1.1 Introduction
Ischemic brain damage refers to the injury caused by reduced blood flow to the brain, leading to insufficient oxygen and glucose supply necessary for neuronal survival. This condition, commonly known as stroke, is one of the leading causes of death and disability worldwide. When brain tissue experiences ischemia, a complex series of cellular and molecular events is initiated, ultimately resulting in neuronal death if blood flow is not restored promptly (Iadecola & Anrather, 2011). Brain ischemia is a condition in which there is insufficient blood flow to the brain to meet metabolic demand (Sullivan, 2021). This leads to poor oxygen supply or cerebral hypoxia and thus leads to the death of brain tissue or cerebral infarction/ischemic stroke (Ischemia, 2003). It is a sub-type of stroke along with subarachnoid hemorrhage and intracerebral hemorrhage (Vespa, 2005). The cascade of ischemic damage is multifactorial and begins within minutes of the reduction in cerebral blood flow. The brain's lack of oxygen triggers a switch from aerobic to anaerobic metabolism, leading to the accumulation of lactic acid, which lowers intracellular pH and disrupts cellular homeostasis (Dirnagl et al., 1999). As ischemia progresses, energy failure due to ATP depletion impairs ion pumps, causing neuronal depolarization and massive influxes of calcium ions (Doyle et al., 2008).
As a prelude to other parts of this study, this chapter will discuss the background upon which this study was initiated, the statement of problems that led to this study, the Aim and Objectives of the study. Others are Significance of the study, Scope of work, Limitation of the study and Definition of technical terms.
1.2 Background of Study
Cerebral ischemia can be global or focal. Global cerebral ischemia is a result of systemic processes, often shock. The most common cause of global brain ischemia is systemic hypotension. Transient cerebral hypoperfusion can occur when autonomic and neurohormonal mechanisms that control blood pressure and heart rate are disrupted, as in vasovagal syncope and postural tachycardia syndromes. Structural and functional heart problems, mostly arrhythmias, are the second most frequent cause of transient global brain ischemia. When the effect is transient, the condition often manifests as a presyncope or syncope. Prolonged global ischemia, on the other hand, can result in permanent neurological injury (Li, 2020).
Brain depends upon oxidative phosphorylation for energy. It is sensitive to disturbances in oxygen and glucose supply. Following focal ischemia there is a profound deprivation of oxygen and glucose. Oxidative stress is linked to excitotoxicity, energy loss, and ionic imbalances and all these events contribute to tissue damage (Researchgate, 2021). Ischemia leads to alterations in brain metabolism, reduction in metabolic rates, and energy crisis (Raichle, 1983). There are two types of ischemia: focal ischemia, which is confined to a specific region of the brain; and global ischemia, which encompasses wide areas of brain tissue. The main symptoms of brain ischemia involve impairments in vision, body movement, and speaking. The causes of brain ischemia vary from sickle cell anemia to congenital heart defects. Symptoms of brain ischemia can include unconsciousness, blindness, problems with coordination, and weakness in the body. Other effects that may result from brain ischemia are stroke, cardiorespiratory arrest, and irreversible brain damage. An interruption of blood flow to the brain for more than 10 seconds causes unconsciousness, and an interruption in flow for more than a few minutes generally results in irreversible brain damage (Hossmann, 1974). In 1974, Hossmann and Zimmermann demonstrated that ischemia induced in mammalian brains for up to an hour can be at least partially recovered (Raichle et al., 2009). Accordingly, this discovery raised the possibility of intervening after brain ischemia before the damage becomes irreversible (Beers et al., 2003).
The pathophysiology of ischemic brain injury involves a series of interconnected cellular and molecular processes. These processes include energy depletion due to loss of oxygen and glucose, excitotoxicity caused by excessive glutamate release, calcium influx, oxidative stress, and inflammation (Lo, Dalkara, & Moskowitz, 2003). Each of these events plays a significant role in neuronal injury and death, contributing to the overall damage observed in ischemic stroke.
Research has shown that one of the primary molecular events in ischemic brain damage is the disruption of ionic homeostasis, leading to neuronal depolarization and calcium overload (Choi, 1994). Calcium ions activate several enzymes that degrade cellular structures, contributing to neuronal death. Furthermore, oxidative stress, resulting from the production of reactive oxygen species (ROS), exacerbates the injury by damaging proteins, lipids, and DNA (Doyle, Simon, & Stenzel-Poore, 2008). Additionally, the inflammatory response triggered by ischemia further promotes secondary injury through the activation of immune cells and the release of pro-inflammatory cytokines.
Therefore, in Nigeria where the research was carried out, the activities that was conducted is to know the Cellular and Molecular Events of Ischemic Brain Damage.
1.3 Statement of Problems
Investigation reveals that Ischemic Brain Damage results in death and dysfunction of brain cells. However, not all brain cells die immediately after an ischemic stroke. Ischemic penumbra is a perilesional area surrounding the ischemic core. Cell death occurs by a necrotic pathway characterized by ischemic or edematous cell changes, by an apoptotic pathway with a number of morphological, biochemical, pharmacological, and molecular characteristics, or by autophagocytosis. Brain depends upon oxidative phosphorylation for energy. It is sensitive to disturbances in oxygen and glucose supply. Following focal ischemia there is a profound deprivation of oxygen and glucose. Oxidative stress is linked to excitotoxicity, energy loss, and ionic imbalances and all these events contribute to tissue damage. In addition to reactive free oxygen species, nitrosative stress contributes to tissue damage. Early after the onset of ischemia, the expression of proinflammatory genes is triggered. Loss of membrane integrity, cell swelling, and organelle failure are the features of cell death following brain ischemia. The chapter discusses the stroke-induced endogenous neuroprotection.
1.4 Aim and Objectives of Study
The aim of the study is to determine the Cellular and Molecular Events of Ischemic Brain Damage. In achieving this aim, the following specific objectives were laid out as follows:
- To examine the role of excitotoxicity, oxidative stress, and calcium overload in the cellular response to ischemia.
- To investigate the molecular signaling pathways activated during ischemic events, particularly those leading to cell death and inflammation.
- To analyze the role of the ischemic penumbra and its importance in therapeutic intervention and recovery.
- To assess the contribution of the immune response and inflammatory mediators in exacerbating ischemic brain damage.
- To evaluate potential therapeutic targets for neuroprotection and the improvement of treatment outcomes in ischemic stroke patients.
1.5 Significance of Study
The findings of this research will provide crucial insights into the mechanisms involved in ischemic stroke, which will contribute to the broader understanding of brain injury. It will help medical professionals and researchers better comprehend the cellular and molecular pathways responsible for neuronal death, potentially guiding the development of new neuroprotective therapies.
Additionally, it will aid in identifying biomarkers that will enhance early diagnosis and targeted interventions for stroke patients. This research will also serve as a valuable reference for further studies in neuroscience, particularly those focusing on ischemic damage and brain recovery mechanisms.
1.6 Scope of Study
The scope of this research is focused on the determination of Cellular and Molecular Events of Ischemic Brain Damage in Nigeria.
1.7 Limitations of the Study
During the course of this study, many things militated against its completion, some of which are:
- Time Constraint: The time frame given to accomplish this project was very short due to school academic calendar and it was carried out under pressure which made the researcher not to implement some necessary features.
- Financial Constraint: Insufficient fund tends to impede the efficiency of the researcher in sourcing for the relevant materials, literature or information and in the process of data collection (internet).
1.8 Definition of Terms
Ischemic Brain Damage:
Ischemic brain damage refers to the injury sustained by brain cells due to a lack of blood supply, which leads to oxygen and nutrient deprivation. This condition is commonly associated with strokes and other cerebrovascular diseases. It results in the death of neurons and glial cells, leading to neurological deficits (Dirnagl et al., 1999).
Neuroprotection:
Neuroprotection is defined as strategies or interventions aimed at preventing or reducing neuronal injury during ischemic events. This includes the use of pharmacological agents, hypothermia, or other therapeutic measures designed to preserve neuronal integrity (Koh et al., 2012).
Apoptosis:
Apoptosis is a form of programmed cell death characterized by specific morphological and biochemical changes. in the context of ischemic brain injury, apoptosis contributes to the loss of neurons and is triggered by various cellular stressors following ischemia (Liu et al., 2017).
Inflammation:
Inflammation is the body's response to injury or infection, involving the activation of immune cells and the release of inflammatory mediators. In ischemic brain damage, inflammation plays a dual role; while it can help clear debris and promote healing, it can also exacerbate tissue damage and worsen outcomes (Iadecola & Anrather, 2011).
Reperfusion Injury:
Reperfusion injury refers to the paradoxical damage that occurs when blood supply is restored to previously ischemic tissue. This restoration can lead to oxidative stress and inflammation, further complicating recovery and cellular integrity (Moskowitz et al., 2010).
