Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
"Ask your doctor if rofecoxib' is for you!"
You're not likely to hear the arcane name of that medicament on a TV commercial. Try again: "Ask your doctor if Vioxx is for you!" In fact, rofecoxib is the chemical term for Vioxx, which has probably become a TV-endowed household word for this nonsteroidal anti-inflammatory agent. So has Celebrex, which is virtually identical to Vioxx in chemical structure and clinical use. They're both prescribed for arthritis - osteo and rheumatoid - as well as acute adult pain.
Both these TV-touted drugs inhibit the inflammatory enzyme cyclooxygenase-2 - COX-2 for short. "COX-2 usually arises in response to the immune system," observed postdoctoral research neurologist Peter Teisman at Columbia University in New York.
"Its expression in the body is very low," he told BioWorld Today, "and we sometimes can't even find it. It occurs in brain lesions where you can locate it at low levels. During arthritis flare-ups," Teisman continued, "COX-2 often gets up-regulated and participates in the inflammation. Its inhibition - as by Vioxx - stops the inflammatory process. Besides arthritis," Teisman added, "the inhibitor may favorably influence Alzheimer's disease and ALS [Lou Gehrig's disease]."
That inhibitor may be in for a totally different gig, as reported in the current Proceedings of the National Academy of Sciences (PNAS), released online April 8, 2003. The article, of which Teisman is first author, bears the title: "Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration."
Its senior author is Serge Przedborski, professor of neurology and pathology at Columbia's College of Physicians & Surgeons. He and Teisman looked for the suspect enzyme in postmortem brain samples from Parkinson's disease (PD) patients. They found that COX-2 expression is induced specifically within substantia nigra dopamine neurons in postmortem PD specimens, and in the MPTP mouse model during destruction of the nigrostriatal pathway.
"Collectively," Teisman summed up, "our data provide evidence for COX-2 up-regulation in MPTP and PD, and support a significant role for COX-2 in both the mechanism and specificity of MPTP- and PD-induced substantia nigra dopaminergic neuronal death. The present PNAS paper," he observed, "suggests that inhibition of COX-2 may be a valuable target for the development of new PD therapies aimed at slowing the progression of the neurodegenerative process. Dopamine sufferers suffer the most neuronal damage from the disease."
"In this PNAS paper," Przedborski said, "we asked whether PD is associated with COX-2 up-regulation, and if so whether COX-2 contributes to the PD neurodegenerative process."
The researchers tested the importance of COX-2 in PD-modeling mice that have an artificial disease almost identical to PD. It's created by treating healthy mice with a neurotoxin called MPTP, made famous (or infamous) 20 years ago by a bunch of heroin addicts who accidentally shot up the wrong chemical. They've remained parkinsonian ever since. (See BioWorld Today, April 2, 2003, and April 4, 2003.)
The MPTP rodents have the same high titers of COX-2 in their dopamine-secreting neurons in the brain's substantia nigra as PD patients do, which makes the mouse a valuable model for studying the human disease. Sure enough, the Columbia team found that COX-2 had an instrumental role in the death of the PD neurons. When they removed COX-2 from the rodents, and abolished their activity with a COX-2 inhibitor - in this case, rofecoxib - 88 percent more dopamine neurons survived with the drug. Without it, survival attained only 41 percent.
Surprisingly, however, when the enzyme was removed from mice, or inhibited with rofecoxib or its synonymous Vioxx, the researchers did not see the reduction in inflammation they expected to see. Evidently, it did not kill those neurons through inflammation. "Instead," Teisman recalled, "we provide evidence that COX-2 inhibition prevents the formation of the reactive oxidant species dopamine-quinon, which has been implicated in the pathogenesis of PD. Our study supports a critical role for COX-2 in both the pathogenesis and selectivity of the PD neurodegenerative process. Because of the safety record of the COX-2 inhibitors, and their ability to penetrate the blood-brain barrier, these drugs may be therapies for PD.
"We found that the COX-2 enzyme may kill neurons by oxidizing other molecules in the dopamine cells. These oxidized molecules then reacted with and damaged other components of the cell. Excessive damage," he noted, "can kill the dopamine-secreting neuron. Many researchers have hypothesized that cell loss caused by reactive oxygen species kills neurons in Parkinson's disease.
"We saw similar up-regulation," Teisman continued, "when we looked at postmortem human brain samples taken from Parkinson's patients, and provided to us by the Columbia Parkinson brain bank."
"Regardless of how COX-2 works in Parkinson's disease," Przedborski pointed out, "the benefit we see in animal models with COX-2 inhibitors suggests that those drugs could be useful in slowing the disease's progression in patients. The drugs are safe, and they get past the blood-brain barrier into the brain reasonably well. We're planning human clinical trials," he concluded, "to test the drug in PD patients."
"Science & Technology Ventures," an activity of the university's Intellectual Property Office, told BioWorld Today, "We are discussing a possible strategy concerning the discovery, at this time."
Pavlovian-Trained Monkeys Test Dopamine Neurons Of Primate Brain Coding Errors In Reward Prediction
A not-unrelated paper in Science dated March 21, 2003, is titled "Discrete coding of reward probability and uncertainty by dopamine neurons." Its authors are at the Institute of Physiology, University of Fribourg, Switzerland, and University of Cambridge, UK.
"Using distinct stimuli to indicate the probability of reward," they report, "we found that the phasic activation of dopamine neurons varied monotonically across the full range of probabilities, supporting past claims that this response codes the discrepancy between predicted and actual reward. The coding of uncertainty suggests a possible role for dopamine signals in attention-based learning and risk-taking behavior."