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Francesca Bosetti, Pharm.D., Ph.D., Investigator Brain Physiology and Metabolism Section E-mail: frances@mail.nih.gov

Biography: Dr. Bosetti received her Ph.D. in molecular and experimental medicine in 2000 from Sant'Anna School, Department of Medicine and Surgery, Pisa, Italy. She also received a degree in Pharm.D., magna cum laude, from the University of Pisa in 1996. She joined the NIA Brain Physiology and Metabolism Section in January 2001 and became a tenure-track investigator in April 2004.

Role of Arachidonic Acid Metabolism in Aging and in Animal Models of Neurodegenerative and Neuropsychiatric Disorders: The focus of my research is to identify the role of brain arachidonic acid (AA) metabolism in animal models of neuroinflammation, excitotoxicity, and neuropsychiatric diseases. The AA cascade involves the hydrolysis of AA from the stereospecifically numbered (sn)-2 position of phospholipids by a phospholipase A2 (PLA2), conversion via cyclooxygenase (COX-1 and COX-2), lipoxygenases and cytochrome P450 epoxygenase of some of the unesterified AA into bioactive eicosanoids. These enzymes are not only physiologically important in their role in AA metabolism but they are also important targets of analgesics and anti-inflammatory agents. Recently, mice deficient in either COX-1 or COX-2 have become available and have been used to advance our understanding of the physiological and pathological role that these enzymes play.

The expression of cyclooxygenase (COX)-2, the enzyme that metabolizes AA to bioactive prostaglandins, is tightly regulated by glutamate neurotransmission, inflammatory mediators, and oxidative stress, factors that are increased in acute and chronic neurological diseases, as well as aging. Thus, in aging as well as in chronic neurodegenerative diseases, cumulative activation of COX-2 over time may lead to downstream cellular changes that impact negatively on neuronal survival and/or synaptic function. While the exact sequence of events that culminate in neuronal death are unknown, an understanding of the genetic characteristics and molecular mechanisms that trigger excitotoxic cell death may offer therapeutic strategies for such disorders. My research goal is to elucidate the role of COX-2 in the mechanism of neurodegeneration in animal models for kainate-induced excitotoxicity, LPS-induced neuroinflammation and chronic b-amyloid-induced neurodegeneration using knockout and transgenic mice models.

Recent Publications:

Choi SH, Langenbach R, Bosetti F. Cyclooxygenase-1 and -2 enzymes differentially regulate the brain upstream NF-kappa B pathway and downstream enzymes involved in prostaglandin biosynthesis. J Neurochem. 2006;98(3):801-811. Weerasinghe GR, Coon SL, Bhattacharjee AK, Harry GJ, Bosetti F. Regional protein levels of cytosolic phospholipase A2 and cyclooxygenase-2 in Rhesus monkey brain as a function of age. Brain Res Bull. 2006;69(6):614-621. Stefanovic B, Bosetti F, Silva AC. Modulatory role of cyclooxygenase-2 in cerebrovascular coupling. Neuroimage. 2006;32(1):23-32. Lee HJ, Ghelardoni S, Chang L, Bosetti F, Rapoport SI, Bazinet RP. Topiramate does not alter the kinetics of arachidonic or docosahexaenoic acid in brain phospholipids of the unanesthetized rat. Neurochem Res. 2005;30(5):677-683. Rao JS, Langenbach R, Bosetti F. Down-regulation of brain nuclear factor-kappa B pathway in the cyclooxygenase-2 knockout mouse. Brain Res Mol Brain Res. 2005;139(2):217-224. Rao JS, Rapoport SI, Bosetti F. Decrease in the AP-2 DNA-binding activity and in the protein expression of AP-2 alpha and AP-2 beta in frontal cortex of rats treated with lithium for 6 weeks. Neuropsychopharmacology. 2005;30(11):2006-2013. Bosetti F, Bell JM, Manickam P. Microarray analysis of rat brain gene expression after chronic administration of sodium valproate. Brain Res Bull. 2005;65(4):331-338. Ghelardoni S, Bazinet RP, Rapoport SI, Bosetti F. Topiramate does not alter expression in rat brain of enzymes of arachidonic acid metabolism. Psychopharmacology (Berl). 2005;180(3):523-529. Bosetti F, Langenbach R, Weerasinghe GR. Prostaglandin E2 and microsomal prostaglandin E synthase-2 expression are decreased in the cyclooxygenase-2-deficient mouse brain despite compensatory induction of cyclooxygenase-1 and Ca2+-dependent phospholipase A2. J Neurochem. 2004;91(6):1389-1397. Ghelardoni S, Tomita YA, Bell JM, Rapoport SI, Bosetti F. Chronic carbamazepine selectively downregulates cytosolic phospholipase A2 expression and cyclooxygenase activity in rat brain. Biol Psychiatry. 2004;56(4):248-254. Weerasinghe GR, Rapoport SI, Bosetti F. The effect of chronic lithium on arachidonic acid release and metabolism in rat brain does not involve secretory phospholipase A2 or lipoxygenase/cytochrome P450 pathways. Brain Res Bull. 2004;63(6):485-489. Rosenberger TA, Villacreses NE, Hovda JT, Bosetti F, Weerasinghe G, Wine RN, Harry GJ, Rapoport SI. Rat brain arachidonic acid metabolism is increased by a 6-day intracerebral ventricular infusion of bacterial lipopolysaccharide. J Neurochem. 2004;88(5):1168-1178. Bosetti F, Weerasinghe GR. The expression of brain cyclooxygenase-2 is down-regulated in the cytosolic phospholipase A2 knockout mouse. J Neurochem. 2003;87(6):1471-1477. Pardue S, Rapoport SI, Bosetti F. Co-localization of cytosolic phospholipase A2 and cyclooxygenase-2 in Rhesus monkey cerebellum. Brain Res Mol Brain Res. 2003;116(1-2):106-114. Bosetti F, Weerasinghe GR, Rosenberger TA, Rapoport SI. Valproic acid down-regulates the conversion of arachidonic acid to eicosanoids via cyclooxygenase-1 and -2 in rat brain. J Neurochem. 2003;85(3):690-696. Weerasinghe GR, Seemann R, Rapoport SI, Bosetti F. Lithium chloride, administered chronically to rats, does not affect the fractional phosphorylation of brain cytosolic phospholipase A2, while reducing its net protein level. Brain Res Bull. 2003;59(4):303-306.

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Updated: Thursday October 11, 2007