Neuroinflammatory Response Characterisation Due To Neurodegenerative Diseases Biology Essay



Neuro degenerative disease is one of the common causes associated with disability and its consequences are as malicious that subsequently many patients lead to mortality throughout the world each year. This particular form of disease includes all disorders in which, an area of the brain is permanently affected by ischemic stroke. This aim of this respective review is enhance the basic overview of the Neuro degenerative diseases and ischemic insult and provide an insight to the inflammatory mechanisms involved. The review also provides the basic understanding of the Parkinson's and Alzheimer's diseases & their inflammatory mechanisms. The description of Pathophysiology of cerebral ischemia furnishes concrete understanding of the background of inflammation in strokes. This combined aims will then conclude the basic understating of Neuro-inflammatory response during strokes and Neuro degenerative diseases. The entire project will be completed through the analysis of medical journals & concrete research.


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Neurodegenerative disease is common conditions in which cells of the brain and spinal cord which are known as neurons, are lost or damaged due to the occurrence of the particular diseases. The brain and the spinal cord are parts of the human body which are composed of neurons performing different functions such as controlling movements, talking, processing sensory information, making decisions and heart functions. Since the Neurons regeneration process is non existent in the body; therefore any excessive damage can lead to clinical disorders which may include Alzheimer's disease and Parkinson's disease. Neurodegenerative diseases result from deterioration of neurons or their myelin sheaths, which may eventually lead to central nervous system or CNS-related dysfunctions and ultimately result in fatal consequences incurring death. Neurodegeneration is often caused by an infectious agent known as prions which bind to the proteins in such a way that they can no longer perform their cellular functions and instead trigger equivalent modifications in normal proteins, thus creating a cascade of damage that prohibits the correct function of the brain as well as human body & eventually results in significant neuronal loss or death.

Stroke and inflammation

Stroke occurs in sudden attack and weakness of the brain. The occurrence of the stroke affects one side of the body. It is the consequences of an interruption to the cerebral flow of the blood. This happens when the brain partially senses an interrupted blood supply. Blood play a vital role in order to provide the brain with essential nutrients and oxygen. Without adequate supply of nutrients and blood, the brain cells can be destroyed. Stroke appears to be one of the major causes of death in developed countries. Every year an estimated 150,000 people in the UK are affected by strokes (Lo EH, Dalkara et al 2003). Most people who are affected by strokes are aged over sixty five years. This analogy however does not exclude children or babies & they are equivalently at risk of stroke at any stage of their life. Stroke is the third common cause of death in the UK. The approximate number of people living with disability caused by stroke is more than 250,000 (Shaheen E lakhan et al 2009)

Over 80% of the strokes are caused by the blockage of artery. This type of stroke is known as ischemic stroke. The pathogenesis of the clot blocks an artery that supplies blood to the brain. The oxygen & neurons are carried by the blood into the brain. The clot is known as cerebral thrombus and cerebral embolism which results in an almost immediate loss of oxygen and glucose. The Cerebral thrombus is formed when a blockage is caused by certain factors including the blood clot, air bubble or fat globule. The Cerebral embolism is formed in the blood vessel in an alternative location in the body and then carried in the bloodstream to the brain where it resides deep within the brain. This indicates that stroke mechanisms are involved in the ischemic injury and inflammation of cerebral tissue (Muir KW et al 2007).

Summarising the theories, the Ischemic stroke results from the sudden decrease or loss of the blood circulation to the area of cerebral tissue & hence the loss of neurological function leads to the nonspecific term encompassing a heterogeneous group of eitologies including thrombosis and embolism as well as hyper fusion. The ischemic cascade plays an essential role by series of subsequent events leading to disintegration of cell membranes and neuronal death. In the core of the brain infarction ischemic stroke begins with severe focal hypoperfusion, which leads to excitoxicity and oxidative damage which gives rise to micro vascular injury & blood-brain barrier dysfunction. This further initiates post-ischemic inflammation (Dirnagl U et al 1999).

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Figure 1 shows the permanent cerebral damage which depends on factors like degree and the duration of ischemia and its capabilities to recover.

Figure 1.


Focal cerebral hypoperfusion

Post-ischemic inflammation


Blood-brain barrier dysfunction

Oxidative stress

Cell death

Cerebral damage

Microvascular injury

Figure 1 was adopted and modified from the journal of inflammatory mechanisms in ischemic stroke: therapeutic approaches. The figure shows ischemic cascade leading to neuronal damage and hypoperfusion of the brain tissue which initiates excitotoxicity, oxidative stress, microvasscular injury, blood-brain barrier dysfunction and post ischemiac inflammation and death of glia and endothelial cells (Shaheen E lakhan et al 2009).

Oxidative factor depends on the pathogencity of stroke. The disruption of physiological balance between oxidants and antioxidants potentially raise the damage related to the brain tissue. Oxidative events also lead to ischemic cell death and involvement in the formation of ROS/reactive nitrogen species through mechanisms of mitochondrial inhibition as well as the overload of Ca2+ influx (Coyle JT, Puttfarcken P, 1993). Ischemic stroke generates huge amount of ROS and it is evident that oxidative stress is important mediator during cerebral injury (Cuzzocrea S, 2001). Ischemic events take several hours or days despite of the full blood circulation. If the restoration of the normal function is not maintained, this can result in secondary ischemic or also known as reperfusion injury (Shaheen E lakhan et al 2009).

Post ischemic inflammation

In post-ischemic inflammation events, it is evident that immune and nervous systems both collaboratively participate in tissue remodelling.

Microglial cells are known to be present macrophages of the brain and play a critical role as resident immunocompetent and phagocytic cells in collaboration with the CNS. Ekdahl et al (2009) and his team described in their study that an increased number of activated microglial cells up to 16 weeks after conducting two hours of MCAO on rats. When the ischemic process was triggered, the microglia transformed into phagocytes and the specimen released a variety of substances many of which are cytotoxic. This introduced indication of the potential to response to an ischemic insult and release pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, as well as other potential cytotoxic molecules including NO, ROS, and prostanoids. Microglia might hold ability to produce neuroprotection by producing neurotrophic molecules such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor I (IGF-I), and several other growth factors (Lucas SM et al, 2006).

Similar to microglia cells Astrocytes hold the ability to secrete inflammatory factors like cytokines and chemokines; they hold ability to regulate the expression of a cell adhesion molecule known as CAMs. The Pro-inflammatory mediators are released within four to six hours, upon circulation leukocytes adhere to vessel walls migrating into the brain (Swanson RA,et al, 2004).

Cytokines and brain inflammation

Groups of small glycoprotein known as cytokines are produced in response to immunological response, which are mediator of regulating immune response. Cytokines are up regulated in cerebral stroke. They are produced by resident brain cells, neurons, glia and also expressed in the cells of the immune system (Barone FC et al, 1999).

In figure 2 of the review it is indicated that the derived cytokines are involved in the cerebral inflammation. On the same time immune cells mononuclear phagocytes, T lymphocytes, NK cells and polymorphonuclear leukocytes are produced to aid the cerebral inflammation (Ferrarese C et al, 1999).

The diagram of (Figure2) shows post ischemic inflammatory response in addition to the release of immune cells.

Neutorphil infiltration

Oxidative stress

Cell death

Endothelial cells


Up regulation of CAM1 and selectins


Reactive Astrocytes

Activated microglia

TNF-alpha, IL 1Beta, IL-6 MCP.1 MIP. 1alpah, MMPsFigure2.

In the modified and adopted figure 2 it is evident that post ischemic inflammatory response includes excitotoxicity and oxidative stress. This is caused by an ischemic cascade which activates microglia and Astrocytes. The immune response secretes cytokines, chemokins and matrix metalloproteases (MMP) & therefore it leads to the up regulation of the cell adhesion through inflammatory mediators. In result the blood derived inflammatory neurons and neutrophils manage to infiltrate the ischemic core of the brain. Neutorphils hold the ability to secrete cytokines, which cause activation of the glial cells. The outcome of this process leads to ischemic brain damage (Shaheen E lakhan et al 2009).

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The main cytokines involved in acute ischemic strokes are tumor necrosis factor α (TNF-α), the interleukins (IL), IL-1β, IL-6, IL-20, IL-10 and transforming growth factor (TGF)-β. While IL-1β and TNF-α, appear to exacerbate cerebral injury, TGF-β and IL-10 which might be neuroprotective (Zhu Y,et al 2002).

Cytokines which direct the migration of blood borne inflammatory cells have its subdivision of chemokines which are moncyte chemoaattractant protein 1. The migrated cells are neutrophils and macrophages which travel towards the chemokine, where they communicate and recruit inflammatory cells. Immunological expressions of chemokines are as MCP-1, pacrophage inflammatory protein-1α (MIP-1α), and fractakline following focal ischemia which is thought to have a deleterious result of increasing leukocyte infiltration (Kim JS et al 1995).

Cellular Adhesion molecules

Cellular adhesion molecule CAMs plays a major role in the acute ischemic stroke. They are up regulated at the first exposure of stroke. Generally cytokines are responsible for the adhesion and migration of the lukocytes which roll on the endothelial surface.

They adhere to the endothelial cells, by interaction between leukocytes and the vascular endothelium. They are transmitted through groups of CAMs, which are selectins, the immunoglobulin gene superfamily and integrins. The selectins further subdivides into E- and P- selectins which recruit and mediate up regulation of the leukocyte rolling in ischemic insult (Zhang R et al. 1998).

The immunoglobulin involved intercellular processes are adhesions molecule which is ICAM-1 and the vascular cell. Investigation on cerebral ischemia is done within hours of onset stroke to view ICAM-1 expression increase to its binding molecule cytokines (Lindsberg PJ, et al 1996).

Parkinson's disease

Parkinson's is a degenerative neuronal condition affecting movements such as walking, talking, and writing and motor functions. It is named after Dr James Parkinson (1755-1824), the London doctor who first identified Parkinson's as a specific condition.

 Parkinson's disease gives rise to common causes of tremor, rigidity, bradykinesia and postural instability.

There are several of non-motor symptoms such as sleep disturbances, constipation, urinary urgency and depression. Parkinson's signs and symptoms are every individual differently. Therefore it is important to remember that everyone has different signs and symptoms for the treatment.

Parkinson's occurs as result of a loss of nerve cells in the part of the brain known as the substantial nigra. These cells are responsible for producing a chemical known as dopamine, which allows messages to be sent to the parts of the brain that co-ordinate movement. With the depletion of dopamine-producing cells, these parts of the brain are unable to function normally. approximately 80% of patients with subsequently diagnosed definite PD become severely disabled or die 10 to 14 years after onset of the disease (Poewe WH, Wenning 1996)

Alzheimer's disease

Alzheimer's disease is one of the most common causes of dementia, affecting around 417,000 people in the UK. The term 'dementia' is used to describe the symptoms that occur when the brain is affected by specific diseases or neural conditions. This incurable, degenerative, and terminal disease was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him.

During the course of the disease, plaques and tangles are developed in the structure of the brain, leading to the neural damage and then to brain death. People with Alzheimer's also have shortage of some important chemicals in their brains. These chemicals are involved with the transmission of messages within the brain. Alzheimer's is a progressive disease, which means that gradually, over time, more parts of the brains are damaged. As this happens, the symptoms become more severe.

Microglia were reported to localize to amyloid plaques in AD brain and since then, the association between neuroinflammation and AD has been extensively investigated (Wyss-Coray T, Mucke, 2002). Human microglia displays an activated phenotype when they surround plaques that includes up regulation of Human Leukocyte Antigen-DR (HLA-DR) (Frank cannon et al 2006). In addition to producing cytokines and other pro-inflammatory mediators (Eikelenboom P, et al 2002) microglia have also been reported to exert toxicity on neurons that have been pre-exposed to low blood supply of Aβ42 via a CD14-dependent process (McAlpine et al, 2009).


The main outcome of the review is based on reviewed medical journals which provide brief overview of the Neuro degenerative disease and the inflammatory mechanisms. The ischemic cascade is involved in series of steps which leads to the ischemic stroke and further to post ischemic inflammatory cascade. The adopted figure 1 summaries the ischemic insult during inflammation of neuronal death. The adopted figure 2 gives an overview of the oxidative stress related to post- ischemic inflammation. The role of immunological molecules confirms the collaborative processes resulting between CNS and immune system responses. These review findings confirm that Neuro degenerative diseases are progressive. Neuro-inflammatory response is due to neurodegenerative, Alzheimer's & Parkinson's diseases. A further development is required to the following literature & it is aimed that the development will further enhance the study of the respective subject & will provide a tangible solution to majority of the problems faced by the medical world today. The research at this stage may contain few aspects which will need further justifications & the evidence must be subjected to further authentication. It can also be concluded that any drawbacks in the literature may have been as a result of excessive literature handling & therefore the final opinion may have been slightly confound, however at this preliminary stage it can be negligible. The available data is limited and needs further expansion, in order to have better research and medical treatments, therefore the studies on Neuro degenerative disease remains main challenge to the world due to the complexity of the respective subject & the availability of the resources.


CNS: Central Nervous system; BBB: Blood Brain Barrier; IL: insulin like growth factor; IL: interlukin; CAM: Cell adhesion molecules