Nephi Stella

nstella@u.washington.edu
Associate Professor, Departments of Pharmacology and Psychiatry & Behavioral Sciences

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Activation of immune cells in the CNS.
Several pathologies, such as Alzheimer's disease and multiple sclerosis (MS), are associated with an inflammation of the CNS. The current line of research in my laboratory is to study the underlying causes and mechanisms linked to these excessive inflammatory responses in order to generate specific drugs that may temper (or even stop) those inflammations and the adjacent neuronal damages. Alzheimer's disease primarily produces memory impairments with attention deficits while MS produces numbness with pain. Interestingly, both pathologies feature over-activated microglial cells which produce diverse toxic agents as well as directly eliminate neuronal cells by phagocytosis. Thus, microglial cells constitute a primary pharmacological target for anti-inflammatory drugs, but a further understanding of how their over-activation in Alzheimer's patients differs from that of MS is still needed.

Traditional medicine provides a remarkable resource to study incurable pathologies, as investigating the mechanisms of action of traditional medicine's active ingredients may reveal the origin of the pathology. MS patients commonly use cannabis-derived preparations to relieve their symptoms. Furthermore, several clinical studies and animal experiments have confirmed that drugs activating cannabinoid receptors, such as marijuana and its active component delta9-tetrahydrocannabinol, can relieve MS symptoms. Our current hypothesis is that the cannabinoid signaling pathway is impaired in MS, an assumption supported by several data:

1. cannabinoid receptors are expressed by microglial cells;
2. cannabinoid drugs produce immuno-suppressive responses, at least in the peripheral immune system;
3. cannabinoid drugs suppress the neurological deficits observed in experimental autoimmune encephalomyelitis, an animal model of MS.

Several studies have shown that excessive stimulation of neuronal cannabinoid receptors produce loss in short-term memory and attention deficits, two cognitive impairments known to be hallmarks of Alzheimer's disease. This similarity between cannabinoid intoxication and Alzheimer's disease suggests a malfunction of the CNS cannabinoid signaling system in senile dementia. This hypothesis is supported by the fact that over-activated microglial cells produce endogenous cannabinoid ligands.

My lab studies the different molecular mechanisms underlying microglial cell activation, with a focus on the cannabinoid signaling pathway. To address this question, we use microglial cells in primary culture and measure the activity of the cannabinoid signaling pathway in the following manners:

1. the amounts of endogenous cannabinoid ligands are measured by gas chromatography/mass spectrometry and
2. the presence of cannabinoid receptors are measured by classic pharmacological approaches (binding, spectrophotometry and immunochemistry).

The long-term goal is to understand the mechanisms underlying the biology of microglial cell activation, which will potentially provide novel therapeutic avenues for the treatment of CNS immune-related pathologies.