**6. Conclusion**

140 Neuroscience – Dealing with Frontiers

survival data. On the basis of these data the currently ongoing phase III study SAPHIRRE was initiated (Hau et al., 2011). In addition, TGF-β inhibition may also be used as a supplementary treatment as it can enhance the therapeutic efficacy of glioma-associated

Apart from ischemia, trauma, or tumors, deafferentation and neurodegeneration also induce TGF-β expression in the central nervous system (Morgan et al., 1993). Therefore, it is not

Alzheimer's disease (AD) is characterized by the presence of amyloid (Abeta) plaques, neurofibrillary tangles, and neuronal loss. The disorder is also frequently associated with cerebrovascular changes, including perivascular astrocytosis, amyloid deposition, and microvascular degeneration, but it is not known whether these pathological changes contribute to functional deficits in AD. TGF-β1 expressed in the astrocytes of transgenic mice induced a prominent perivascular astrocytosis, followed by the accumulation of basement membrane proteins in microvessels, thickening of capillary basement membranes, and later, around 6 months of age, deposition of amyloid in cerebral blood vessels. At 9 months of age, various AD-like degenerative alterations were observed in endothelial cells and pericytes. These results suggest that chronic overproduction of TGF-β1 triggers a pathogenic cascade leading to AD-like cerebrovascular amyloidosis, microvascular degeneration, and local alterations in brain metabolic activity (Wyss-Coray et al., 2000). A specific impairment of TGF-β1 signaling pathway has also been demonstrated in AD brain. The deficiency of TGF-β1 signaling has been shown to increase both Abeta accumulation and Abeta-induced neurodegeneration in AD models. The loss of function of TGF-β pathway also seems to contribute to tau pathology and neurofibrillary tangle formation (Caraci et al., 2009). Growing evidence suggests a neuroprotective role for TGF-β1 against Abeta toxicity both in vitro and in vivo models of AD. Different drugs, such as lithium or group II mGlu receptor agonists are able to increase TGF-β1 levels in the central nervous system. The combined Abeta- and TGF-β1-driven pathology recapitulates salient cerebrovascular, neuronal, and cognitive AD landmarks and yields a versatile model toward highly anticipated diagnostic and therapeutic tools for patients featuring Abeta and TGF-β1 increments (Ongali et al., 2011). Thus, TGF-β1 might be considered as new neuroprotective

A defective expression or activity of neurotrophic factors, such as brain- and glial-derived neurotrophic factors, is known to contribute to neuronal damage in Huntington's disease (HD). Asymptomatic HD patients also showed a reduction in TGF-β1 levels in the peripheral blood, which was related to trinucleotide mutation length and glucose hypometabolism in the caudate nucleus. Immunohistochemical analysis in post-mortem brain tissues showed that TGF-β1 was reduced in cortical neurons in HD patients. In mouse models of HD, the animals showed a reduced expression of TGF-β1 in the cerebral cortex, localized in neurons, but not in astrocytes. In these mice, glutamate receptor agonist failed to increase TGF-β1 formation in the cerebral cortex and corpus striatum, suggesting that a defect in the regulation of TGF-β1 production is associated with HD. Accordingly, reduced TGF-β mRNA and protein levels were found in cultured astrocytes transfected with mutated exon 1 of the human huntingtin gene, and in striatal knock-in cell lines expressing

surprising that TGF-βs were implicated in a variety of neurodegenerative diseases.

**5.4 Neuroprotective function in additional neurological diseases** 

antigen vaccines (Ueda et al., 2009).

tools against Abeta-induced neurodegeneration.

TGF-βs are a class of growth factors and cytokines with a special biochemistry and range of actions thoughout the organs of the body. Our knowledge on their roles in the central nervous system is accumulating fast in the last years. Neverthless, their neurochemistry is not well described, and often we can only anticipate that their synthesis, activation, and signal transduction pathways is similar to that in other tissues. The potential differences are to be determinded in future studies. Our understanding of the physiological functions of endogenous TGF-βs is also limited despite recent significant progress in the field. An increasing body of evidence suggests the otherwise logical assumption that TGF-βs play a role in the development of the nervous tissue. Recent studies revelased that TGF-βs are also involved in the physiological functions of the adult nervous system as well. So far, the best established functions include synaptic transmission and neuronal plasticity. Somewhat surprisingly, however, the direct involvement of TGF-βs in neuroendocrine functions has also been supported. The experiments often did not differentiate between the 3 different isoforms of TGF-β. Therefore, future studies are needed to elaborate their specific functions. Based on differences in the distribution of TGF-β1, TGF-β2, and TGF-β3, they possess separate neural functions.

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TGF-βs also participate in a number of pathophysiological processes. It has been long established that they are neuroprotective during excitotoxicity and ischemia. Strong evidence supports that TGF-βs constitute part of an endogenous neuroprotective system involved in ischemic preconditioning. This action of TGF-βs may or may not be related to their role in astroglial scar formation following injury. Nevertheless, the pharmacologic potentiation of this endogenous defensive mechanism might represent an alternative and novel strategy for the therapy of hypoxic-ischemic cerebral injury. TGF-β also play a pivotal role in brain tumor formation. The anti-proliferative actions of TGF-βs on astrocytes can be converted in tumor cells. Therefore, TGF-β-antagonistic treatment strategies are among the most promising of the current innovative approaches for glioblastoma, particularly in conjunction with novel approaches of cellular immunotherapy and vaccination.

#### **7. Acknowledgements**

Grant support was provided by the Bolyai János Grant from the Hungarian Academy of Sciences, as well as NFM-OTKA NNF2 85612, OTKA K100319, and NKTH TECH\_09\_A1 grants.

#### **8. References**


TGF-βs also participate in a number of pathophysiological processes. It has been long established that they are neuroprotective during excitotoxicity and ischemia. Strong evidence supports that TGF-βs constitute part of an endogenous neuroprotective system involved in ischemic preconditioning. This action of TGF-βs may or may not be related to their role in astroglial scar formation following injury. Nevertheless, the pharmacologic potentiation of this endogenous defensive mechanism might represent an alternative and novel strategy for the therapy of hypoxic-ischemic cerebral injury. TGF-β also play a pivotal role in brain tumor formation. The anti-proliferative actions of TGF-βs on astrocytes can be converted in tumor cells. Therefore, TGF-β-antagonistic treatment strategies are among the most promising of the current innovative approaches for glioblastoma, particularly in

Grant support was provided by the Bolyai János Grant from the Hungarian Academy of Sciences, as well as NFM-OTKA NNF2 85612, OTKA K100319, and NKTH TECH\_09\_A1

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Jessen, K.R. (2001). Transforming growth factor beta (TGFbeta) mediates Schwann cell death in vitro and in vivo: examination of c-Jun activation, interactions with survival signals, and the relationship of TGFbeta-mediated death to Schwann cell differentiation. *Journal of Neuroscience*, 21, pp. 8572-8585, ISSN 1529-2401

growth, motility, angiogenesis, and immune escape. *Microscopic Research* 

(1994). TGF beta 2 and TGF beta 3 are potent survival factors for midbrain

prevents glutamate neurotoxicity in rat neocortical cultures and protects mouse neocortex from ischemic injury in vivo. *Journal of Cerebral Blood Flow and Metabolism*,

Evidence that members of the TGFbeta superfamily play a role in regulation of the GnRH neuroendocrine axis: expression of a type I serine-threonine kinase receptor for TGRbeta and activin in GnRH neurones and hypothalamic areas of the female

(2009). In vivo requirement of TGF-beta/GDNF cooperativity in mouse development: focus on the neurotrophic hypothesis. *International Journal of* 

factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. *Journal of Biological Chemistry*, 274, pp. 35053-35058, ISSN 0021-9258 (Print), 0021- 9258 (Linking)


**7** 

*Japan* 

**Neurochemistry in the** 

 **Pathophysiology of Septic Encephalopathy** 

 Hiroshi Ogura1, Takeshi Shimazu1, Takashi Jin5 and Akitoshi Seiyama3,4 *1Department of Trauma and Acute Critical Care Center, Osaka University Hospital 2Department of Molecular Oncology,Kyoto University Graduate School of Medicine* 

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

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

 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

4

**1. Introduction** 

unit, **'septic encephalopathy'**.

encephalopathy.

Yukio Imamura1,3,4, Huan Wang1,2, Naoya Matsumoto1,

*3Unit for Liveable Cities, Kyoto University Graduate School of Medicine* 

*Human Health Science, Kyoto University Graduate School of Medicine* 

*5Laboratory for Nano-Bio Probes, Quantitative Biology Center,* 

glioma-associated antigen peptide vaccines. *Clinical Cancer Research*, 15, pp. 6551- 6559, ISSN 1078-0432 (Print), 1078-0432 (Linking)

