Update on Inflammatory Biomarkers and Treatments in Ischemic Stroke

Aldo Bonaventura, Luca Liberale, Alessandra Vecchié, Matteo Casula, Federico Carbone, Franco Dallegri, Fabrizio Montecucco, Aldo Bonaventura, Luca Liberale, Alessandra Vecchié, Matteo Casula, Federico Carbone, Franco Dallegri, Fabrizio Montecucco

Abstract

After an acute ischemic stroke (AIS), inflammatory processes are able to concomitantly induce both beneficial and detrimental effects. In this narrative review, we updated evidence on the inflammatory pathways and mediators that are investigated as promising therapeutic targets. We searched for papers on PubMed and MEDLINE up to August 2016. The terms searched alone or in combination were: ischemic stroke, inflammation, oxidative stress, ischemia reperfusion, innate immunity, adaptive immunity, autoimmunity. Inflammation in AIS is characterized by a storm of cytokines, chemokines, and Damage-Associated Molecular Patterns (DAMPs) released by several cells contributing to exacerbate the tissue injury both in the acute and reparative phases. Interestingly, many biomarkers have been studied, but none of these reflected the complexity of systemic immune response. Reperfusion therapies showed a good efficacy in the recovery after an AIS. New therapies appear promising both in pre-clinical and clinical studies, but still need more detailed studies to be translated in the ordinary clinical practice. In spite of clinical progresses, no beneficial long-term interventions targeting inflammation are currently available. Our knowledge about cells, biomarkers, and inflammatory markers is growing and is hoped to better evaluate the impact of new treatments, such as monoclonal antibodies and cell-based therapies.

Keywords: auto-antibodies; biomarkers; inflammation; injury; ischemic stroke; neutrophils.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of neuronal death in acute ischemic stroke. After brain ischemia occurs, a reduction in the oxygen and glucose supply is carried out leading to the depolarization of membranes and finally to a great increase in intracellular calcium concentration and release of glutamate. Glutamate receptors, once activated, are responsible for the further increase in calcium concentration. The detrimental effects of this huge calcium concentration are proteolysis, lipolysis, mitochondrial damage, and increase in nitric oxide synthase activity. Despite the re-oxygenation should favor the recovery, it triggers reactive oxygen species production, amplifying the damage, ultimately leading to death of neuronal cells. Ca2+: calcium. NOS: nitrix oxide synthase. ROS: reactive oxygen species.
Figure 2
Figure 2
Inflammatory cells in post-ischemic brain injury and reparation. Inflammatory mediators released by the ischemic zone promote neutrophil activation and recruitment with a resulting effect on the blood-brain barrier and brain parenchyma. Resident macrophages of the brain (microglia) and circulating monocytes are early involved in the inflammatory response through an M1-switching with production of inflammatory mediators, such as reactive oxygen species, matrix metalloproteinases (MMPs), cytokines, and chemokines. Both neutrophils and macrophages (in particular M2 phenotype) are involved in late resolution through the production of anti-inflammatory and pro-angiogenic mediators. The adaptive immunity contribution is partly mediated by lymphocytes. CD4+, CD8+, and γδ T cells play a detrimental role, while Treg and Breg lymphocytes are involved in the resolution phase. IL: interleukin; TNF-α: tumour necrosis factor α; CCL: C-C motif chemokine ligand; VEGF: vascular endothelial growth factor; TGF-β: transforming growth factor β; IFN-γ: interferon γ.
Figure 3
Figure 3
Estimated pathways mediated by oxidative stress. ROS can activate a great variety of cell signaling pathways within a neuronal cells with contrasting properties. Pathways involved in the promoting of cell death are represented by p38, c-Jun N-terminal kinase, p53, and extracellular signal-regulated kinase, while protective pathways are those mediated by phosphoinositide 3-kinase/Akt, hypoxia-inducible factor 1, and heat shock transcription factor 1. ROS: reactive oxygen species. JNK: c-Jun N-terminal kinase. ERK: extracellular signal-regulated kinase. MAPK: mitogen-activated protein kinase. ASK-1: apoptosis signal-regulating kinase-1. PKC: protein kinase C. JAK: Janus kinase. STAT: signal transducer and activator of transcription. ATM: ataxia telangectasia mutated. PI3K: phosphatidylinositol 3-kinase. NFκB: nuclear factor kappa-light-chain-enhancer of activated B cell. PCLγ1: phospholipase C gamma 1. HSF1: heat shock transcription factor 1. HIF1: hypoxia-inducible factor 1.
Figure 4
Figure 4
Diagnostic and prognostic markers in ischemic stroke. APN: adiponectin. CRP: C-reactive protein. H-FABP: heart-type fatty acid binding protein. HMGB: high mobility group box. IL: interleukin. MDA: malonildyaldeide. MMP: matrix metalloproteinase. MPO: myeloperoxidase. NSE: neuron-specific enolase. PCT: procalcitonin. TBARS: thiobarbituric acid reactive substances. VCAM: vascular cell adhesion molecule. “?” stands for putative or uncertain role.
Figure 5
Figure 5
Anti-inflammatory treatments in stroke pathophysiology. Inflammatory and immune-mediated mechanisms of neuronal injury have been fully investigated in last years. As a result, many drugs modulating these pathways have been tested initially in animal models of stroke and then in humans. Neuronal depolarization and excitotoxicity are main targets for citalopram and donepezil. Edaravone mainly acts as a reactive oxygen species scavenger, while statins share several mechanisms with other drugs and furthermore promote angiogenesis. BBB: blood-brain barrier; CD: cluster of differentiation; COX: cyclooxygenase; IL: interleukin; O2−: superoxyde ion; TNF: tumor necrosis factor; Ra: receptor agonist.

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