Discipline: Biological Sciences
Subcategory: Cell and Molecular Biology
Jordy Sepulveda - Hunter College, The City University of New York
Co-Author(s): Alec Levine, Hunter College, New York, NY; Lei Xie, Ph.D., Hunter College, New York, NY; Patricia Rockwell, Ph.D., Hunter College, New York, NY; and Maria E. Figueiredo-Pereira, Ph.D., Hunter College, New York, NY
Chronic neuroinflammation is a major factor initiating/exacerbating neurodegeneration in Alzheimer’s disease (AD). The pro-inflammatory enzyme cyclooxygenase-2 (COX-2) is highly expressed in AD brains and its activity correlates with the severity of AD. COX-2 catalyzes the synthesis of prostaglandins, some of which are neuroprotective while others are neurotoxic. Anti-inflammatory drugs that target COX-2 can prevent/inhibit inflammation. However, this anti-inflammatory strategy can produce adverse side effects, including renal failure, heart attack and stroke, as well as preventing the synthesis of neuroprotective prostaglandins. Therefore, to prevent the effects of neurotoxic prostaglandins without interfering with the neuroprotective ones, would offer a significant therapeutic benefit to the treatment of AD. Prostaglandin J2 (PGJ2) is an endogenous product of inflammation and is considered to be one of the most toxic prostaglandins that is produced downstream from COX-2 activation. Our in vitro studies with human neuroblastoma SY5Y cells overexpressing APP695 (APP695-SY5Y), showed that PGJ2 recapitulates pathological events relevant to AD, including neurotoxicity, caspase-3 activation, and the accumulation/aggregation of ubiquitinated proteins. We investigated the therapeutic potential of Diazoxide (DZ) against the neurotoxic effects induced by PGJ2 in APP695-SY5Y cells. DZ is a well-known potassium channel activator, is safe, is an FDA-approved drug for hypertension, and was also shown to positively modulate glutamate receptors indicating that it has potential to enhance cognition. Our in silico studies predicted that DZ binds to multiple kinases that are responsible for the pathology of AD. Our in vitro studies established that DZ significantly reduces the accumulation of ubiquitinated proteins and caspase-3 activation in the SY-APP695 cells. Our data support that DZ protects the neuronal cultures from PGJ2-induced neurodamage. The deeper study of DZ will provide insights for a therapeutic approach to overcome the neurotoxic effects of neuroinflammation and for enhancing neuronal survival in AD.Not Submitted
Funder Acknowledgement(s): Supported by NIH [BP-ENDURE, MD007599 to Hunter College from NIMHD] and the City University of New York (Graduate Center).
Faculty Advisor: Maria E. Figueiredo-Pereira, firstname.lastname@example.org
Role: I carried out the in vitro studies with the help of Alec levine in which we established that DZ significantly reduces ubiquitinated proteins and caspase-3 activation.