Recent studies suggest important roles for glial cells-astroglia and microglia-in the development, differentiation and survival of neurons in the brain. Both astroglia and microglia become activated in response to brain injury, a process termed "reactive gliosis." However, these two kinds of activated glial cells exert very different effects on the neighboring neurons. Microglia, which are the predominant cell type in the central nervous system that express the major histocompatibility complex class II molecule, play an important role in immune surveillance. However, during reactive gliosis, microglia secrete neurotoxic substances, such as excitatory amino acids, proinflammatory cytokines or free radicals, which kill neurons and have been proposed to be the major causes of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Because neurodegeneration is a common sequela for patients exposed to a variety of environment-related neurotoxins, information generated from this line of research should further the Neuropharmacology Group’s understanding of the mechanisms of action for neurotoxicants.
Major areas of research:
Molecular mechanisms of activation of glial cells
Mechanisms of glia-mediated neurotoxicity
Creation of inflammation-mediated rodent PD models.
In an effort to evaluate the role of inflammation in the pathogenesis of PD, the group first developed new PD animal models and primary midbrain neuron-glia cultures. The salient features of these models are:
Prominent inflammation in the process of producing neuronal death
Delayed, progressive, and selective nature of dopaminergic (DA) neuronal death, both in vivo and in vitro
These models were the first to mimic the delayed and progressive nature of the disease symptoms in PD patients.
Mechanism of inflammation-mediated degeneration: role of microglia
The group has demonstrated that microglia are the major player in mediating the inflammation related-neurodegeneration of DA neurons, triggered by a variety of environmental toxins. These findings are critical to the novel concept that microglia do not merely serve a passive role as scavengers. Instead, microglia play an active role in the pathogenesis of PD and other neurodegenerative diseases. Group members have identified a series of pro-inflammatory factors released from activated microglia, which mediate toxin-induced neuronal damage. Moreover, the Neuropharmacology Group has elucidated the molecular mechanisms underlying the regulation of expression for these pro-inflammatory genes.
Development of novel anti-inflammatory therapy for PD
Information generated from the above studies has provided insights for the development a series of novel anti-inflammatory and neuroprotective agents. Unique from the conventional strategies for developing anti-inflammatory drugs, which often target a specific pro-inflammatory factor, the group’s approach is to prevent the over-production of the majority of pro-inflammatory factors through the inhibition of the over-activation of microglia, which would prevent the subsequent inflammatory process. Furthermore, the group has discovered several small molecules, including peptides and alkaloids, which are both anti- inflammatory and neuroprotective at femtomolar concentrations. In addition to their potential therapeutic benefits, the discovery of femtomolar-acting peptides also offers valuable insight to the potential physiological mechanisms governing microglial activation and DA neuron survival in the substantia nigra.
Jau-Shyong Hong, Ph.D., heads the Neuropharmacology Group within the Laboratory of Pharmacology. He received his Ph.D. from the Department of Pharmacology, University of Kansas School of Medicine in 1973. He has published over 300 peer-reviewed articles in leading biomedical journals, as well as 50 book chapters. He was a Senior Staff Fellow at NIMH before joining NIEHS in 1980.