**1. Introduction**

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Neurochemical studies clarify scientific mechanisms for neurochemicals in the nervous system. These include identification and characterization of neurotransmitters and neuromodulators supportive for neurotransmission in neuronal and glial cells networks in the brain. Neurochemicals based on neural mechanisms have been explained by the ongoing evolution of scientific techniques. These neurochemical techniques include immunohistochemistry, immunoblotting using species' specific antibodies or radio-labeled substances, etc. And these techniques with electrophysiological methods will be powerful tools to describe the pathophysiological mechanisms of sepsis-related brain dysfunction.

Neurochemical techniques are useful to examine the physiological mechanism of normal brain function such as synaptic transmission, plasticity and neurogenesis. On the other hand, these techniques are available to find pathogenesis of the brain. In this chapter, we'd like to focus on the brain pathophysiology, which is often confronted in an intensive care unit, **'septic encephalopathy'**.

In normal condition, our brain is protected for its environment such as neurochemical balance by the barrier called 'blood brain barrier (guardian of the brain)'. However, sepsis leads to be the impairment of blood brain barrier function (i.e., enhancement of permeability through blood brain barrier) and imbalance of neurotransmission. In addition, following sepsis, apoptotic signaling pathway is activated (Hotchkiss RS & Nicholson DW, 2006) and/ or chemical mediators passing through disrupted blood brain barrier lead to necrotic neuronal cell death accompanying with ischemia (Sharshar T et al, 2004) and edema (Kafa IM et al, 2007). These phenomena finally lead to the imbalance of brain activity after septic encephalopathy.

 Next section, we introduce the neurochemical techniques in terms of the contents: 1) what are pathophysiological phenomena in sepsis and its related encephalopathy in combination

Neurochemistry in the Pathophysiology of Septic Encephalopathy 151

pituitary dysfunction in severe sepsis is alleviated in the rat (Flierl MA et al, 2009). Hence,

Because of the amplification of systemic inflammatory states after sepsis, without appropriate intensive care including antibiotic therapy, vasopressor medications, mechanical dialysis (Dellinger RP et al, 2008), systemic inflammatory response syndrome and cytokine storm then lead to be multiple organ dysfunction syndrome. Once sepsis is reached to multiple organ dysfunction syndrome, the patients are destined to be coma or delirium. Multiple organ dysfunction syndrome implicates in the pathogenesis of septic

Septic encephalopathy is devastating syndrome results from systemic inflammatory response syndrome in sepsis. In patients after multiple organ dysfunction syndrome, septic encephalopathy is appeared. The symptoms of septic encephalopathy patients are characterized as long-term cognitive impairment including deficits in memory, attention, concentration of consciousness (Streck EL et al, 2008). Why do these symptoms occur?

A lot of research groups have performed to tackle and continue the challenging to uncover the mystery of septic encephalopathy. Typical characteristic in septic encephalopathy is that the chemical substances in the whole body can access to the neuronal function in the brain after blood brain barrier (a guardian of brain) disruption. In fact, we find that occludin, the marker for tight junction, is drastically reduced in the mouse brain after septic encephalopathy (Imamura Y et al, 2011). This may cause the edema after septic encephalopathy (Papadopoulos MC et al, 1999). Then, what is the pathophysiology in the

Several decade ago, several lines of research reports have been addressed for the possibility of neurotransmitters imbalance in septic encephalopathy. One of the possible suggestions to septic encephalopathy-induced abnormalities stems from amino acid derangements in septic patients (Freund HR et al, 1978). The altered patterns of plasma amino acids are well correlated between non- septic encephalopathy and severe septic encephalopathy groups (Freund H et al, 1979). For example, several amino acids including glutamate, aspartate and tryptophan are altered in septic encephalopathy patient. These amino acids serve as neurotransmitters or are utilized for synthesization of neurotransmitters. Furthermore, using an animal model of septic encephalopathy, it is also suggested that these amino acid alteration affect the neurotransmitter in the brain. After cecal ligation and puncture, an animal model of septic encephalopathy, in rat, neurotransmitters serotonin and norepinephrine are altered and the altered patterns are correlated with these differences of amino acids (Freund HR et al, 1986). Hence, monoamine neurotransmitters are aberrant in septic encephalopathy. In addition, as shown in the following section, glutamatergic neurotransmission may be also affected and synaptic plasticity is disturbed (Imamura Y et al, 2011). Altogether, a whole body inflammation after sepsis 1) leads to blood brain barrier disruption, 2) affects the neurotransmitter levels and 3) may lead to be the symptoms of

C5a will be a hopeful target for cytokine storm regulation after sepsis.

neurochemical substances related to septic encephalopathy?

**2.1.4 Multiple organ dysfunction syndrome**

encephalopathy.

**2.2 Septic encephalopathy** 

septic encephalopathy.

of inflammatory response, 2) how to examine the aberrant brain function, 3) what is the future for sepsis research.
