RESEARCH: Apoptosis inhibitors prevent Parkinson's

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Apoptosis inhibitors prevent Parkinson's

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Researchers today revealed new therapeutic targets aimed at

preventing the premature or aberrant loss of vulnerable neurons,

critical in neurodegenerative disorders like Parkinson's. Such

therapies are " the Holy Grail of drug development, " noted one

leading scientist.

Investigator: S. Park

http://news.bmn.com/conferences/list/view?rp=2002-WCP-2-S1

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Report: Apoptosis inhibitors prevent Parkinson's

Investigator: S. Park

Tuesday Jul 9th, 2002

by Anne son

Neurodegenerative disorders involve the premature or aberrant loss of

vulnerable neurons, often through programmed cell death, or apoptosis.

Researchers today revealed new therapeutic targets aimed at preventing

neuronal suicide.

Drugs that block apoptosis could inhibit neuronal degeneration and

ultimately slow or halt progression of neurodegenerative disorders such as

Parkinson's disease (PD), said Saporito of Cephalon Inc., in West

Chester, Pennsylvania. Saporito chaired a session on unique molecular

targets for disease intervention.

One of the best models for PD involves treating animals with a mitochondrial

toxin called 1,2,3,6-tetrahydropyridine (MPTP). The toxin produces a

clinical phenocopy of human PD, although its pathology is slightly

different. MPTP destroys nigrostriatal neurons throughout the nigra region

of the brain indiscriminately, and typical Lewy bodies are not produced.

In both the MPTP animal model of PD, and in human disease, calcium-dependent

proteases, or calpains, play a key role in the loss of dopamine neurons,

according to work presented by S. Park, assistant professor of

molecular medicine at the University of Ottawa.

When Park administered MPTP to mice in vivo, he observed a progressive

increase in calpain-related proteolytic activity in dopamine neurons in the

substantia nigra. By inhibiting calpains - either through infusion of a

calpain inhibitor or over-expression of the endogenous calpain inhibitor,

calpastatin - the team triggered a striking decrease in MPTP-induced

neuronal apoptosis.

Inhibiting calpain protected against neurodegeneration in two other ways.

First, the treatment decreased motor deficits associated with MPTP

treatment. Second, it prevented MPTP-induced post-synaptic changes in the

striatum.

Interestingly, dopamine levels in the striatum did not mediate this

protection, suggesting that protection of the substantia nigra alone may

improve behavioral outcomes.

To further characterize the role of calpain in human PD, Park and his

colleagues used immunohistochemistry to evaluate human post-mortem midbrain

samples for patterns of calpain activity. Though tissues from PD patients

showed evidence of significant calpain activation in the substantia nigra,

the researchers did not find elevated calpain in tissues from control

patients.

" Taken together, our findings suggest a potentially novel link between

calpain activity in the MPTP model of Parkinson's disease and the etiology

of Parkinson's disease in humans, " Park said.

Drugs that interfere with calpains, caspases, and the JNK signaling

pathway - which is also implicated in apoptosis - are all titillating

targets for drug therapy, said E. Burke, a professor of neurology and

pathology at Columbia University in New York.

Both medical and surgical therapies now available are aimed toward relieving

symptoms, but none is directed at preventing the neurodegenerative process,

Burke said, adding therapies that prevent the neurodegenerative process are

" the Holy Grail of drug development. "