1. Neuronal and glial cell degeneration
Blockade of NMDA glutamate receptors and activation of GABA receptors during late fetal or early neonatal life trigger widespread apoptotic neurodegeneration in the developing brain of mammals. Research in these studies also suggested that glutamate, acting at NMDA receptors, controls neuronal survival. The lab further clarified the deleterious effect of ethanol (with NMDA receptor antagonist & GABA receptor agonist actions) on the developing brain. The Dikronian laboratory have characterized the robust neuronal apoptotic cell death caused by these agents and were able for the first time to give very detailed electron microscopic description of the stages of programmed cell death in cortical, brainstem and cerebellar neurons. The lab demonstrated these effects also in primates. Ethanol and select anesthetics such as propofol, isofurane and others promoted programmed cell death in both the neuronal and oligodendrocyte cell population. These findings show that similar acting anesthetics can potentially have impact on human neurodevelopmental disorders involving prenatal (drug-abusing mothers, fetal alcohol syndrome) or postnatal (pediatric anesthesia) exposure to drugs that block NMDA receptors or induce GABA-mediated inhibition during the brain growth spurt.
2. Traumatic brain injury
This laboratory has extensively contributed to studies that characterized in detail brain/head trauma induced neurodegeneration in the developing mammalian brain. The lab analyzed the nature and topographic distribution of acute and chronic cell degeneration. The laboratory demonstrated that early post trauma neurodegeneration is excitotoxic in nature and is followed by a wave of apoptotic cell degeneration. For the first time in the experimental traumatic brain literature we presented results on the temporal sequence of axonal degeneration and cell death. The lab demonstrated that early axonal disruption between communicating brain areas is followed by bilateral apoptotic neuronal cell death in these regions. The lab also characterized the role of repetitive head injury in the adult brain. Further laboratory studies on the application of diffusion tensor imaging in brain trauma experiments in an animal model of traumatic brain injury revealed that this imaging approach can successfully identify areas of axonal disruption. The lab’s current collaborative studies relate to mechanisms via which traumatic brain injury accelerates Alzheimer’s disease related pathologies and concern therapeutics in TBI-related tauopathy. Electron microscopy will be routinely used.
3. Collaborative studies
In the lab’s collaborative studies on animal models of Alzheimer’s disease, tauopathies and Prion’s disease the lab has studied and characterized the electron microscopic features of the developing brain pathology including cell degeneration, axonopathy and fibrillar and non-fibrillar plaque structures. These studies have helped in clarifying the degree of involvement of axonal and cellular structures in the progression of the disease process in various experimental transgenic animals.
The lab’s experience in the morphology of the CNS has also contributed to research related to some aspects of the Human Connectome Project. Studies are ongoing in relation to the trajectory and pattern of distribution of myelinated axons at the white matter/grey matter boundary in primates. Their relevance in studies applying dtMRI and tractography is to be evaluated.
- Smith SE, Chen X, Brier LM, Bumstead JR, Rensing NR, Ringel AE, Shin H, Oldenborg A, Crowley JR, Bice AR, Dikranian K, Ippolito JE, Haigis MC, Papouin T, Zhao G, Wong M, Culver JP, Bonni A. Astrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway: Nature Communications. 2020; 11:6164.
- Dikranian K, Bridgman P. Guide to Medical Histology, iBooks, 2015.
- Dikranian K, Holtzman DM. The ultrastructural identity of Alzheimer’s pathology: Lessons from animal models. Journal of Neurological Disorders. 2014; 2(3):e111.
- Van Essen D, Glasser M, Chen C, Dikranian D, Sotiropoulos S, Jbabdi S, Behrens T. Mapping Connections in Humans and Nonhuman Primates: Aspirations and Challenges for Diffusion Imaging. Diffusion MRI, Second Edition. Johansen-Berg and Behrens, eds. Ch. XVI, pp 336-356, Elsevier, 2013.
- Creeley C, Dikranian K, Dissen G, Martin L, Olney J, Brambrink A. Propofol induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain. Br J Anaesth. 2013; 110 Suppl. 1:i29-38.
- Musiek ES, Lim MM, Yang G, Bauer AQ, Qi L, Lee Y, Roh JH, Ortiz-Gonzalez X, Dearborn JT, Culver JP, Herzog ED, Hogenesch JB, Wozniak DF, Dikranian K. Giasson BI, Weaver DR, Holtzman DM, Fitzgerald GA. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. Journal of Clinical Investigation. 123:5389-5400.
- Dikranian K, Kim J, Stewart FR, Levy MA, Holtzman, DM. Ultrastructural studies in APP/PS1 mice expressing human ApoE isoforms: implications for Alzheimer’s disease. Int J Clin Exp Pathol. 2012; 5(6):482-495.
- Christensen H, Dikranian K, Li A, Baysac K, Walls K, Olney J, Roth K, Harris D. A highly toxic cellular prion protein induces a novel, non-apoptotic form of neuronal death. Am J Pathol. 2010; 176:2695-2706.
- Dikranian K, Cohen R, MacDonald C, Pan Y, Brakefield D, Bayly P, Parsadanian A. Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamaic neurons. Exp Neurol. 2008; 211:551-560.
- MacDonald CL, Dikranian K, Bayly P, Holtzman D, Brody D. Diffusion tensor imaging reliably detects experimental traumatic axonal injury and indicates approximate time of injury. J Neurosci. 2007; 27:11869-11876.
- Dikranian K, Qin Y, Labruyere J, Nemmers B, Olney J. Ethanol-induced apoptotic cell death in the developing rodent cerebellum and related brainstem structures. Dev Brain Res. 2005; 155:1-13.
- Dikranian K, Ishimaru M, Tenkova T, Labuyere J, Qin YO, Ikonomidou C, Olney J. Apoptosis in the in vivo mammalian forebrain. Neurobiol Dis. 2001; 8:359-379.
- Ikonomidou CH, Bittigau P, Ishimaru M, Wozniak D, Koch CH, Genz K, Price M, Stefovska V, Hoster F, Tenkova T, Dikranian K, Olney J. Ethanol-induced apoptotic neurodegeneration and the fetal alcohol syndrome. Science. 2000; 287:1056-60.
- Steudel W, Watanabe M, Dikranian K, Jacobson M, Jones R. Expression of nitric oxide synthase isoforms (NOS II and NOS III) in adult rat lung in hyperoxic pulmonary hypertension. Cell Tissue Research. 1999; 295:317-329.
- Ikonomidou CH, Bosh F, Miksa M, Bittigau P, Volker J, Dikranian K, Tenkova T, Stefovska V, Turski L, Olney J. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999; 283:70-74.
- Jevtovic-Todorovic, Todorovic SM, Mennerick S, Powell S, Dikranian K, Benshoff N, Zorumski C, Olney JW. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nature Medicine. 1998; 4:460-463.
- Dikranian K, Loesch A, Burnstock G. Localization of nitric oxide synthase and its colocalisation with vasoactive peptides in coronary and femoral arteries. An electron microscope study. J Anat. 1984; 184(Pt 3):583-590.
See a complete list of Dr. Dikranian’s publications on PubMed.
1972-1978 MD, Medical University, Varna, Bulgaria
1992 PhD, Medical Academy, Sofia, Bulgaria
1988 European Science Foundation Fellowship, France
1989 Calouste Gulbenkian Research Fellowship, England
1995 Fogarty International Research Collaboration Award, USA
1999, 2009, 2011, 2014 Lecturer of the Year Award, Washington University School of Medicine
2005-2008, 2010, 2012, 2013, 2015 Distinguished Service Teaching Award, Washington University School of Medicine
2007 Samuel Goldstein Leadership Award in Medical Student Education, Washington University School of Medicine
2014 Loeb Fellowship Award, Washington University in Saint Louis
2004 Richard Brand Award (Program in Physical Therapy)
2011 Honorary Member, Bulgarian Society for Cell Biology
2013 Honorary Consultant, Varna Medical University, Varna, Bulgaria