Department of Anesthesiology/Critical Care Medicine and Pediatrics
The Johns Hopkins University School of Medicine
Bloomberg Children's Center 6318-A
1800 Orleans Street
Baltimore, MD 21287
Phone: (410) 502-2669
Fax: (410) 502-5312
As a pediatric critical care physician, Dr. Courtney Robertson sees many children in the pediatric intensive care unit who have suffered some form of head trauma. In the laboratory, Dr. Robertson is working toward identifying interventions that could minimize the neurological deficits that can persist after such traumatic brain injury (TBI). Following TBI multiple pathologic intracellular cascades ensue, many of which involve mitochondrial dysfunction, which can lead to metabolic failure and cell death. To that end, she and her team are using a preclinical model to study potential disruption of mitochondrial function and alterations in cerebral metabolism. After the brain mitochondria are isolated, they measure mitochondrial respiration, calcium uptake, production of reactive oxygen species, membrane potential, and the activity levels of key enzymes. Dr. Robertson has found that a substantial amount of mitochondrial dysfunction is present in the first 6 hours after TBI. Mitochondria isolated from the peri-trauma region show alterations in both active, phosphorylating respiration (State 3) and in resting (State 4) rates of respiration. In addition, she has shown a decrease in the activity of the mitochondrial enzyme pyruvate dehydrogenase, the enzyme that converts pyruvate to acetyl-Co A, the first substrate in the energy-producing Krebs cycle. In addition to their study of isolated mitochondria, they are also using nuclear magnetic resonance spectroscopy to evaluate global and regional alterations in brain metabolism after TBI.
In a related study, Dr. Robertson is collaborating with investigators at the University of Pennsylvania to compare mitochondrial function after head injury in different clinically relevant models. Using the two models, they are testing whether the FDA-approved drug cyclosporin A is capable of mitochondrial rescue and improving histologic and neurologic outcomes after TBI. Because cyclosporin A blocks the formation of the permeability transition pore in mitochondria, they are hopeful that the drug will prevent the loss of the membrane proton gradient, which is essential to energy production by mitochondria. Dr. Robertson is hopeful that treatments like these, targeted at mitochondrial rescue, will ultimately lead to the development of clinically useful neuroprotective strategies for the developing brain.
- Robertson C, Bell M, Kochanek P, Adelson P, Ruppel R, Wisniewski S, Mi Z, Janesko K, Clark R, Jackson E. Increased adenosine in cerebrospinal fluid after severe traumatic brain injury in infants and children: association with severity of injury and excitotoxicity. Crit Care Med 29:2287–93, 2001.
- Robertson C, Bucci C, Fiskum G. Mitochondrial response to calcium in the developing brain. Res Brain Dev Brain Res 151:141–8, 2004.
- Robertson CL, Puskar A, Hoffman GE, Murphy AZ, Saraswati M, Fiskum G. Physiologic progesterone reduces mitochondrial dysfunction and hippocampal cell loss after traumatic brain injury in female rats. Exp Neurol 197:235–43, 2006.
- Ahn ES, Robertson CL, Vereczki V, Hoffman GE, Fiskum G. Normoxic ventilatory resuscitation following controlled cortical impact reduces peroxynitrite-mediated protein nitration in the hippocampus. J Neurosurg 108:124–31, 2008.
- Robertson CL, Soane L, Siegel ZT, Fiskum G. The potential role of mitochondria in pediatric traumatic brain injury. Dev Neurosci 28:432–46, 2006.
- Robertson CL, Saraswati M, Fiskum G. Mitochondrial dysfunction early after traumatic brain injury in immature rats. J Neurochem 101:1248–57, 2007.
- Casey PA, McKenna MC, Fiskum G, Saraswati M, Robertson CL. Early and sustained alterations in cerebral metabolism after traumatic brain injury in immature rats, J Neurotrauma 25:603–614, 2008.
Current Laboratory Members/Key Associates
Manda Saraswati, PhD
Gary Fiskum, PhD – University of Maryland
Mary McKenna, PhD – University of Maryland
Susan Margulies, PhD – University of Pennsylvania/Children’s Hospital of Philadelphia