30 November 2001. Two papers published this week offer data that might further the search for therapies in neurodegenerative disease, particularly in Parkinson's.
Writing in PNAS, Steven Paul and colleagues at Eli Lilly and Company, Indiana, and Phillips-University in Marburg, Germany, report that an antibiotic can protect the vulnerable substantia nigra (SN) neurons in the MPTP model of Parkinson's disease.
The neurotoxin MPTP induces Parkinson's-like neuropathology and motor problems in both humans and animal models by selectively destroying the SN dopamine cells. Recently, evidence has surfaced that the mechanism of this attack may be more complicated than a direct toxicity of MPTP metabolites on the neurons; it may also involve the activation of surrounding glial cells, which can upregulate various toxic substances. Using in vivo and in vitro methods, the researchers found that the antibiotic minocycline protects dopaminergic neurons following MPTP administration. Interference with glial cell up-regulation of the toxic nitric oxide (NO) molecule (and possibly also cytokines) appears to be the mechanism of this protection.
However, the results do not support giving minocycline or other tetracycline antibiotics to Parkinson's patients, the authors write. The MPTP model only partially mimics Parkinson's, and the doses required would have unacceptable side effects. Rather, the study suggests more research into the mechanisms of MPTP toxicity and into separating the antibiotic and neuroprotective properties of the drug.
In another report relevant to the development of therapeutics, Dale Edmondson and colleagues at Emory University in Atlanta, Georgia, and the University of Pavia, Italy, describe the structure of the enzyme monoamine oxidase B (MAO B). MAO B and its isoform, MAO A, help to produce toxic oxygen free radicals. The enzyme is elevated threefold in aged human brain tissue, and inhibitors are used to treat Parkinson's and depression. There are also suggestions that MAO B inhibition could be helpful in Alzheimer's disease.
In the December Nature Structural Biology, Edmondson and colleagues describe the crystal structure of the enzyme, revealing the architecture of the catalytic center and of sites that are important to its binding to mitochondrial membranes. The information will aid in the design of more specific inhibitors for MAO B and MAO A.-Hakon Heimer.
Reference:(1) Du Y et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. PNAS 2001 Dec 4;98(25):14669-74.
(2) Binda C et al. Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. Nat Struct Biol 2001 Nov 26. Abstract