Date of Award

1-1-2016

Document Type

Dissertation

Degree Name

Ph.D.

Organizational Unit

Biological Sciences

First Advisor

Daniel A. Linseman, Ph.D.

Second Advisor

Robert Dores

Third Advisor

Nancy Lorenzon

Fourth Advisor

Keith Miller

Fifth Advisor

Nicholas Ormes

Keywords

Neurodegeneration, Death mechanisms, Therapeutic implications

Abstract

Neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), include the progressive loss of structure and function of neurons leading to neuronal death. All of these diseases are fatal, as there is no cure for them. The causes of these diseases are unknown; however, there are many proposed mechanisms that lead to neurodegenerative diseases. Oxidative stress is the leading cause of cell death in neurodegenerative diseases, in addition to other mechanisms including endoplasmic reticulum stress, proteasome inhibition, nitrosative stress, inflammation and excitotoxicity. More understanding of the death mechanisms at work in neurodegeneration is necessary to find ways to block those mechanisms in order to slow or stop the progress of these disorders. Interest in nutraceutical compounds has increased recently because of the discovery their bioactive properties. Many studies have suggested that nutraceutical compounds have the ability to inhibit the different death pathways.

In this study, we investigated the neuroprotective efficacy of seven natural compounds in several in vitro models of cell death. In primary cultured rat cerebellar granule neurons (CGNs), pre-incubation with caffeic acid, which is abundant in green coffee beans, completely protected against cell death induced by several mechanisms. Caffeic acid protected against effects of sodium nitroprusside (SNP), an agent that induces nitrosative stress, glutamate /glycine which prompts excitotoxicity, hydrogen peroxide, an inducer of oxidative stress, proteasome inhibitors, 5K medium that induces caspase-dependent apoptosis, and endoplasmic reticulum stressors. Furthermore, caffeic acid reduced inflammation induced by lipopolysaccharides in BV2 mouse microglial cell line. Chlorogenic acid and ferulic acid protected from one agent. Chlorogenic acid only protected CGNs from SNP; however, ferulic acid protected the CGNs from glutamate toxicity. Quinic acid did not protect from any agents or stressors. Rosmarinic acid protected the CGNs against glutamate toxicity, and carnosic acid protected the cells from 5K medium that typically induces apoptosis. Both rosmarinic acid and carnosic acid protected the cells from SNP and subsequent nitrosative stress. We further suggeste that carnosic acid protects CGNs from caspase-dependent apoptosis through activation of the phosphoinositide 3-kinase (PI3K) pro-survival pathway. Pyrroloquinoline quinone (PQQ) also showed a significant protection against oxidative stress typically induced by hydrogen peroxide and copper chloride. The cumulative data suggest that nutraceutical compounds hold promising therapeutic implications for neurodegenerative disease.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Rights Holder

Faten I. Taram

Provenance

Received from ProQuest

File Format

application/pdf

Language

en

File Size

155 p.

Discipline

Biology, Neurosciences

Download



Share

COinS