"It's our hope that this discovery serves as the impetus for a proper
clinical trial to evaluate the potential of drugs like ampicillin for
early-onset torsion dystonia," said Dr. Guy Caldwell, associate
professor of biological sciences at The University of Alabama.

Dystonia is, like Parkinson's disease, a movement disorder. Combined,
this class of diseases affects millions worldwide. People with early-
onset dystonia have one good copy of the gene DYT1, and one
problematic copy, in their DNA. These genes contain the information to
make a protein called torsinA.

"When proteins go bad, they often cause disease, but they always have
a normal function in our cells," Guy Caldwell said. "We looked to find
molecules - not necessarily that reversed the mutated form of the
protein - but instead enhanced the normal activity of the protein,
thereby overcoming the deficiency caused by the mutant."

The UA researchers discovered that ampicillin, a common antibiotic of
the penicillin group, serves to activate torsinA, which, in its normal
form, appears to protect cells from stresses, such as protein
misfolding - a problem known to impact various movement disorders.

Using a nematode animal model designed to evaluate torsinA activity,
the UA lab rapidly screened through hundreds of compounds to identify
those that were most effective at enhancing torsinA's normally
protective function.

"From there, we collaborated with researchers at Harvard and UAB to
validate our findings in human patient cells and mice," said Dr. Kim
Caldwell, associate professor of biological sciences at UA.

"In human dystonia patient cells, ampicillin was efficacious and
restored the patient cells back to the normal function," Kim Caldwell
said. "And, the drug restored normal movement to mice that were
genetic mimics of dystonia."

Collaborators in the UA-led study were Drs. Xandra O. Breakefield and
her colleagues at Harvard and Yuqing Li and his colleagues at The
University of Alabama at Birmingham, known as UAB. Dr. Songsong Cao, a
former doctoral student in the Caldwell Lab, is the study's lead
author; two UA doctoral students, Alexander J. Burdette and Pan Chen;
and one former UA student, Amber Clark Buckley, are among the co-
authors.

Furthermore, the research shows ampicillin enhances the capacity of
torsinA to protect, within animal models, the neurons which produce
dopamine from dying. The death of these neurons in human brains leads
to the hallmark symptoms of Parkinson's disease.

In a statement accompanying the paper, the researchers caution against
the long-term use of an antibiotic in disease treatment.

"We have taken ampicillin and used that as a base structure to find
things that work like ampicillin but which aren't ampicillin," Guy
Caldwell said. "Finding molecules that are not antibiotic and still
have the capacity to activate torsinA has been an ongoing effort of
our lab, and we have some exciting leads in that direction."

UA filed patents covering the use of antibiotics and other novel
chemicals as activators of torsinA for treatment of dystonia and other
diseases, including Parkinson's disease. The University has also
entered into a collaborative research and licensing agreement with
QRxPharma, a clinical stage pharmaceutical company, to identify,
develop and commercially exploit new torsinA activator drugs.

The UA/QRxPharma research program is directed at re-engineering
existing drug therapies for new clinical applications and identifying
new drug candidates for uses including the treatment of dystonia,
Parkinson's disease and other neurological disorders.

The project exemplifies, the researchers said, how disease model
systems can be used to accelerate the development of gene and drug
discovery and bring pharmaceuticals more quickly to the clinical trial
stage.

Bringing a drug that does not already have FDA approval from the
research and development stage to a patient takes an estimated 12
years and $800 million dollars, said Kim Caldwell. By evaluating the
potential of molecules already pre-screened for toxicity and that have
FDA approval provides a potentially quicker route to clinical trials.

"What we were hoping to do was circumvent a lot of the cost in
bringing pharmaceutical help to dystonia patients," Kim Caldwell said.

More information: This work is published in Issue 3/4 of Volume 3 in
the medical research journal Disease Models and Mechanisms (DMM)
http://dmm.biologists.org

Provided by The Company of Biologists

-

Stability Constants of Cu2 , Fe3 ↦ Zr4 Chelates of Ampicillin,
Dopamine and -Methyl L-Dopa in Aqueous Medium
M. G. Abd El Wahed a; M. Ayad© a
a Chemistry Department, Faculty of Science, Zagazig University,
Analytical Letters, Volume 17, Issue 3 1984 , pages 205 - 216
Analytical Chemistry; Chemical Spectroscopy; Forensic Chemistry;

Abstract
Formation constants of chelates of ampicillin, dopamine, and
-methyl L-dopa with Cu 2+, Fe3+ and Zr4+ have been determined
in aqueous medium at ionic strength of 0.1 M (KC1) using
Calvin-Bjerrum technique as applied by Irving and Rossotti.
Zirconium forms relatively more stable chelates with ampicillin as
compared to copper and iron.
However, in case of dopamine and -methyl L-dopa the chelation
with iron is the more stable.
The order of stability of copper and iron is in agreement with the
Irving-Villiems order.
The mixed ligand chelates have been, also, investigated.
The stability sequence has been found to be Cu2+ < Fe3+ < Zr4+

Keywords: Ampicillin; Dopsmine;  -Methyl L-Dopa; Metal chelate;
Protonation constant; Stability constant; Potentiometric titration
DOI: 10.1080/00032718408065279

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