Neururoinflammatory Case Study

All of the activated T-cells then release cytokines and adhesion molecules that enable the T-cells to adhere to and cross over the blood-brain barrier, which normally prohibits the flow of substances into the brain (8,9). The proteins in these T-cells bind to myelin fragments on microglial cells and undergo a secondary activation (10), after which they multiply and release more cytokines, further invading the nervous system (11) and inflaming and damaging the blood-brain barrier. The greatly weakened barrier becomes easily permeable, allowing additional immune system cells, such as B-cells and cytotoxic T-cells to cross over (12). Once through the barrier, B-cells produce antibodies which bind to the oligodendracytes (the cells of the CNS which create myelin) and the myelin itself. Associated macrophages procede to destroy the myelin and may also damage the oligodendracytes (13).

When inflammation occurs, the barrier becomes more permeable. The bacteria invade the respiratory passages and are disseminated by the bloodstream to the cerebrospinal fluid (CSF) space and the meninges of the brain and spinal cord. A gathering of fluid damages the cranial nerves, destroys cerebral spinal fluid pathways, and induces vein

Some area’s affected by neuronal loss are the cerebral cortex, the hippocampus, locus coeruleus, and cerebellum. Even with a single TBI, neuronal loss does occur, and evidence suggests this neuronal loss continues beyond the initial injury phase. White matter degeneration does occur as well, and while this study has little information on this, it is noted that white matter injury as well as axonal pathology has been suggested as a mechanism of rapid Aβ genesis. Also seen in neurodegeneration is neuroinflammation that is beyond repair. This inflammation continues after the initial injury in the white matter region, including the corpus callosum. Finally, changes in the cerebellar pathology are noted, in particular loss of cerebellar neurons. Smith, Johnson, & Stewart (2013) note atrophy and demyelination of the folial white matter present in those affected by

Many scientists hypothesize that protein dysfunction plays a role in the progressive damage and death of nerve cells. The nerve cells may be blocked from communication

Sepsis associated encephalopathy (SAE) is a complex and potentially serious consequence of sepsis appearing in many clinical forms. SAE is no more than the manifestation of a sinister cascade of damaging molecular interactions that can potentially lead to irreversible neurocognitive dysfunction. The pathophysiology of SAE is unknown but recent animal studies have shed some important information about some of the responsible molecular mechanisms and potential sites for future interventions. These pre-clinical studies have demonstrated the role of classic inflammatory factors that lead to blood-brain barrier dysfunction, astrocyte dysfunction, apoptosis, and neuronal death. Further studies are warranted to enhance our understanding of the process

Furthermore, inflammation is linked with bipolar disorder and can explain some of the comorbidities such as diabetes, heart disease, and obesity, that result in decreased life expectancy. Inflammatory molecules are produced in the periphery by immune cells such as helper T cells and macrophages, in response to pathogens or cell damage. The proinflammatory molecules produced in the body can stimulate the microglia and other neuroimmune cells, by entering the brain through regions where the blood brain barrier (BBB) is more permeable, by active transport through the endothelial cells that make up the BBB, or by vagal nerve signalling (Muneer). The presence of inflammatory molecules in the brain stimulates the microglia to release

It is a well-known biomarker of brain injury associated with Alzheimer’s disease, concussion and epilepsy. Based on literature review, an overproduction of soluble S100B from the astrocytes binds to the receptor for advanced glycation end products (RAGE) leading to various responses including increased reactive oxygen species (ROS) formation, release of pro-inflammatory markers, and activation of stress response kinases resulting in neuronal cell death. The ongoing neuronal injury and inflammation further promotes cellular apoptosis and impairs neurogenesis in epileptic brain. Identification of this mechanistic relationship between acquired epilepsy and inflammation will provide an important therapeutic target pathway for prevention of

Neurorestorative events include neurogenesis, gliogenesis, angiogenesis, synaptic plasticity and axonal sprouting. neuroprotection mentions to the relative preservation of neuronal structure or function. Numerous mechanisms behind neurodegeneration are the same. General mechanisms consist of increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory alters, iron accumulation, and aggregation of protein. Some of neuroprotective treatments including Glutamate antagonists, Caspase inhibitors, Trophic factors, Anti protein aggregation agents, Therapeutic hypothermia, Erythropoietin has been reported to protect nerve cells from hypoxia-induced glutamate

Microglia are resident immune cells in the CNS, separated from many blood-borne molecules by the BBB. However, evidence suggests that BBB endothelial cells either act as transporters of hormones and cytokines across the BBB or as classic receptor sites, possibly reacting to signals in the blood by secreting other signals into the CNS.8 By these mechanisms, microglia can become activated in response to inflammatory stimulation such as the cytokines and hormones that cross the BBB.9 Also, metabolic disease frequently leads to compromise of the BBB, providing greater access for circulating molecules to the CNS. It is not clear whether metabolic disease causes microglia to weaken the BBB, or whether the BBB is weakened first, with microglia then

In general, each neuron releases a single type of neurotransmitter. Neurons that release the neurotransmitter acetylcholine are called cholinergic neurons and degeneration of cholinergic neurons in the brain are associated with Alzheimer’s (Sherwood). Drugs classified as short-term cholinesterase inhibitors are used to treat Alzheimer’s because the drugs prolong the effect of acetylcholine. There are special cells called microglia that are associated with Alzheimer’s disease as well. Microglia are immune defense cells in the CNS (central nervous system) or brain and spinal cord. The remove foreign and degenerate material in the CNS. Overactive microglia appear to be involved in a variety of inflammation-related disorders like Alzheimer’s (Sherwood). Inflammation is triggered by the body’s immune system and is a factor that plays in the progression of the disease (Alzheimer’s Disease & Dementia).

At adult normal physiological condition, microglial display surveillance or so-called ‘resting’ phenotypes gauged by small cell body with extensively ramifying processes that actively surveying the CNS microenvironment. In this steady state, the turnover processes is primarily confined and well-maintained through local self-renewal of the long-lived resident microglial. Anomalies in the CNS such as infections, tissues damage, and accumulation of abnormal protein or biochemical can trigger microglial activation and in turn cause inflammation in CNS. Different from steady state, inflammatory condition may have disrupted the integrity of blood brain barrier and allowed recruitment of circulating myeloid cells and promotes their differentiation into microglial with more potent inflammatory properties and resulting heterogeneity of microglial . Activated microglial rapidly proliferate undergo phenotypic transition where they will exit from the ‘resting’ or ‘surveying’ form and mounted inflammatory effectors functions. Evidences showed that activated microglial capable of upregulated its phagocytose properties and secrete of inflammatory mediators chemokines, cytokines, nitrite, reactive oxygen species, and free radicals to execute repair

The sub-acute phase continues from the acute phase and characterized by new events such as formation of free radicals, delayed calcium influx, apoptotic cell death, inflammatory response, central cavitation initiation, and astroglial scar initiation (28). Neutrophils are the first immune cells to respond/arrive at injury, removing microbial intruders and tissue debris. Neutrophils release protease metalloproteinase, ROS, TNF-α, IFN-γ, IL-1, 8, 12 and other pro-inflammatory factors to activate other inflammatory and glial cells (29, 30). While initially beneficial, neutrophil persistence significantly increases damage through continuous production of pro-inflammatory cytokines and proteolytic enzymes (31). Therefore, neutrophil activation is limited to a couple days, and is contained to the sub-acute phase. Microglia and macrophages become active in response to neutrophils and the injury, also releasing numerous

HMGB1 is a prototypic damage-associated molecular pattern (DAMP) protein highly secreted by activated macrophages and monocytes as a cytokine mediator of inflammation. This DNA-binding nuclear protein is released both passively during cell death and actively following cytokine stimulation. It is also implicated in both infectious and sterile inflammatory disorders [32-36] affecting the central nervous system (CNS) such as in Parkinson's disease (PD) [37], multiple sclerosis (MS) [38,39], ischemic stroke [40], traumatic brain injury (TBI) [41] and Alzheimer’s disease - AD [42-44]. HMGB1 activates cells by differential engagement of several membrane receptors including advanced glycation end products (RAGE), toll-like receptor 2 (TLR2), and TLR4 which are primarily responsible for HMGB1 pro-inflammatory activity and BBB impairment [45,46]. Specific to the proposed work, several studies have clearly outlined the role of OS in the development of microvascular and cardiovascular complications of 2DM [47].

Nitric oxide (NO) is an important cellular signaling molecule that participates in diverse physiological functions in mammals, including vasodilation, smooth muscle relaxation, neurotransmission, and the immune response. NO, a free radical, is produced by a family of enzymes called nitric oxide synthases (NOS) by the oxidation of L-arginine to L-citrulline. There are three isoforms of NOS. Two of them, neuronal NOS (nNOS) and endothelial NOS (eNOS), are constitutively expressed, while the third one is inducible and is thus termed iNOS. nNOS is primarily found in the nervous system and is necessary for neuronal signaling, while eNOS is localized to the endothelium and is essential for vasodilation and control of blood pressure (5). These two isoforms produce nanomolar amounts of NO for short periods of time (seconds to minutes) in a calcium/calmodulin (CaM)-dependent manner (1, 91, 189).

When they are activated that mediates Ca2+ entry. It has become gradually clear that detrimental effects can arise from either hyperactivity or hypofunction of NMDARs. Moreover, NMDARs dysfunction has emerged as a common theme in several major nervous system disorders, including ischemic brain injury, chronic neurodegenerative diseases, pain, depression and schizophrenia, altered NMDARs presence/functions can be contributed in central nervous system (CNS) disease in several ways