Date of Award

Summer 8-18-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmacology and Experimental Neuroscience

First Advisor

Huangui Xiong

Abstract

Methamphetamine (Meth) is a psychostimulant drug that is widely abused all around the world. The administration of Meth causes a strong instant euphoria effect, and long-term of abuse is correlative of drug-dependence and neurotoxicity. The neuroimaging studies demonstrated that the long-term abuse of Meth is associated with the reduction of the dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) in the striatum. Neuroinflammation is well-accepted as an important mechanism underlying the Meth-induced neurotoxicity. The over-activated microglia were found both in Meth human abusers and animal models.

NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is the most predominant Nod-like receptor (NLR) expressed in microglia and is involved in the pathogenesis of many neurodegenerative diseases. In recent years, multiple lines of evidence suggest that the activation of NLRP3 inflammasome is associated with drug abuse induced innate immune system activation both in central nervous system (CNS) and peripheral nervous system (PNS). We investigated the role of NLRP3 inflammasome in Meth-induced microglial activation. Meth induced the production of mitochondrial ROS and disruption of lysosomal membrane integrity, which served as the second activation signal of NLRP3 inflammasome. The activation of NLRP3 inflammasome led to the cleavage of pro-IL-1β and subsequent release of biologically active IL-1β. By blocking the inflammasome activation, we successfully attenuated the neuronal apoptosis induced by supernatants of Meth-treated microglia.

It is well-known that Meth abuse exacerbates HIV-1-associated neurocognitive disorders (HAND). However, the mechanism of how Meth potentiates HAND is not fully understood. Ample evidence indicates that both Meth and HIV-1 cause microglial activation and resultant secretion of proinflammatory molecules leading to neuronal injury and ultimately the development of HAND. Inflammasome is the key signaling platform involved in HIV-1-associated microglia activation and the production of proinflammatory molecules. We studied the synergistic effects of HIV-1 glycoprotein protein 120 (gp120) and Meth in microglial NLRP3 inflammasome activation. Gp120 upregulated the pro-IL-1β and thus, primed the microglia as the first signal. The subsequent stimulation of Meth as the second signal further activates the inflammasome that promotes the processing and release of IL-1β. The overactivated ROS system is potentially relative to gp120- and Meth-induced inflammasome activation.

Available for download on Friday, May 17, 2019

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