**2.2 Septic encephalopathy**

150 Neuroscience – Dealing with Frontiers

of inflammatory response, 2) how to examine the aberrant brain function, 3) what is the

Sepsis is a systemic inflammatory state in the whole body by bacteria infection in the blood stream (i.e., systemic inflammatory response syndrome) (Bone RC et al, 1992). In systemic inflammatory response syndrome, the innate immune systems are overactivated. The systemic inflammatory response syndrome is characterized by the symptoms such as fever and hypotension in patients. In severe sepsis pathology, immunohistochemical studies using both of postmortem human and an animal model of sepsis in rodents reveal the brain ischemia (Sharshar T et al, 2004), edema (Pfister D et al, 2008), hemorrhage (Casanova E et al, 2001) after sepsis. On the other hand, following sepsis, several kinds of symptoms such as polyneuropathy are also observed. These symptoms enhance complexity of the septic pathophysiology (Bolton CF et al, 1993; Nauwynck M & Huyghens L, 1998). Hence, the

Molecular mechanism of immunology for sepsis is investigated. When pathogen (bacteria etc.) is invaded into the blood stream, it is recognized to be pathogen-associated molecular pattern such as lipopolysaccaride, bacterial component in immunological dendritic cells and T cells. When the pathogen-associated molecular pattern binds to toll-like receptor, the tolllike receptor facilitates cytokine release (Kim KD et al, 2007). After the cytokine release, the septic condition triggers downstream signaling pathways. These pathways translocate and activate NF-kappa B in the nucleus through I-kappaB degradation and mitogen-activated protein kinase (MAPK) and JUN kinase activation. Finally, NF-kappaB drives transcription

These activations lead to be **cytokine storm** (Harrison C, 2010). In fact, 30% of septic patients have serious symptoms without bacteremia in their blood (Sprung CL et al, 1990). The result suggests that after removal of bacteria, cytokine storm is a major factor for the tissue injury after severe sepsis. What is a player for accelerating cytokine storm? Recent finding suggests that small protein 'complement' creates cytokine storm (Ward PA, 2010). The complement serves as a supportive factor to enhance the efficacy of antibodies in order to clear pathogen in the blood. The complement C5a has their receptors, C5aR and C5L2, in the pituitary and their receptors are up-regulated after sepsis. C5a is also performed as a central hub to activate various inflammatory responses including disseminated intravascular coagulation, systemic inflammatory response syndrome, lethal bacteremia, immunosuppression, septic shock and heart failure (Rittirsch D et al, 2008). Conversely, when the C5a is neutralized by specific antibody, blood brain barrier disruption and

of interleukin family (interleukin -1, 2, 6, 8 and 12) and tumor necrosis factor-.

future for sepsis research.

**2.1 Pathogenesis of sepsis** 

**2.1.2 Molecular mechanisms** 

**2.1.3 Cytokine storm**

septic conditions include neurological symptoms.

**2. Sepsis** 

**2.1.1 Symptoms** 

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 neurochemical substances related to septic encephalopathy?

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 septic encephalopathy.

Neurochemistry in the Pathophysiology of Septic Encephalopathy 153

procedure is summarized in Figure 1A. In brief, immunohistochemical staining is usually performed in following steps: 1) septic brain is fixed in 1-4% paraformaldehyde solution in

Fig. 1. Experimental procedure. A, immunohitochemistry. B, immunoblotting
