SCoBIRC FACULTY

Linda J. Van Eldik, Ph.D.

Director, Sanders-Brown Center on Aging
Director, University of Kentucky Alzheimer’s Disease Center
Professor, Department of Anatomy and Neurobiology
Ph.D., Duke University, Microbiology & Immunology
Postdoctoral training at Rockefeller University, NY, Cell and Molecular Biology

The Van Eldik Lab: (left to right) Ed Dimayuga, Adam Bachstetter, Bin Xing, Danielle Goulding and Pradoldej (Bob) Sompol.

Research Interests

Signal transduction, glia-neuron interactions, neuroinflammation, drug discovery for neurodegenerative disorders
Research in the Van Eldik lab aims to elucidate the mechanisms by which abnormal activation of glia in the brain, especially astrocytes and microglia, leads to damage of the neurons and progressive neurodegeneration in diseases like Alzheimer's disease (AD) and traumatic brain injury (TBI). The overall goal is to utilize knowledge of potentially "druggable" pathways to develop new therapeutics. The normal role of the glia is to cooperate with the neurons to keep the brain operating smoothly. When an injury or change in the brain occurs, the glial mount a beneficial inflammation response to fight off the insult and restore the brain to its proper functioning. While a controlled inflammatory response is an important element in protecting the brain, this beneficial process sometimes gets out of balance and the inflammation becomes too strong or does not shut off on schedule. In neurodegenerative diseases, the glia are over-activated, producing detrimental inflammatory molecules called proinflammatory cytokines that can contribute to nerve cell death and accelerate the progression of the disease. Although neuroinflammation appears to play a pivotal role in the development and progression of neurodegeneration, the molecular mechanisms underlying the process and approaches to downregulate the neuroinflammation have received little attention. This raises the logical question of whether drugs can be developed to selectively target cytokine up-regulation in glia, with the hope that such drugs would slow down or perhaps even prevent disease progression.

Projects in the Van Eldik lab are focused on identification of signal transduction pathways that mediate the neuroinflammatory responses of activated glia and exploration of how aberrant glial-neuronal interactions contribute to or influence neurodegenerative processes. In collaborative research with medicinal chemistry and integrative pharmacology colleagues, we have extended this knowledge of pathophysiology progression to drug discovery efforts that have yielded novel small molecules that are candidates for drug development as well as tools to explore the potential of improved neurologic outcomes by restoration of activated glia back towards homeostasis.

Representative Publications

Sheng JG, Ito K, Skinner RD, Mrak RE, Rovnaghi CR, Van Eldik LJ and Griffin WST (1996) In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis.  Neurobiology of Aging 17:761-766.

Craft JM, Watterson DM, Frautschy SA and Van Eldik LJ (2004) Aminopyridazines inhibit b-amyloid induced glial activation and neuronal damage in vivo.  Neurobiol Aging 25:1283-1292.

Craft JM, Watterson DM, Van Eldik LJ (2006) Human amyloid b-induced neuroinflammation is an early event in neurodegeneration. Glia 53: 484-490.

Ralay Ranaivo H, Craft JM, Hu W, Guo L, Wing LK, Van Eldik LJ and Watterson DM (2006) Glia as a therapeutic target: selective suppression of human Ab-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration. J Neurosci 26:662-670.

Hu W, Ralay Ranaivo H, Roy SM, Behanna HA, Wing LK, Munoz L, Guo L, Van Eldik LJ, Watterson DM (2007) Development of a novel therapeutic suppressor of brain proinflammatory cytokine up-regulation that attenuates synaptic dysfunction and behavioral deficits. Bioorg Med Chem Lett 17:414-418.

Somera-Molena KC, Robin B, Somera CA, Anderson C, Koh S, Behanna HA, Van Eldik LJ, Watterson DM and Wainwright MS (2007) Glial activation links early-life seizures and long-term neurologic dysfunction: evidence using a small molecule inhibitor of pro-inflammatory cytokine upregulation. Epilepsia 48: 1785-1800.

Munoz L, Ralay Ranaivo H, Roy SM, Hu W, Craft JM, McNamara LK, Wing Chico L, Van Eldik L, and Watterson DM (2007) A novel p38a MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer’s disease mouse model.
J Neuroinflammation 4: 21.

Lloyd E, Somera-Molina KC, Van Eldik LJ, Watterson DM and Wainwright MS (2008) Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurology outcome in a mouse model of traumatic brain injury.
J Neuroinfl 5:28.

Thompson WL and Van Eldik LJ (2009) Inflammatory cytokines stimulate the chemokines CCL2/MCP-1 and CCL7/MCP-7 through NFkB and MAPK dependent pathways in rat astrocytes. Brain Res 1287: 47-57.

Somera-Molina KC, Nair S, Van Eldik LJ, Watterson DM and Wainwright MS (2009) Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a ‘two-hit’ seizure model. Brain Res 1282: 162-172.

Chico LK, Van Eldik LJ and Watterson DM (2009) Targeting protein kinases in central nervous system disorders. Nature Rev Drug Discovery 8: 892-909. Bachstetter AD and Van Eldik, LJ (2010) The p38 MAP kinase family as regulators of proinflammatory cytokine production in degenerative diseases of the CNS. Aging and Disease 1: 199-211.