously, our laboratory has provided evidence that pre-administration of the antioxidant, lipoic acid covalently bonded to various naturally occurring antioxidants, enhanced neuroprotective capacity compared to the administration of lipoic acid on its own. The naturally occurring compound scopoletin, a coumarin derivative, has been shown in various in vitro studies to have both antioxidant and anti-inflammatory mechanism of actions. To date, the effect of scopoletin on neuronal cell death in an in vivo model of ischemia or ischemia-reperfusion has not been investigated. Therefore, the present investigation was designed to determine if scopoletin on its own, or a co-drug consisting of lipoic acid and scopoletin covalent bond, named UPEI-400, would be capable of demonstrating a similar neuroprotective efficacy. Methods: Using a rodent model of stroke in male rats (anesthetized with Inactin®; 100 mg/kg, iv), the middle cerebral artery was permanently occluded for 6 hours (pMCAO), or in separate animals, occluded for 30 min followed by 5.5 hrs of reperfusion (ischemia/reperfusion; I/R). Results: Pre-administration of either scopoletin or UPEI-400 significantly decreased infarct volume in the I/R model (p<0.05), but not in the pMCAO model of stroke. However, UPEI-400 was ~1000 times more potent as compared to scopoletin on its own. The optimal dose of UPEI-400 was then injected during the occlusion and at several time points during reperfusion and significant neuroprotection was observed for up to 150 mins following the start of reperfusion (p<0.05). Conclusion: The data suggest that synthetic combination of scopoletin with lipoic acid (UPEI-400) is a more effective neuroprotectant that either compound on their own. Also, since UPEI-400 was only effective in a model of I/R, it is possible that it may act to enhance neuronal antioxidant capacity and/or upregulate anti-inflammatory pathways to prevent the neuronal cell death.

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