**4. Acknowledgment**

This chapter was possible because of the collaboration of Stephen Cunnane's laboratory, and was based on this following work:

Tremblay-Mercier, J. (2009) Étude des fibrates en tant qu'agent stimulateurs de la synthèse des cétones, des substrats énergétiques pour le cerveau vieillissant. Master's thesis, the Medecine and Health Science Faculty of Université de Sherbrooke , Sherbrooke, Qc, Canada, 19 January 2009.

Tremblay-Mercier, J., Tessier, D. Plourde, M. Fortier, M. Lorrain, D. Cunnane, S.C. (2010). Bezafibrate mildly stimulates ketogenesis and fatty acid metabolism in hypertriglyceridemic subjects. *J Pharmacol Exp Ther,* Vol. 334 No.1 pp. 341-346.

## **5. References**

136 Pharmacology

Fibrates act as synthetic ligands for PPARα and are commonly used to treat hypertriglyceridemia and to prevent coronary heart disease. PPARα is also involved in the anti-inflammatory response and in improvement of mitochondrial function. Fibrate therapy reduces the incidence and delays the onset of type II diabetes and seems to improve insulin sensibility in humans (Goldenberg et al., 2008). A recent clinical study suggests that in hypertriglyceridemic individuals, bezafibrate increase the production of ketone bodies, the alternative energy source for the brain (Tremblay-Mercier et al., 2010). Thus, by reducing triglycerides, enhancing glucose availability, providing alternative brain fuel and improving cardiovascular profile, PPARα agonist could have relevant impact on the maintenance of a good cognitive health later in life (figure 8). Fibrate therapy may have potential as pharmacological agents aiming to reduce the risk of AD and future research are needed to determine if secondary prevention with fibrate therapy is able to delay the apparition of

Fig. 8. Summary diagram on the PPARα agonist's action on modifiable risk factors for

This chapter was possible because of the collaboration of Stephen Cunnane's laboratory, and

Tremblay-Mercier, J. (2009) Étude des fibrates en tant qu'agent stimulateurs de la synthèse des cétones, des substrats énergétiques pour le cerveau vieillissant. Master's thesis, the Medecine and Health Science Faculty of Université de Sherbrooke , Sherbrooke, Qc, Canada,

Tremblay-Mercier, J., Tessier, D. Plourde, M. Fortier, M. Lorrain, D. Cunnane, S.C. (2010). Bezafibrate mildly stimulates ketogenesis and fatty acid metabolism in hypertriglyceridemic

**3. Conclusions** 

cognitive decline.

cognitive decline.

19 January 2009.

**4. Acknowledgment** 

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**7** 

*Poland* 

Krzysztof Bryniarski

*Jagiellonian University Medical College, Department of Immunology, Krakow,* 

**The Influence of Cyclophosphamide on** 

**Immune Function of Murine Macrophages** 

**1.1 The structure of cyclophosphamide (CY) and its active metabolites acrolein (ACR)** 

Cyclophosphamide (CY), an alkylating compound is commonly used as a cytoreductive agent in the treatment of cancer ( blood, breast, ovary) because of its ability to interfere with DNA synthesis and its pharmacological action on dividing cells (Ben Efraim 2001). Its action is however more complex since it exerts a strong influence on the immune system. Studies on cyclophosphamide are conducted for a long time, but its effect on macrophages (Mf) was

CY is *in vitro* inactive by itself, and is converted *in vivo* into two ultimately biologically active alkylating metabolites: phosphoramide mustard (PM) and acrolein (ACR).The first step of that complicated pathway of CY metabolism occurs in the liver and results in the formation of derivative hydroperoxycyclophosphamide and then it is followed by several enzymatic reactions that format carbonamide, aldehyde and carboxylacide inactive structures or lead to non-enzymatic formation of phosphoramide mustard and acrolein, active metabolites of cyclophosphamide which were tested in our immune research. Instead of highly unstable phosphoramide mustard (PM), we used nitrogen mustard (NM, mechlorethamine) (see **Fig 1**.) which is structurally and functionally related to PM, previously shown *in vitro* and *in vivo* to have the same activity as CY (Bryniarski et al. 1996).

Fig. 1. The chemical structure of cyclophosphamide and nitrogen mustard

**1. Introduction** 

**and phosphoramide mustard (PM)** 

not yet definite, therefore this study was attempted.
