Areas of Interest
Clinically, stroke is increasingly recognized as a sexually
dimorphic disease. Most international databases demonstrate that
women enjoy lower stroke incidence relative to men until
advanced age. This native neuroprotection is lost after
menopause, often attributed to loss of estrogen. It is equally
well established that tissue damage and functional outcome after
experimental brain injury are shaped by biologic sex. Emerging
data suggest that cell death in brain may follow differing
mechanistic paths depending on gender, in addition to sex
steroid exposure. In our work we are attempting to discover the
underlying mechanisms of these gender differences. We have
recently found that a striking gender difference occurs in one
basic pathway of cell death. A major mechanism of
ischemia-induced neuronal cell death results from
overstimulation of neuronal nitric oxide synthase (nNOS) leading
to enhanced production of nitric oxide (NO), consequent
peroxynitrite (ONOO) formation and nitrosative DNA damage. In
response to this DNA damage, the energy consuming DNA repair
enzyme poly ADP ribose polymerase-1 (PARP-1) is activated. The
extensive damage that occurs during ischemia leads to exuberant
energy consumption, mobilization of mitochondrial pro-apoptotic
molecules and cell death However the evidence establishing NO
toxicity/PARP-1 activation as a major cytotoxic mechanism has
accumulated from studies utilizing exclusively male animals with
deletions of nNOS (nNOS-/-) or PARP (PARP-/-) or mixed cell
cultures. We have recently demonstrated that significant gender
differences exist in this basic cell death pathway after an
ischemic insult in vivo. Genetic deletion of nNOS or PARP-1,
although neuroprotective in male animals, led to an exacerbation
of damage in females after middle cerebral artery occlusion (MCAO).
We have also found that similar gender differences exist at the
cellular level. XY-derived (male) hippocampal slice cultures
exhibited increased cell death after exposure to oxygen-glucose
deprivation compared to those derived from XX (female) neurons.
Lab Rotation Projects
My primary research focus is the basic mechanisms involved in
cerebral ischemia. Our major focus has been centered on
examining how the male and female brain differ in their response
to ischemia. We are also currently examining how to manipulate
energy metabolism in the ischemic brain to promote neuronal
survival after stroke.
Selected Publications
McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD
(2005). Ischemic nitric oxide and poly (ADP-Ribose) polymerase-1
in cerebral ischemia: male toxicity, female protection. JCBFM
25:502-12.
McCullough LD, Zeng Z, Li H, Landree LE, McFadden J, Ronnett
GV (2005). Pharmacological inhibition of AMP-activated protein
kinase provides neuroprotection in stroke. J Biol Chem. Mar 16;
[Epub ahead of print].
McCullough LD, Kofler J, Hurn PD. Gender differences in
stroke pathobiology: Therapeutic implications, in Acute
Stroke: Bench to Bedside, Bhardwaj A (ed), Marcel Dekker
Publishing, New York, 2006, in press.
Ardelt AA, McCullough LD, Korach KS, Wang M, Munzenmaier DH,
Hurn PD (2005). Estradiol regulates angiopoietin-1 mRNA
expression through estrogen receptor- in a rodent experimental
stroke model. Stroke 36:337-41.
Graham SM, McCullough LD, Murphy SJ (2004). Animal models of
ischemic stroke: balancing experimental aims and animal care.
Comp Med 54:486-96.
Li X, Blizzard K, Zeng Z., Derives AC, Hurn PD, McCullough LD
(2004). Chronic behavioral testing after focal ischemia in the
mouse: functional recovery and the effects of gender.
Experimental Neurology 187:94-104.
McCullough LD, Wu L, Haughey N, Liang X, Hand T, Wang Q,
Breyer R, Andreasson K (2004) Neuroprotective function of the
PGE2 EP2 receptor in cerebral ischemia. J of Neuroscience
24:257-268.
Murphy SJ, McCullough LD, Smith, JM (2004). Stroke in the
female: Role of biological Sex and Estrogen. ILAR 45: 147-159.
Murphy SH, Littelton-Kearney MT, McCullough LD & Hurn PD
(2004). Sex, hormones, and the endothelium. In: Principles of
sex based physiology: 34: 71-84. Miller V. and Hay MH, eds.
Elsevier.
McCullough LD & Hurn PD (2003). Estrogen and ischemic
neuroprotection: An integrated view. Trends in Endo and
Metabolism 14: 228-35.
McCullough LD, Blizzard KK, Oz O, Simpson E & Hurn PD (2003).
Aromatase Cytochrome P450 and extragonadal estrogen play a role
in ischemic neuroprotection. J of Neuroscience 23:8701-8705.
Murphy SJ, McCullough LD, Littleton-Kearney M & Hurn PD
(2003). Estrogen and selective estrogen receptor modulators:
Neuroprotection in the Women’s Health Initiative Era. Endocrine
21:17-26.
Hurn PD, Ardelt AA, Alkayed NJ, Crain BJ, Hu W, Kearney ML,
McCullough LD, Murphy SJ, Toung TJK, Traystman RJ, Wang MM.
(2002). Estrogen and Testosterone as Neuroprotectants in Stroke.
In: Pharmacology of Cerebral Ischemia: Krieglstein J, editor.
Medpharm Scientific Publishers, Stuttgart, Germany.
McCullough LD, Beachamp NB & Wityk R. (2001). Advances in the
diagnosis and treatment of stroke. Surveys of Ophthalmology 45:
317-330.
McCullough LD, Alkayed N, Williams M., Traystman RJ & Hurn
PD. (2001). Post-ischemic estrogen reduces hypoperfusion and
secondary ischemia after experimental stroke. Stroke 32:
796-802.
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