Environmental Factor, November 2006, National Institute of Environmental Health Sciences
Intramural Lecturer Presents Combined Therapy Model for PD
By Eddy Ball
Laboratory of Pharmacology and Chemistry (LPC) Supervisory Pharmacologist John Hong, Ph.D., delivered a lecture on Parkinson's Disease (PD) on October 12 in F193 as part of the LPC Seminar Series. Hong, who was host for the LPC Seminar with guest lecturer Donato Di Monte the previous week, focused on the "Role of Inflammation in the Pathogenesis of Parkinson's Disease: Models, Mechanisms and Therapeutic Interventions." Introduced by Host John Pritchard, Ph.D., chief of the LPC, Hong's lecture explored a complementary model using the endotoxin lipopolysaccharide (LPS) to trigger the inflammatory cascade that induces damage to neurons in the substantia nigra. This inflammation is characteristic of PD and other neurodegenerative diseases. Experiments with the model have led Hong to develop a novel combined therapy for these disorders.
The mechanistic studies and the novel interventions Hong's lab has tested offer additional insights into PD and other diseases. The lab tested LPS treatment in vivo and in vitro, finding what Hong described as "delayed, progressive and selective loss of dopaminergic (DA) neurons" in the substantia nigra following dosing. Hong and his colleagues found that age was an important variable in the results, with older animals experiencing a significantly greater response than younger animals to exposure.
Hong and his colleagues have used two types of toxins, LPS and MTPT, to study the possible mechanism underlying the progressive nature of neurodegeneration. They determined that LPS causes neuronal death indirectly through the activation of migratory nervous system cells called microglia, while MPTP can damage dopamine neuron directly. However, whether initiated by LPS or MPTP, neuronal death will cause "reactive microgliosis" to further activate microglia to release proinflammatory factors and induce further neuronal damage.
Hong's laboratory has developed a two-pronged therapy for PD. The therapy targets microglia, by inhibiting the over-production of multiple inflammatory factors and oxidative damage to neurons, and transport cells in the brain known as astroglia, by stimulating production and release of neurotrophic factors. Neurotrophic factors protect neurons by increasing their plasticity and their ability to rebound from assault by inflammatory compounds activated by the microglia.
Hong's lab built on previous research in a variety of neurodegenerative disease animal models demonstrating the neuroprotective effects of morphinans, a series of compounds that are structurally similar to morphine.
Hong explored the possibility that morphinan neuroprotection was due to anti-inflammatory effects resulting from the prevention of microglia over-activation. Hong's colleagues tested several types of morphinans and finally selected an opioid receptor antagonist, naltrexone, which does not produce the pleasurable and often addicting side effects of many morphinans. Additional research demonstrated that dextromethorphan (DM), an active ingredient in cough mixtures, and its final metabolite, 3-hydroxy-morphinan, are safe, potent and inexpensive neuroprotective agents.
For the second prong of combined therapy, Hong's lab tested valproic acid (VPA), a short-chain fatty acid commonly used to treat bipolar disorder and seizures. VPA has been shown to activate cell survival factors and induce release of neurotrophic factors. Moreover, VPA promotes neuron outgrowth and DA uptake, helping neurons rebound after inflammatory insult. Hong's lab found that astroglia in the brain played a critical role in mediating VPA-induced neurotrophic and neuroprotective effects and constituted a potential target for intervention.
Although the combined therapy model is still several steps away from testing in humans, it holds promise as an innovative treatment for PD and other neurodegenerative diseases. It utilizes existing therapeutic compounds that are commercially available, have few side effects and have demonstrated clinical utility. The therapy also operates both protectively, by strengthening neurons, and remedially, by down-regulating inflammatory compounds, to produce a synergetic therapeutic effect. Hong's work embodies the translational emphasis of innovative research at NIEHS in its efforts to connect basic scientific research and clinical interventions.