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Back To Blog > Could Reducing Neuroinflammation Following Stroke Provide Better Therapeutic Outcomes for Patients?


This post is by guest blogger Matthew Savage 

What is a stroke and why is it so dangerous?

Ischaemic stroke is a serious condition that has limited treatments and often results in lasting functional and psychological damage. The quicker a person receives treatment the better, but people who survive stroke are often left with long term problems. It is defined as a neurological deficit attributed by an acute episode of focal dysfunction in the central nervous system (CNS) (Zhang, 2016), but is more simply a loss of blood supply to the brain. Amid the various events that lead to disability and mortality, neuroinflammation post stroke plays a significant role in both the damage and repair of brain tissue. Following ischaemic stroke, glial cells such as microglia and astrocytes are activated within just a few hours, producing a range of chemokines and cytokines, small proteins vital for cell signalling. However, this activation following ischemic insult can also become dysfunctional, leading to cell death. This makes them a very important as a therapeutic target for treatment.

The dangers of Microglia and Astrocytes activation following stroke

Following ischaemic stroke, microglia are activated and undergo both phenotypical and morphological changes. Reactive microglia are divided into two different phenotypes, or expressions: pro-inflammatory phenotype (M1) and anti-inflammatory phenotype (M2). Anti-inflammatory processes tend to occur in the early stages of ischaemic stroke, with pro-inflammatory processes occurring at later stages. M1 microglia encourage the release of pro-inflammatory cytokines, exacerbating brain injury, whilst M2 microglia work to reduce inflammation, providing protective effects. Sun et al. (2015) showed that suppressing the activation of microglia with 2% of isoflurane, a type of general anaesthetic, in rats with transient focal cerebral ischaemia resulted in reduced apoptosis (cell death) and volume of infarction, or tissue death. In addition to this, Sun et al noted a significant decrease of microglial activation in the ischaemic penumbra. This was an important find, as the ischaemic penumbra refers to a rim of tissue lying just outside the core ischemic region, the area most severely damaged by stroke or ischemic event. Within this area, blood and oxygen flow are often diminished significantly, resulting in serious neuronal death.

Astrocytes – Specialist cells which can help and hinder our brain

Astrocytes are usually involved in negative responses to brain injury, however, they are also specialised glial cells that play a significant role in mediating homeostatic functions of the neurovascular unit through energy provision, regulation of blood flow and many other important functions. However, following ischaemic stroke, astrocytes multiplication occurs and this increases glial fibrillary acidic protein (GFAP) levels, a protein that provides support and strength to cells under normal circumstances. In excess, GFAP has been linked with neurological disability and decreased positive outcomes in patients following a traumatic brain injury (Nylen et al, 2005) due to the Glial scarring it causes. This is the most characteristic profile of the reactive astrogliosis, a process whereby astrocytes abnormally increase in numbers and this then inhibits axon regeneration, causes inflammation and increases neurotoxicity, which is brought about by an increase of pro-inflammatory factors. Conversely, processes of reactive astrogliosis can have beneficial effects which protect CNS tissue and regulate the immune system, induces neurogenesis, and maintains the blood–brain barrier (BBB). Because of this fact, the balance of astrocytes in the brain has an optimum level and it is vital this is maintained to ensure more positive outcomes for patients following stroke.

Neuroinflammation as a therapeutic target for ischaemic stroke

Certain stem cells have shown promise in their ability to reduce inflammation following stroke and thus aid to reduce damage to the brain. Transplantation of mesenchymal stem cells (MSCs) into animal models of ischaemic stroke mediate an immune response by stimulating neurogenesis, astrogenesis and oligondendrogenesis, the process by which oligodendrocytes (another large glial cell which is responsible for producing the myelin sheath that insulate neuronal axons and speed up the transportation of electrical nerve impulses) are produced. In vitro experimental studies in brain ischaemia models suggest that even a brief presence of MSCs have a significant positive effect on neurons at the site of injury whereby undesirable inflammatory processes are significantly reduced (Huang et al., 2014). Hung et al. (2007) showed the positive effects of MSCs by combining the supernatant from MSC culture with a primary culture of endothelial cells isolated from human aorta. The addition of MSCs to endothelial cells injured by ischaemia resulted in a decrease of apoptosis, and the promotion of angiogenesis. Experiments that use neuroblastoma cells and neurons have demonstrated that MSCs decrease ischaemia induced death of these cells in experiments that use either supernatants from MSCs culture or co-cultures of cells, thus further supporting the neuroprotective effects of MSCs (Scheibe et al., 2012). This reduces inflammation and aims to stop continuation of damage in the brain past the acute stage.

Conclusion

Accumulating evidence suggests that neuroinflammation plays a significant role in ischaemic stroke pathogenesis, thus making neuroinflammation an intriguing target for potential therapeutic intervention. However, there has been significant evidence that demonstrates the multiphasic roles of inflammatory cells, whereby the inhibition of a particular pathway at the incorrect time may exacerbate stroke induced injury. Stroke pathophysiology therefore requires further study with time-defined treatment to allow for optimum treatment and long-term protective effects. Mechanism of how genetically modified astrocytes maintain a neuroprotective state for a significant period is unknown, but this provides an exciting avenue for further study. Investigating the modulators of the activation & polarisation of microglia is important as it provides more potential therapeutic targets of microglia as a treatment of ischaemia. Further research should also combine models of ischaemic stroke with relevant clinical conditions (e.g.atherosclerosis) to translate the results from these experimental studies to clinical significance, thus allowing for the development of successful stroke treatments.

About Matt Savage

Matthew Savage has an MSc in Psychology, is a qualified personal trainer, and has worked within the field of cognitive rehabilitation for 5 years. He is an FA qualified football coach, with a keen interest in moral behaviour and wellbeing within team sports. 

References

Dabrowska, S., Andrzejewska, A., Lukomska, B., & Janowski, M. (2019). Neuroinflammation as a target for treatment of stroke using mesenchymal stem cells and extracellular vesicles. Journal of neuroinflammation, 16(1), 178. DOI: 10.1186/s12974-019-1571-8

Dimitrijevic, O., Stamatovic, S., Keep, R. and Andjelkovic, A., (2005). Effects of the Chemokine CCL2 on Blood–Brain Barrier Permeability during Ischemia–Reperfusion Injury. Journal of Cerebral Blood Flow & Metabolism, 26(6), pp.797-810.

Sacco, R., Kasner, S., Broderick, J., Caplan, L., Connors, J., Culebras, A., Elkind, M., George, M., Hamdan, A., Higashida, R., Hoh, B., Janis, L., Kase,

C., Kleindorfer, D., Lee, J., Moseley, M., Peterson, E., Turan, T., Valderrama, A. and Vinters, H., (2013). An Updated Definition of Stroke for the 21st Century. Stroke, 44(7), pp.2064-2089.

Scheibe, F., Ladhoff, J., Huck, J., Grohmann, M., Blazej, K., Oersal, A., Baeva, N., Seifert, M. and Priller, J., (2012). Immune Effects of Mesenchymal Stromal Cells in Experimental Stroke. Journal of Cerebral Blood Flow & Metabolism, 32(8), pp.1578-1588.

Shi, Y., Zhang, L., Pu, H., Mao, L., Hu, X., Jiang, X., Xu, N., Stetler, R., Zhang, F., Liu, X., Leak, R., Keep, R., Ji, X. and Chen, J., (2016). Rapid endothelial cytoskeletal reorganization enables early blood–brain barrier disruption and long-term ischaemic reperfusion brain injury. Nature Communications, 7(1).

Sun, G., Chen, Z., Jasmer, K., Chuang, D., Gu, Z., Hannink, M. and Simonyi, A., (2015). Quercetin Attenuates Inflammatory Responses in BV-2. Microglial Cells: Role of MAPKs on the Nrf2 Pathway and Induction of Heme Oxygenase-1. PLOS ONE, 10(10), p.e0141509.

Yang, Y., & Rosenberg, G. A. (2015). Matrix metalloproteinases as therapeutic targets for stroke. Brain research, 1623, 30–38. DOI: 10.1016/j.brainres.2015.04.024

Yong, H., Rawji, K., Ghorbani, S., Xue, M. and Yong, V., (2019). The benefits of neuroinflammation for the repair of the injured central nervous system. Cellular & Molecular Immunology, 16(6), pp.540-546.

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