**1. Introduction**

Brain ischemia and its consequences in humans are third most frequent cause of disability in 80% of survivors [1], the second most common cause of dementia, and second leading cause of death in the world [2–6]. Every year brain ischemia affects 17 million people worldwide, of whom 6 million die, and the other 5 million are permanently disabled [5,7,8]. The incidence of ischemic stroke in men is around 63 per 100,000 and in women around 59 per 100,000, which suggests that men are more affected by the disease than women [8]. The risk of ischemic stroke is age-related, with about 75% of all cases occurring in patients over 64 years of age, and about 25% of cases occurring in young people, suggesting that the pathology does not only affect the elderly [8]. Worldwide, the number of post-ischemic cases is currently estimated at around 33 million [5,7]. According to forecasts, the number of cases will increase to about 77 million in 2030 [5,7]. If the trend in ischemic stroke incidence continues, there will be about 12 million deaths by 2030, 70 million people will survive a stroke, and more than 200 million disability-adjusted life years will be recorded worldwide annually [5,9]. In 2010, the annual cost of treating stroke patients in Europe was around EUR 64 billion [5]. In the UK, stroke results in therapeutic and social costs of GBP 9 billion per year, with care costs accounting for about 5% of the national health system expenditure [10].

Human and animal studies have revealed that brain ischemia/ischemic stroke are risk factors for Alzheimer's disease [11–13] and vice versa [14,15]. In the first year poststroke, 4 out of 10 cases have some degree of cognitive impairment [16]. The diagnosis of dementia immediately post-stroke is difficult due to additional deficits in both global and individual cognition, e.g., attention and processing speed, language, memory, and

**Citation:** Pluta, R.; Januszewski, S.; Czuczwar, S.J. Neuroinflammation in Post-Ischemic Neurodegeneration of the Brain: Friend, Foe, or Both? *Int. J. Mol. Sci.* **2021**, *22*, 4405. https:// doi.org/10.3390/ijms22094405

Academic Editor: Anne Vejux

Received: 6 April 2021 Accepted: 19 April 2021 Published: 23 April 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

frontal executive functions may be impaired [9]. History of ischemic stroke has been shown to be an important risk factor for the development of dementia [4,9,11,15,17,18]. It has been shown that cerebral ischemia accelerates the onset of dementia by 10 years [19]; in 10% of cases dementia will develop soon after the first stroke, and in about 41% cases it develops after a repeated stroke [9,20]. Within 25 years of post-stroke survival, the estimated development of dementia is approximately 48% [5].

The phenomena following experimental cerebral ischemia and human ischemic stroke are under constant investigation and are revealing interesting new data. Studies conducted over the last 5 years have significantly expanded our understanding of the genetic basis of brain neurodegeneration following ischemia. It is now well known that development of ischemic brain neurodegeneration is caused by a set of genetic changes that lead to neuronal loss in an amyloid and tau protein dependent manner [21–25], with progressive neuroinflammation [26,27] resulting in uncontrolled irreversible brain atrophy [17,28–30] with the development of full-blown dementia [31–33]. Disruption of blood supply to the brain causes neuronal death and, consequently, brain atrophy with progressive dementia. Disruption of many pathways, including oxidative stress, excitotoxicity, neuroinflammation, blood–brain barrier permeability, and others, at least partially explains post-ischemic neurodegeneration of the brain. Post-ischemic damage to neurons causes a significant release of glutamate, leading to over-activation of N-methyl-D-aspartate (NMDA) receptors and a massive Ca2+ inflow to neurons, resulting in their death [34]. As a result of ischemia, neurons and astrocytes produce reactive oxygen species (ROS), and the same mechanism reduces glutathione, an essential antioxidant that prevents DNA damage from ROS [35]. Irreversibly damaged brain cells and their remains, without the presence of microorganisms, trigger neuroinflammation after cerebral ischemia [8,36]. Post-ischemic oxidative stress and inflammatory processes, inter alia, cause additional damage to the blood–brain barrier and enable activated blood immune cells, such as T-lymphocytes, platelets, and neutrophils, to reach the ischemic site of the brain [8,37,38]. After the accumulation of activated immune cells from the blood in the ischemic areas of the brain, microglial cells are activated as a result of an increase in extracellular ATP after its release from the membranes of necrotic cells [39]. The activated microglia secretes pro-inflammatory factors such as cytokines and develops phagocytic properties [40]. Microglia activation has beneficial effects as it promotes the generation of growth factors such as brain-derived neurotrophic factors and removes necrotic tissue and ischemic debris, but the release of pro-inflammatory cytokines (such as tumor necrosis factor α (TNF-α)), nitric oxide, and ROS is harmful to the brain tissue after ischemia [8]. Increasing expression of cytokines promotes the expression of adhesion molecules on endothelial cells, which results in additional recruitment of, for example, leukocytes and platelets from the blood to the brain [37,38]. As neuronal death and brain tissue damage increase, there is a further increment in active microglia, infiltrating platelets, and leukocytes, resulting in more pro-inflammatory cytokines as a consequence of feedback [37]. This post-ischemic phenomenon increases both neuronal death and the infarct volume and causes poorer neurological outcomes. Neuroinflammatory changes in the brain are present in all stages of an ischemia episode, from cerebral blood flow arrest to late recirculation processes in ischemic brain tissue [26,27]. Neuroinflammation promotes further brain damage, causing the death of surviving neurons from the primary ischemia, but it also has a beneficial function to aid recovery and develop glial scaring. In this review, we look at the beneficial and harmful roles of neuroinflammation in post-ischemic brain neurodegeneration and possible future therapeutic strategies to reduce pathological responses following ischemia.

Moreover, inflammatory mechanisms are largely portrayed as deleterious to postischemic pathology, while in fact many immune processes such as phagocytosis help to reduce the consequences of ischemia. In this review, we strive to delineate the delicate balance between the beneficial and harmful aspects of inflammatory/immune activation in post-ischemic brain neurodegeneration, as a more detailed understanding of these processes is crucial for the development of effective therapies.
