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P4‐175: Resolution of neuroinflammation by Cytochrome P4504f: Implication in Alzheimer's disease
Author(s) -
Sehgal Neha
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.04.742
Subject(s) - neuroinflammation , neuroprotection , inflammation , microglia , leukotriene b4 , chemokine , pharmacology , cytokine , immunology , proinflammatory cytokine , chemistry , biology
Background: Inflammatory processes are known to be involved in the progression of Alzheimer’s disease (AD). Microglia contributes to the neurodegenerative process by augmenting the production of inflammatory mediators. Resolution of inflammation could potentially alter the progression of the disease and afford neuroprotection. Cytochrome P450 (P450) are an important family of enzymes involved in the metabolism of xenobiotics. The P4504f subfamily hydroxylate the potent pro-inflammatory mediator, leukotriene B4 (LTB4) to 20-hydroxy-LTB4,thereby inactivating its inflammatory response. Thus, P4504f could be an attractive target for anti-inflammatory action in the brain. The objective of this study is to examine the role of Cyp4f in modulating inflammation in the brain, affording neuroprotection in acute and chronic inflammatory conditions, such as AD. Methods: The acute model of neuro-inflammation was generated by systemic injection of LPS to male C57Bl6j mice. The transgenic APPswe/PSEN1dE9 (PS1-APP) mice were used to model AD. The individual P4504fs were cloned by RT-PCR using mRNA from mouse brain cortex. Levels of cytokines and chemokine were measured using cytokine bead array and quantitative real time PCR. Results: P4504f13, 14, 15, 16 and 18 were all expressed in robust amounts in the mouse brain. Amongst these P4504f15 was present in highest amount and also hydroxylated LTB4 very efficiently. Administration of LPS resulted in increased levels of chemokine and cytokines which was exacerbated when a chemical inhibitor of P4504f was pre-administered. In BV-2 microglial cells, downregulation of P4504f using shRNA resulted in increased inflammatory response while induction of P4504f protected the cells. In the AD transgenic mice P4504fs were induced at 3 months of age, when inflammation was minimal. However, in 10-12 month old mice, when the inflammation was rampant, P4504f expression was significantly reduced. P4504Fs are also expressed in human brain and induction of P4504f represents an attractive target for reducing neuroinflammation. Conclusions: We demonstrate for the first time that P4504f may play a prominent role in the regulation of inflammation in brain through the metabolism of LTB4 to 20-hydroxy-LTB4 . Thus, we present a new drug target which can be considered for therapeutic intervention in AD to reduce the inflammation which contributes to the progression of the disease.