Sci. Aging Knowl. Environ., 19 November 2003
Product of neuron-damaging enzyme cleared of wrongdoing
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/46/nw159
Key Words: cerebral ischemia superoxide dismutase EP2 EP3
NEW ORLEANS, LOUISIANA--In a brain-cell murder mystery, a prime suspect has turned out to be a hero, according to work presented here 8 and 11 November 2003 at the Society for Neuroscience Annual Meeting. A molecule produced by an enzyme implicated in amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases protects rather than harms neurons. The observation suggests possible new treatments for ALS, stroke, and other conditions that kill nerve cells.
Patients with ALS lose motor neurons in their spinal cord. As a result, muscle control falters and eventually they die of respiratory failure. An overdose of the neurotransmitter glutamate, which kills neurons, underlies the neuronal demise in ALS. Inflammation also apparently contributes to the disease. In their spinal fluid, patients with ALS carry high concentrations of the enzyme cyclooxygenase 2 (COX-2), which crafts molecules called prostaglandins that rev up immune cells. Compounds that inhibit COX-2 protect nerve cells from a glutamate overdose, at least in culture. Neurologist Kati Andreasson and colleagues at Johns Hopkins University School of Medicine in Baltimore, Maryland, tested whether a particularly abundant prostaglandin--PGE2--that typically fans inflammation could explain COX-2's lethality to neurons.
The researchers bathed sections of rat spinal cord in PGE2 and ramped up glutamate concentrations. Unexpectedly, fewer motor neurons died in slices treated with PGE2 than in those that weren't, suggesting that the prostaglandin buffers neurons from glutamate damage.
PGE2 provokes physiological responses by binding to receptor proteins on cell surfaces. To discern whether this clasp was responsible for PGE2's cell-saving power, the researchers added different drugs, each of which activates one of two types of PGE2 receptor that they identified in motor neurons. Tickling either receptor preserved neuron integrity in the face of a glutamate glut; this finding suggests that PGE2 protects neurons by activating these receptors.
Andreasson wants to know whether PGE2 protects neurons in ALS patients and plans to test her results in rodent models of the disease. Additional studies by her team already suggest that PGE2 protects mice from stroke. Mice that lack one of the PGE2 receptors show more extensive damage from stroke than do normal animals, and treatment with one of the PGE2 receptor-tickling compounds reduced stroke carnage--even when given several hours after the event. Together the results suggest that PGE2 shields neurons even though the enzyme that produces it--COX-2--inflicts harm.
"It's a neat observation," says neuroscientist Sandra Hewett of the University of Connecticut Health Center in Farmington. Many people think of PGE2 as an instigator of harmful inflammation, and in that sense the result is a paradox, she says. COX-2 generates reactive oxygen species as it operates, she notes, and that ability could explain why COX-2 causes trouble (see "Parkinson's Shake-Up"). PGE2--and perhaps other prostaglandins--might help quench those oxidants; recent studies have suggested that prostaglandin precursors activate enzymes that temper oxidative damage. Goading PGE2 receptors could represent a new strategy for tackling the mystery of brain death in aging-related diseases.
--R. John Davenport
November 19, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150