Date of Award

Summer 8-19-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmacology and Experimental Neuroscience

First Advisor

Shilpa Buch

Abstract

While the advancement of highly active antiretroviral therapy (HAART) has transformed the course of HIV/AIDS from a death sentence to a manageable chronic condition, the prevalence of a constellation of neurological disorders collectively termed as HIV-associated neurocognitive disorders (HAND) continues to persist in these patients. HAND is characterized by cognitive dysfunction, depression, impaired memory and/or deficits in motor skills. The underlying factors leading to HAND have been the subject of extensive research and are thought to be associated with HIV infection in the CNS combined with robust immune activation of resident cells of the CNS. In addition, there is a strong correlation between chronic substance abuse and the manifestation of HAND, posing a major challenge for health care management in HIV-positive drug abusers. One of the hallmark features of cocaine and opiate abuse is the increased neuronal toxicity in the setting of HIV infection.

Among the various commonly abused drugs, cocaine has been extensively studied for its ability to exacerbate the neuropathogenesis of HAND. Ample evidence suggests that cocaine not only facilitates viral replication in astrocytes and microglia, enhances the permeability of the blood-brain barrier (BBB) and exacerbates neuroinflammatory responses, working synergistically with viral proteins such as HIV Tat and virus envelop protein Gp120 to promote neuronal injury. Sigma-1 receptors (Sig-1R) are recognized as a unique class of non-G protein-coupled intracellular protein that binds to their ligands such as cocaine, resulting in dissociation of Sig-1R from mitochondrion-associated ER membrane (MAM) to the endoplasmic reticulum (ER), plasma membrane, and nuclear membrane, regulating function of various proteins. Sig-1R has diverse roles in both physiological as well as in pathogenic processes. The disruption of Sig-1R pathways has been implicated as causative mechanism(s) in the development of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington Disease (HD). Additionally, the interaction of cocaine and Sig-1R has more recently been implicated in potentiating the pathogenesis of HAND through impairment of BBB, microglial activation and astrogliosis.

Opiates such as morphine are commonly used clinically in palliative care and pain management. Chronic exposure to morphine and other opioids however, can result in significant detrimental effects on cognition. Our findings suggest that morphine dysregulates synaptic balance in the hippocampus, a key center for learning and memory, via a novel signaling pathway involving reactive oxygen species (ROS), endoplasmic reticulum stress (ER stress) and autophagy. We demonstrate herein that morphine treatment leads to a reduction in excitatory and a concomitant enhancement of inhibitory synapse densities in the hippocampal neurons via activation of the mu opioid receptor. Furthermore, these effects are mediated by the ability of morphine to upregulate intracellular ROS from nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase), which in turn, promotes ER stress and the induction of autophagy, leading ultimately to decreased excitatory and increased inhibitory synapse densities. The detrimental effects of morphine on synaptic densities were shown to be reversed by platelet-derived growth factor (PDGF), a pleiotropic growth factor, that has been implicated in neuroprotection, at the level of intracellular ROS. Both abnormal unfolded protein response (UPR) and impaired autophagy have also been implicated as a causative mechanism in the development of various neurodegenerative diseases. The common underlying feature of most neurodegenerative diseases such as AD, prion diseases, PD, and ALS involves accumulation of misfolded proteins leading to initiation of endoplasmic ER stress and stimulation of the UPR. Additionally, ER stress has more recently been implicated in the pathogenesis of HAND. Autophagy plays an essential role in the clearance of aggregated toxic proteins and degradation of the damaged organelles. These results thus identify a novel cellular mechanism involved in morphine-mediated synaptic alterations with implications for impaired cognition as well as neurocognitive disorders. Furthermore, based on our findings, it can be speculated that therapeutic strategies aimed at activating PDGF signaling can be envisioned as possible approaches to block morphine-mediated cognitive decline.

Available for download on Wednesday, August 01, 2018

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