Project Title: The Role of SUR1-TRPM4 in Creutzfeldt -Jakob disease

Principal Investigators: Bradley R. Smith1, J Marc Simard1,2,3, Vladimir Gerzanich1, David Kurland1, Jesse
Stokum1, Min Kwon1, Seung Kyoon Woo1, Orest Tsymbalyuk1, Svetlana Ivanova1,
1

Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA;

Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA;

Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA;

Objectives: The upregulation of SUR1-TRPM4 in the Central Nervous System (CNS) is implicated in
progressive neurologic deterioration in human patients. Glibenclamide, an FDA approved diabetes treatment,
pharmacologically inhibits SUR1-TRPM4 and provides substantial neuroprotection in animal models of
ischemic injury. However, despite the role of Excitotoxicity in mediating progressive neurodegeneration in both
ischemia and CJD, the role of SUR1-TRPM4 in CJD has never been investigated. The objectives of this
project are to (i.) demonstrate the expression of SUR1-TRPM4 in sectioned human tissues afflicted with CJD,
(ii.) confirm the transcriptional upregulation of SUR1-TRPM4 in an animal model of CJD, and (iii.) characterize
the efficacy of glibenclamide in ameliorating progressive neurological degeneration in an animal model of CJD.
Relevance to Human Prion Diseases:
Human prion diseases, upon their manifestation in patients, are invariantly fatal. Deterioration of patients
showing symptoms of CJD occurs inevitably, as there is no known treatment for prion disease. Clinical
worsening of individuals afflicted with CJD occurs through deterioration of the cerebral architecture in
conjunction with progressive neuroinflammation. The neuropathological fingerprint of CJD is a sponge-like
pattern of neuronal necrosis which propagates throughout the CNS. A process that is fueled by the accelerated
aggregation of misfolded cellular prion protein (PRPsc), progressive necrotic cell death in CJD is incompletely
understood. However, numerous neuropathological studies and recent molecular pathophysiological
experiments have indicated that excitotoxicity, a process that involves overactivation of NMDA Receptors and
ensuing cell death, represents a final common pathway of neuronal death in CJD. PRPsc directly potentiates
excitotoxic cell death, which is abolished by subsequent blockade of the NMDA Receptor. Through detailed
electrophysiological experiments, it has recently been demonstrated that Excitotoxic cell death unilaterally
depends on the function of TRPM4; a nonselective monovalent cation channel. However, due to the
sulfonylurea agent used to block TRPM4-like currents in these experiments, the contribution of TRPM4 alone
does not suffice to explain this result. Instead, excitotoxic cell death must depend on the expression and
activation of Sulfonylurea Receptor 1 (SUR1) - TRPM4: a nonselective monovalent cation channel selectively
upregulated after injury to the CNS. SUR1-TRPM4, when activated by high intracellular calcium levels and low
intracellular ATP levels, allows for the unchecked influx of sodium cations into the cytoplasm. The resulting
chloride influx and osmotically driven water influx leads to oncotic cell swelling and necrotic cell death. It has
been shown that in neuronal excitotoxicity, large levels of sustained intracellular calcium loading and ATP
depletion resulting from overactivation of the NMDA Receptor directly activate SUR1-TRPM4. Experimentally,
excitotoxic cell death is erased after inhibition of SUR1-TRPM4. Linking the neurotoxicity of NMDA Receptor
overactivation to the SUR1-TRPM4 channel provides an opportunity to abolish excitotoxic cell death through
inhibiting SUR1-TRPM4. The excitotoxicity of PRPsc in prion disease is well-founded, yet the role of SUR1TRPM4 in CJD has never been recognized. The presence of transcriptionally upregulated SUR1-TRPM4 in
CJD would thus allow for protection against PRPsc-mediated neurodegeneration. Glibenclamide, a safe, FDA
approved sulfonylurea used for the treatment of diabetes, pharmacologically blockades SUR1-TRPM4. In
previously discussed experiments, the blockade of SUR1-TRPM4 with Glibenclamide proved to eliminate
excitotoxic cell death. The inhibition of SUR1-TRPM4 in human prion disease with Glibenclamide, a drug with
pre-existing FDA approval, represents the potential for a new treatment option for patients with CJD.