Most Significant Scholarly Contributions

The following represent, in chronological order, what I believe are my most significant scientific articles or areas of study.

1.         a) Ellis, E.F., O. Oelz, L.J. Roberts, N.A. Payne, B.J. Sweetman, A.S. Nies and J.A. Oates: Contraction of coronary arterial smooth muscle by a substance released from aggregating platelets: Evidence that it is thromboxane A2. Science 193: 1135-1137, 1976.
b) Ellis, E.F., A.S. Nies and J.A. Oates: Cerebral arterial smooth muscle contraction by thromboxane A2. Stroke 8: 480-483, 1977.

In these two studies we were the first to show that when human platelets aggregate, as they do in hemostasis or infarction, thromboxane A2 is released and that it is capable of contracting heart and brain arteries. This is important because blood platelet aggregation and subsequent blood vessel contraction could lead to further decreases in heart and brain blood flow. The fact that aspirin blocks formation of the platelet pro-aggregatory and vasoconstrictor thromboxane A2 is part of the rationale for the regular use of aspirin in the prevention of heart attack and stroke.

2.         Ellis, E.F., P.S. Jones, K.F. Wright, D. Richardson and C.K. Ellis: The effect of oral aspirin dose on platelet aggregation and vascular prostacyclin (PGI2) synthesis in humans and rabbits. J. Cardiovasc. Pharmacol. 2: 387-397, 1980.

This human and animal study was the first to fully document and prove that very low oral aspirin doses are capable of blocking the formation of blood platelet thromboxane, which constricts arteries, while leaving intact the blood vessels’ capacity to form the anti-aggregatory prostaglandin I2. Thus a low (80 mg, 1/4 of 1 tablet) aspirin dose provides a platelet anti-thrombotic effect and a relatively reduced risk for the gastrointestinal side effects of aspirin. This evidence provided support for the medical use of low dose aspirin to reduce the chance of heart attack or stroke.

3.         Kontos, H.A., E.P. Wei, J.T. Povlishock, W.D. Dietrich, C.J. Magiera and E.F. Ellis: Cerebral arteriolar damage by arachidonic acid and prostaglandin G2. Science 209: 1242-1245, 1980.

In collaborative studies with Drs. Kontos and others, and our own independent studies (total of 22+ peer-reviewed articles), we examined the role of tissue-injuring oxygen radicals after traumatic brain injury. We found that damage could be prevented by oxygen radical scavengers and antioxidants. Oxygen free radicals have been implicated not only in brain trauma but also in neurodegenerative processes such as Alzheimer’s and Parkinson’s disease.

4.         a) Adesuyi, S.A., C.S. Cockrell, D.A. Gamache and E.F. Ellis: Lipoxygenase metabolism of arachidonic acid in the brain. J. Neurochem. 45: 770-776, 1985.
b) Amruthesh, S.C., and E.F. Ellis. Brain synthesis and cerebrovascular action of epoxygenase metabolites of arachidonic acid. J. Neurochem. 58: 503-510, 1992.

In these two HPLC-GC/MS analytic studies we were the first to definitively show the existence of the lipoxygenase and epoxygenase pathways of arachidonic acid metabolism in brain tissue. We showed that these pathways are comparable in magnitude to the cyclooxygenase pathway, which produces prostaglandins, whose synthesis is inhibited by aspirin and aspirin-like drugs. The role of lipoxygenase and epoxygenase enzyme metabolites in the normal and injured brain and brain circulation is the subject of continuing research in several laboratories.

5.         a) Haberl., R.L., M.L. Heizer, A. Marmarou and E.F. Ellis. Laser Doppler assessment of the brain microcirculation: Effect of systemic alterations. Am. J. Physiol., 256: H1247-H1254, 1989.
b) Haberl., R.L., M.L. Heizer and E.F. Ellis. Laser Doppler assessment of the brain microcirculation: Effect of local alterations. Am. J. Physiol., 256: H1255-H1260, 1989.

In these two companion studies we were the first to definitively employ a new blood flow measuring technique for the study of highly localized brain blood flow. While the technique had been employed on skin it had not been rigorously applied to, or validated in, the brain circulation. We validated this technique by comparing it to more traditional techniques. In the process we were able to also make conclusions concerning the practical application of Poiseuille’s centuries-old equation for the measurement of flow in tubes. Dr. Haberl and I had to overcome much skepticism, however laser Doppler flowmetry has become one of the standard, international laboratory approaches for the measurement of local changes in brain perfusion. A computer search shows that since 1989 over 1000 studies of brain blood flow have employed laser Doppler flowmetry.

6.         In vitro stretch (strain) injury (see also cell injury publications on this website)

After having studied in vivo traumatic brain injury for approximately 15 years I came to the conclusion that an additional tissue culture approach would allow us to better understand basic cellular mechanisms of injury that could not be studied in intact animals. I therefore created a new model wherein tissue cultured brain cells are grown on a flexible elastic membrane and then subjected to a 50 msec strain (stretch) injury, similar to that which can occur during in vivo traumatic brain injury. We had to invent and trouble-shoot the experimental approach and then document its relevance to in vivo injury. With an excellent laboratory cadre we were able to address the criticism and skepticism of our reviewers.
We believe employment of this novel and relevant tissue culture approach in our own, as well as collaborative, studies has led to important information concerning the intracellular processes and membrane receptor alterations that occur after strain injury. Our work has become frequently cited by others. It was specifically my intent when designing the model that it be inexpensive and commercially available so that it could be employed by others. Our injury device is now employed in at least 14 different brain injury research laboratories in the US, Europe, Australia, New Zealand and Canada. Our original cell injury device has been improved and updated and is commercially available, thus providing a uniform manner to injure cells and gain new information.

7.         Zhang, L., B.A. Rzigalinski, E.F. Ellis and L.S. Satin. Reduction of the voltage-dependent Mg2+ blockade of NMDA current in mechanically injured cortical cells. Science 274: 1921-1923, 1996.

For years it has been known that following traumatic brain injury there is a massive release of the brain neurotransmitter glutamate, which in turn quickly initiates a number of very detrimental brain-injuring cascades. The action of the released glutamate is very rapid and it is not presently possible to reverse this injurious cascade except with clinically non-relevant pre-injury glutamic acid receptor antagonists. The cause of this glutamate receptor damange, acting through the NMDA glutamate receptor, was unknown. Using our in vitro model, Dr. Satin, his post-doctoral fellow Lei Zhang and my laboratory's post-doctoral fellow Beverly Rzigalinski were able to definitively show that trauma to in vitro neuronal cells caused a reduction of the voltage-dependent magnesium blockade of the NMDA current, thus allowing the NMDA current to initiate more both long- and short-term detrimental consequences. This study shed definitive light on a basic mechanism by which trauma causes a post-traumatically irreversible initiation of far-reaching post-traumatic injury events and has been widely quoted.

8.         Rzigalinski, B.A., K.A. Willoughby, S.W. Hoffman, J.R. Falck and E.F. Ellis. Calcium influx factor: Further evidence it is 5,6-epoxyeicosatrienoic acid. J. Biol. Chem. 274: 175-182, 1999.

Calcium is the primary regulator of many intracellular biochemical processes. One of the mechanisms for regulation of intracellular calcium dynamics and allowing influx of extracellular Ca2+ in response to hormones and other agents is through the “capacitative pathway” as originally described by Putney. Drawing upon my laboratory’s experience with epoxide derivatives of arachidonic acid and Dr. Beverly Rzigalinski’s expertise with measurement of intracellular calcium we provided substantial additional evidence that 5,6-epoxyyeicosatrienoic acid, an epoxide metabolite of arachidonic acid, may be a heretofore unidentified factor controlling capacitative calcium influx into cells. This is important because 5,6-epoxyeicosanoic acid may play a universal role in regulation of calcium in many cell types. This study was well received and is the subject of ongoing study by several laboratories. Additionally, we were the first to confirm important alterations in capacitative calcium entry in traumatically injured neurons (Weber, et al., J. Biol. Chem 216: 1800, 2001).

9.         a) Willoughby, K.A., A. Kleindienst, C. Müller, T. Chen, J.K. Muir and E.F. Ellis. S100B protein is released by in vitro trauma and reduces delayed neuronal injury. J. Neurochem. 91: 1284-1291, 2004..
b) Ellis, E.F., K.A. Willoughby, S.A. Sparks and T.A. Chen. S100B protein is released from rat neonatal neurons, astrocytes, and microglia by in vitro trauma and anti-S100 increases trauma-induced delayed neuronal injury and negates the protective effect of exogenous S100B on neurons. J. Neurochem. 101: 1463-1470, 2007.

In 2002-03 we were introduced to the potential importance of the calcium binding protein S100B in traumatic brain injury by Dr. Andrea Kleindienst, a visiting post-doctoral fellow. To that point in time, S100B was thought to be merely a marker of brain trauma. Using our in vitro model of traumatic brain cell injury we showed that astrocytes, microglia and neurons release S100B after trauma and that addition of exogenous S100B significantly reduces injury. Furthermore, we showed that addition of an antibody to S100 worsened injury. Therefore we provided substantial evidence that S100B was not simply a marker of injury, but rather an important endogenous substance for the repair of neurons following traumatic brain injury.