Rao M. Adibhatla

 

 

Integration of Cytokine Biology to Lipid Metabolism After Stroke

E-mail: adibhatl@neurosurg.wisc.edu

Research Strengths: Molecular Neuroscience, Neurobiology of Disease

The focus of my laboratory objective is to learn how cytokines regulate lipid metabolism after CNS injury.

Phosphatidylcholine (PtdCho) is an important phospholipid: PtdCho constitutes ~50% of the total membrane phospholipid content of mammalian cells; a 10% loss is sufficient to alter membrane function and induce cell death. PtdCho also serves as a source for lipid messengers such as phosphatidates, 1,2-diacylglycerol, and arachidonic and docosahexaenoic acids. Patho-physiological breakdown of membrane PtdCho causes growth arrest and threatens cell viability. PtdCho levels can be restored by increasing its synthesis or inhibiting its breakdown or both. CTP:phosphocholine cytidylyltransferase (CCT) synthesizes cytidine-5’-diphosphocholine (CDP-choline) and regulates PtdCho synthesis in the brain. PtdCho is hydrolyzed by phospholipase A2 (PLA2), PtdCho-phospholipase C (PtdCho-PLC) and phospholipase D (PLD). We showed ~20% loss of PtdCho in a stroke model due to phospholipase activation and loss of CCTa. PtdCho metabolism can be altered by various stimuli including cytokines.

CDP-choline showed benefit in stroke. CDP-choline improved the outcome of patients in phase III clinical trials of stroke and showed benefit in a number of CNS injury models. Although experimental evidence is limited, the therapeutic action of CDP-choline is thought to be due to stimulation of PtdCho synthesis in a damaged brain. CDP-choline actions may go beyond restoring the PtdCho levels. Understanding the actions of CDP-choline could lead to development of more efficient treatment strategies for CNS injury. We have recently shown that CDP-choline significantly restored the phosphatidylcholine levels and reduced the infarction volume by differentially affecting PLA2 and CCT after stroke. CDP-choline down-regulated secretory PLA2 (sPLA2) IIA and up-regulated CCTa, which may be due to effects on cytokines and subsequent phosphorylation of MAP kinases and activation of caspases.

Cytokines regulate lipid metabolism and CDP-choline may counteract the cytokine response. Tumor necrosis factor-a (TNF-a) and interleukin-1 (IL-1a/ß) are pro-inflammatory cytokines that are up-regulated in the brain after stroke. Neutralization of TNF-a or IL-1a/ß attenuated ischemic brain injury. Phospholipases including sPLA2 and PtdCho-PLC are induced by TNF-a and IL-1 and mediate their cytotoxicity. TNF-a/IL-1 also down-regulate CCTa. TNF-a and IL-1a/ß disrupt membrane PtdCho integrity by up-regulating phospholipases and down-regulating CCTa, and contribute to stroke injury. CDP-choline actions may counteract the cytokines responses in restoring the lipid metabolism including preserving the PtdCho levels after stroke. These studies will provide vital information on the alterations in lipid metabolism including PtdCho homeostasis in stroke and other CNS injuries.

Lab Website:

http://www.neurosurg.wisc.edu/labs/adibhatla/

Selected Publications:

• Adibhatla, R.M., R. Dempsey, and J.F. Hatcher. 2007. Integration of cytokine biology and lipid metabolism in stroke. Front. Neurosurg. Res. In press.. [PDF]
• Adibhatla, R.M. and J.F. Hatcher. 2007. Role of lipids in brain injury and diseases. Future Lipidology 2: 403-422. [PDF]
• Adibhatla, R.M., E.C. Larsen, and J.F. Hatcher. 2007. Effect of D609 on phospholipid metabolism and cell death during oxygen-glucose deprivation in PC12 cells. Neuroscience 146: 945-961. [PDF]
• Adibhatla, R.M. and J.F. Hatcher. 2007. Secretory phospholipase A2 IIA in up-regulated by TNF-alpha and interleukin-1alpha/beta after transient focal cerebral ischemia in rat. Brain Res. 1134: 199-205. [PDF]
• Adibhatla, R.M., J.F. Hatcher, and R.J. Dempsey. 2006. Lipids and lipidomics in brain injury and diseases. APPS J. 8: E314-E321. [PDF]
• Adibhatla, R.M., J.F. Hatcher, E.C. Larsen, X. Chen, D. Sun, and F. Tsao. 2006. CDP-choline significantly restores the phosphatidylcholine levels by differentially affecting phospholipase A2 and CTP-phosphocholine cytidylyltransferase after stroke. J. Biol. Chem. 281: 6718-6725. [PDF]
• Adibhatla, R.M. and J.F. Hatcher. 2006. Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic. Biol. Med. 40: 376-387. [PDF]
• Adibhatla, R.M., J.F. Hatcher, and R.J. Dempsey. 2006. Lipids and lipidomics in brain injury and diseases. AAPS J. In press.
• Adibhatla, R.M. and J.F. Hatcher. 2005. Cytidine 5'-diphosphocholine (CDP-choline) in stroke and other CNS disorders. Neurochem. Res. 30: 15-23. [PDF]
• Adibhatla, R.M., J.F. Hatcher, and K. Tureyen. 2005. CDP-choline liposomes provide significant reduction in infarction over free CDP-choline in stroke. Brain Res. 1058: 193-197. [PDF]
• Adibhatla, R.M., J.F. Hatcher, and R.J. Dempsey. 2004. Cytidine-5'-diphosphocholine (CDP-choline) affects CTP: Phosphocholine cytidylyltransferase and lyso-phosphatidylcholine after transient brain ischemia. J. Neurosci. Res. 76: 390-396.
• Adibhatla, R.M., J.F. Hatcher, and R.J. Dempsey. 2003. Phospholipase A2, hydroxyl radicals and lipid peroxidation in transient cerebral ischemia. Antioxid Redox Signal 5: 647-654.
• Adibhatla, R.M. and J.F. Hatcher. 2003. Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia. J. Neurosci. Res. 73: 308-315.
• Adibhatla, R.M., J.F. Hatcher, and R.J. Dempsey. 2002. Citicoline: Neuroprotective mechanisms in cerebral ischemia. J. Neurochem. 80: 12-23. [PDF]
• Adibhatla, R.M., J.F. Hatcher, and R.J. Dempsey. 2001. Effects of citicoline on phospholipid and glutathione levels in transient cerebral ischemia. Stroke 32: 2376-2381. [PDF]
• Adibhatla R.M., J.F. Hatcher, and R.J. Dempsey. 2001. Does CDP-choline modulate phospholipase activities after transient forebrain ischemia? Brain Res. 893: 268-272. [PDF]
• Adibhatla, R.M., J.F. Hatcher, and R.J. Dempsey. 2000. Lipid alterations in transient forebrain ischemia: Possible new mechanisms of CDP-choline neuroprotection. J. Neurochem. 75: 2528-2535. [PDF]