Post-stroke inflammation—target or tool for therapy?

Abstract

Inflammation is currently considered a prime target for the development of new stroke therapies. In the acute phase of ischemic stroke, microglia are activated and then circulating immune cells invade the peri-infarct and infarct core. Resident and infiltrating cells together orchestrate the post-stroke inflammatory response, communicating with each other and the ischemic neurons, through soluble and membrane-bound signaling molecules, including cytokines. Inflammation can be both detrimental and beneficial at particular stages after a stroke. While it can contribute to expansion of the infarct, it is also responsible for infarct resolution, and influences remodeling and repair. Several pre-clinical and clinical proof-of-concept studies have suggested the effectiveness of pharmacological interventions that target inflammation post-stroke. Experimental evidence shows that targeting certain inflammatory cytokines, such as tumor necrosis factor, interleukin (IL)-1, IL-6, and IL-10, holds promise. However, as these cytokines possess non-redundant protective and immunoregulatory functions, their neutralization or augmentation carries a risk of unwanted side effects, and clinical translation is, therefore, challenging. This review summarizes the cell biology of the post-stroke inflammatory response and discusses pharmacological interventions targeting inflammation in the acute phase after a stroke that may be used alone or in combination with recanalization therapies. Development of next-generation immune therapies should ideally aim at selectively neutralizing pathogenic immune signaling, enhancing tissue preservation, promoting neurological recovery and leaving normal function intact.

Continuous administration of the p38α inhibitor neflamapimod during the subacute phase after transient ischemia-induced stroke in the rat promotes dose-dependent functional recovery accompanied by increase in brain BDNF protein level

“…Brain-derived neurotrophic factor (BDNF) promotes neural plasticity and recovery after stroke [35] and the proinflammatory cytokine interleukin-1 beta (IL-1) is upregulated after ischemic stroke [36][37][38][39][40]. In subacute/chronic inflammatory conditions, IL-1 is known to be a key component of the inflammatory response in the brain that mediates neurodegenerative effects of inflammation on cognition and synaptic plasticity [41].…”

Neurofilaments: The C-Reactive Protein of Neurology

“…Single molecule array technology (Simoa™) was introduced in 2010 [3], however, and its higher sensitivity has greatly helped in establishing NF-L as a biomarker in CSF, serum, and plasma [4,5]. Here, we review fundamental developments in the assessment of NFs as biomarkers in Neurofilament immunohistochemical staining was performed on parallel tissue sections from post-mortem ischemic brain tissue used in previous studies [6][7][8][9]. Staining was performed using similar protocols and the following antibody: monoclonal mouse anti-neurofilament (phosphorylated and non-phosphorylated NF-H chain) antibody (clone N52, 1:1000, Sigma-Aldrich, St. Louis, MO, USA).…”

A pragmatic, adaptive clinical trial design for a rare disease: The FOcal Cerebral Arteriopathy Steroid (FOCAS) trial

“…3,4 However, there are potential downsides: experimental evidence suggests that the post-stroke inflammatory response has beneficial (in addition to detrimental) effects, with roles in infarct resolution, and brain remodeling and repair. 5 Hence, pediatric stroke experts agree on the need for a clinical trial to guide FCA management. 1 However, design of an FCA trial faces two major challenges: the rarity of FCA and its acuity.…”