Education

Research Interest

We investigate the roles of heme oxygenase (HO) and carbon monoxide (CO), the HO derived endogenous gaseous mediator, in regulating blood flow to the brain and in promoting survival of brain endothelial cells during cerebral vascular insult caused by seizures and oxidative stress. Seizures cause sustained cerebral vascular injury, reduction of brain endothelial dilator function, and subsequent loss of cerebral blood flow autoregulation. Glutamate, a major excitatory neurotransmitter, and TNF-a, a pro-inflammatory cytokine, are major injurious factors involved in the pathogenesis of seizure-induced cerebral vascular injury and endothelial apoptosis. Activation of endogenous HO/CO system or pharmacological delivery of CO to the brain reduces or prevents cerebral vascular endothelial injury and restores cerebral vascular endothelial function. We investigate the HO/CO system as a critical component of anti-apoptotic mechanisms involved in protecting the brain from cerebral vascular injury caused by seizures and oxidative stress. The projects involve in vivo and in vitro studies in newborn pigs using the closed cranial window techniques for detection of cerebral blood flow responses, isolated cerebral resistance arterioles, and primary cultures of cerebral vascular endothelial, smooth muscle, and glial cells.

Research Support

04/01/04 - 03/30/09, NIH/NINDS RO1 NS046385 "Heme oxygenase and cerebral vascular injury", P.I.
07/01/00 - 06/30/10 , NIH/NHLBI RO1 HL42851 "Carbon Monooxide in Newborn Cerebral Circulation", Co-P.I.
04/1/07 - 07/31/12, NIH/NHLBI RO1 HL34059 "Control of Neonatal Circulation", Co-I

Selected Publications

Publications: 2003-Present

1. Fiumana E, Parfenova H, Jaggar JH, And Leffler CW.  Carbon monoxide mediates vasodilator effects of glutamate in isolated pressurized cerebral arterioles of newborn pigs. Am J Physiol Heart Circ Physiol 284: H1073-9, 2003.
2. Parfenova H, Fedinec A, and Leffler CW.  Ionotropic glutamate receptors in cerebral microvascular endothelium are functionally linked to heme oxygenase.  J Cereb Blood Flow Metab 23: 190-7, 2003.
3. Leffler CW, Balabanova L, Sullivan D, Wang X, Fedinec AL, and Parfenova H. Regulation of CO production in cerebral microvessels of newborn pigs. Am J Physiol Heart Circ Physiol  285: H292-7, 2003
4. Leffler CW, Balabanova L, Fedinec AL, Waters CM, and Parfenova H.  Mechanism of glutamate stimulation of CO production in cerebral microvessels. Am J Physiol Heart Circ Physiol 285: H74-80, 2003
5. Carratu P, Pourcyrous M, Fedinec A, Leffler CW, and Parfenova H. Endogenous heme oxygenase prevents impairment of cerebral vascular functions caused by seizures. Am J Physiol Heart Circ Physiol 285: H1148-57, 2003
6. Xi Q, Tcheranova D, Parfenova H, Horowitz B, Leffler CW, and Jaggar JH.  Carbon monoxide activates K_Ca channels in newborn arteriole smooth muscle cells by increasing the apparent Ca²⁺ sensitivity of the a-subunit. Am J Physiol Cell Physiol 28: H610-8, 2004.
7. Parfenova H, Daley ML, Carratu P, and Leffler CW. Heme Oxygenase Inhibition Reduces Neuronal Activation Evoked by Bicuculline in Newborn Pigs. Brain Res 1014:87-96, 2004.
8. Parfenova H, Carratu P, Tcheranova D, Fedinec A, Pourcyrous M, and Leffler CW.  Epileptic seizures cause extended postictal cerebral vascular dysfunction that is prevented by HO-1 overexpression. Am J Physiol Heart Physiol 288: 2843-50, 2005.
9. Leffler CW, Parfenova H, Jaggar JH, and Wang R. Carbon monoxide and hydrogen sulfide: gaseous messengers in cerebrovascular circulation. J Applied Physiol 100: 1065-1076, 2006.
10. Leffler CW, Parfenova H, Fedinec AL, Basuroy S, and Tcheranova D. Contributions of astrocytes and CO to pial arteriolar dilation to glutamate in newborn pigs. Am J Physiol Heart Circ Physiol 291: H2897-2904, 2006.
11. Parfenova H, Basuroy S, Bhattacharya S, Tcheranova D, Qu Y, Regan RF, and Leffler CW. Glutamate induces oxidative stress and apoptosis in cerebral vascular endothelial cells: contributions of HO-1 and HO-2 to cytoprotection. Am J Physiol Cell Physiol 290: C1399-410, 2006.
12. Basuroy S, Bhattacharya S, Tcheranova D, Qu Y, Regan RF, Leffler CW, and Parfenova H. Heme oxygenase-2 provides endogenous protection against oxidative stress and apoptosis caused by TNF-a in cerebral vascular endothelial cells. Am J Physiol Cell Physiol 291: C897-908, 2006.
13. Zimmermann A, Leffler CW, Tcheranova D, Fedinec AL, and Parfenova H.  Cerebroprotective effects of the CO-releasing molecule CORM-A1 against seizure-induced neonatal vascular injury.  Am J Physiol Heart Circ Physiol 293: H2501-07, 2007.