**7. Conclusions**

Neuroinflammation in post-ischemic brain neurodegeneration is extremely complex, with multiphase pro-inflammatory responses without causal treatment. In the case of ischemic neuronal cell damage, the locally and systemically released chemokines, cytokines, and ROS play an important and mutual role of triggering neuroinflammation in the brain. In inflammation of the nervous system, the blood–brain barrier is partially impaired and allows for increased, but not completely uncontrolled, entry of immune cells into the brain. Changes in the perivascular space and chemokine environment, coupled with impairment of the glial limitans, ultimately allow immune cells to infiltrate into the parenchyma of the brain, resulting in impaired brain function and hence exacerbation of clinical disease symptoms. An in-depth understanding of the specific pathological mechanisms used by different types of immune cells to cross the blood–brain barrier would improve therapeutic targeting by inhibiting potentially brain-damaging subsets of immune cells, while leaving the brain's positive immune surveillance largely intact. Post-ischemic brain neurodegeneration with neuroinflammation begins in earnest when monocytes and leukocytes reach the brain, activating resident cells such as astrocytes and microglia and endothelial cells, and releasing another pool of pro-inflammatory mediators. Moreover, the evidence shows that cells involved in neuroinflammation have dual helper and deleterious functions, in fact, the same pathway, inactivated at different times, can increase or decrease ischemic damage to brain tissue. In view of the above, any future therapies should take into account the timing of their application post-ischemia. Based on the latest data, many genes can influence the course, extent of the damaged area, and prognosis in post-ischemic brain neurodegeneration. Neuroinflammation is a complex phenomenon governed by many factors that play a key role not only in the pathogenesis of post-ischemic injury, but also in determining its evolution; therefore, post-ischemic neuroinflammation may be a promising target in developing new therapeutic strategies for neurodegenerative diseases.

In summary, neuroinflammatory cells may express various activities leading eventually to either beneficial of harmful outcomes (Figure 1). No doubt, neuroinflammation is a key player in the development of ischemic neuropathology, as discussed in Section 6. A good example of the ambivalent role of neuroinflammation may be the broadly expressed pleiotropic protein osteopontin, which plays a role in neurodegenerative conditions, including Alzheimer's disease [124]. On one hand, osteopontin is associated with detrimental effects on neurons due to recruiting inflammatory cells to the lesioned area. On the other hand, the protein may promote neuronal repair/regeneration via the inflammatory response [124]. These clearly opposed activities may be partially due to different functional domains of osteopontin that are exposed following MMP or thrombin cleavages [124].

**Author Contributions:** Conceptualization, R.P. and S.J.C.; methodology, S.J.; software, S.J.; validation, R.P. and S.J.C.; formal analysis, R.P.; investigation, S.J.; resources, S.J.; data curation, R.P.; writing original draft preparation, R.P.; writing—review and editing, R.P. and S.J.C.; visualization, R.P.; supervision, R.P.; project administration, R.P.; funding acquisition, R.P. and S.J.C. All authors have read and agreed to the published version of the manuscript.

**Funding:** The authors acknowledge the financial support from the following institutions: The Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland (T3-RP) and the Medical University of Lublin, Lublin, Poland (DS 475/20-SJC).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
