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Faculty Louise McCullough
Associate Professor of Neurology and Neuroscience
Director of Stroke Research
lmccullough@uchc.edu
- M.D., University of Connecticut Health Center
- Ph.D., University of Connecticut Storrs
- Neurology Residency (1996-2000) and Cerebrovascular Post Doctoral
Training (2000-2002); Johns Hopkins University
- Neuroscience
Graduate Program
- Accepting students for Lab Rotations: Fall '08, Spring '09
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. |
