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Guest Lecturer Discusses Glia Signaling and Neurotoxicity

By Eddy Ball
February 2007

David Miller, O'Callaghan and Hong
Following the lecture, LPC Senior Investigator David Miller, Ph.D., right, discusses the research model with O'Callaghan, left, and Hong. (Photo by Eddy Ball)

On January 11 in Rall F-193, National Institute for Occupational Safety and Health (NIOSH) scientist James P. O'Callaghan, Ph.D., presented a lecture jointly sponsored by the Laboratory of Pharmacology and Chemistry (LPC) and the Laboratory of Molecular Toxicology. O'Callaghan spoke to a capacity audience on "Neurotoxicity Due to MPTP and Methamphetamine: Glia Signaling and a Role for TNFα."

LPC Supervisory Pharmacologist John Hong, Ph.D., was the lecture host. O'Callaghan is the head of the Centers of Disease Control (CDC) Molecular Neurotoxicology Laboratory. He is also the CDC Distinguished Consultant at the Toxicology and Molecular Biology Branch of the NIOSH Health Effects Laboratory Division. The lecture was the first of three he presented at NIEHS and EPA during his visit to the RTP campus.

O'Callaghan's presentation focused on the role of microgliosis in chemically induced neurotoxicity. Microgliosis refers to the activation of microglia, non-neural cells in the central nervous system, in the earliest stages of disease. In response to the presence of neurotoxin in the brain, microglia mount an immune-like response in the central nervous system to defend the organism and initiate a cascade of events that lead to striatal dopaminergic nerve terminal damage and dopamine (DA) depletion.

Two compounds that researchers have studied in regard to microgliosis are MTPT, a neurotoxin that produces Parkinson's-like symptoms, and methamphetamine (METH), a widely used street drug. Understanding the glial response following injury is important for discovering pharmacological antagonists that can modulate or even block the effects of neurotoxic exposures and help preserve normal dopamine synthesis.

In their studies of MTPT and METH neurotoxicity, O'Callaghan and his colleagues used a single dose of neurotoxin to reduce dopamine levels in laboratory animals to about 50 percent of normal. The single-dose regimen produces a moderate degree of neurotoxicity and allows researchers to measure changes over short periods of time. This model also permits a closer examination of the disease process by eliminating the confounding effects that can occur with multiple dosing. Unlike much of the research on neurotoxicity in cell loss models, O'Callaghan's research focused on early stage nerve terminal damage and glial response that occur over a 48- to 72-hour period.

These investigations have sought to identify the cellular events that activate microglia and signals of activation by using protein immunoassays to pinpoint molecular markers to serve as guides for intervention. The investigators found that one of the central proteins whose levels increased in reaction to chemically induced neural damage was glial-fibrillary acidic protein (GFAP), which is a marker for astroglia.

O'Callaghan hypothesized that an increase in GFAP, which is evident as early as six hours after dosing, would be a simple indicator of neurotoxicity and the best marker for neurodegeneration. In a series of experiments, he demonstrated that induction of GFAP paralleled neurotoxicant-induced reductions in striatal levels of DA and its synthesizing enzyme, tyrosine hydroxylase. Conversely, treatment with a known neuroprotective agent, such as the dopamine reuptake inhibitor nomifensine, corresponded to a drop in GFAP levels and an increase in DA and tyrosine hydroxylase.

Using the same model to study the role of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) in neuropathology at nerve terminals, O'Callaghan's team found a pattern of TNFα induction after dosing, but prior to increases in levels of GFAP. Treating with nomifensine, they were able to block TNFa before microglial activation could occur.

Because of the involvement of TNFα induction so early in striatal dopaminergic neurotoxicity, the cytokine may be a promising target for intervention. However, O'Callaghan emphasized that researchers need to understand more about the cascade of events involved in MTPT and METH neurotoxicity. Some pro-inflammatory cytokines and chemokines may have region-selective effects in the brain. TNFα, for example, performs a dual role in the brain, as a promoter of neurodegeneration in striatum and as a protector against neurodegeneration in the hippocampus.

Nevertheless, the ability to measure microglial activation in its earliest stages and the identification of a target cytokine are major steps forward in understanding how to protect against the effects of MTPT- and METH-induced neurotoxicity. Further study of biomarkers and neuroprotective agents, such as the antibiotic minocycline, should help scientists pair the most effective agents to specific neurotoxicants, target sites and dose responses.

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