Interesting study on minocycline

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http://www.eurekalert.org/pub_releases/2008-10/uoc--urp100308.php

Public release date: 3-Oct-2008

UCR researchers propose minocycline as a promising drug for patients

with Fragile X syndrome

Study leader Iryna Ethell awarded FRAXA Breakthrough Award for 2008

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First row (left to right): Iryna Ethell, Tina Bilousova; second row (L

to R): Aye, Ethell, Lorraine Dansie,

( Ngo, not shown). Iryna Ethell is holding...

Click here for more information.

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RIVERSIDE, Calif. ­ A UC Riverside-led team of biomedical scientists has

found that a readily available drug called minocycline, used widely to

treat acne and skin infections, can be used to treat Fragile X syndrome,

the most common inherited cause of mental impairment and the most common

cause of autism.

The study's findings have already impacted future therapies, with the

approval of a new clinical trial in Toronto, Canada, that will test

minocycline in patients with Fragile X.

Neurons in the brain communicate with each other at specialized contact

sites called synapses, with many of these synapses occurring on small

mushroom-shaped structures called dendritic spines.

During early development dendritic spines have immature finger-like

shapes. But learning stabilizes the synapses and dendritic spines take

on a mature mushroom shape, which make them more efficient.

The brains of patients with Fragile X syndrome have an overabundance of

immature dendritic spines.

In their report, the researchers, led by Iryna Ethell and

Ethell, faculty members in UCR's Division of Biomedical Sciences,

describe how dendritic spine development in mice with Fragile X is

delayed by enzymes called matrix metalloproteinases (MMPs), which are

involved in normal brain development and physiological processes. They

report that high levels of certain MMPs keep the synapses immature and

inefficient.

But minocycline, they found, reduces these MMP levels in the mice,

allowing the synapses to mature and make more efficient contacts between

neurons in the brain. The outcome: corrected brain abnormalities in

dendritic spines, reduced anxiety and improved cognitive function.

Study results appear online, ahead of print, in the Journal of Medical

Genetics.

In their experiments, the Ethells found that young Fragile X mice

treated with minocycline showed an increase of dendritic spine

maturation in the hippocampus, a brain area that is critical for

learning and memory. Besides less anxiety, minocycline-treated mice

showed better exploration skills as compared to untreated mice.

The Ethells are enthusiastic about how their discovery already is

leading to a clinical trial.

" Clinical studies often quickly follow such basic science because once

there is a solid understanding of how problems arise, it is much easier

to come up with solutions, " said Iryna Ethell, an associate professor of

biomedical sciences.

The study was funded by a grant from the FRAXA Research Foundation.

FRAXA was founded in 1994 by three parents of children with Fragile X to

support scientific research aimed at finding a treatment and a cure for

Fragile X.

Dr. Tranfaglia, FRAXA's chief scientific officer, said of the

UCR researchers, " This group has done something unique and incredibly

valuable: They have identified an off-the-shelf treatment for Fragile X

through their basic research. By bringing their unique perspective to

Fragile X research, they have helped us to understand why neurons are

malformed in this disorder, and more importantly, how we can treat it.

" We were so impressed with their work that we just awarded Dr. Iryna

Ethell the FRAXA Breakthrough Award for 2008. This is easily the most

important scientific breakthrough in the Fragile X field in many years. "

According to Dr. Carl Paribello, president of Fragile X Research

Foundation of Canada and the director of the clinical trial (scheduled

for early 2009) at Surrey Place Centre Fragile X Clinic in Toronto,

Canada, the UCR-led study " will go a long way towards dispelling the

idea that mental impairment cannot be treated. "

" The work could lead to the first treatment that actually targets the

underlying defect in Fragile X syndrome and not just the symptoms, " Dr.

Paribello said.

UCR's Ethell, an assistant professor of biomedical sciences,

noted that effective therapies for Fragile X syndrome are few and far

between. " This is a good time for identifying highly effective

therapeutic strategies that might work in Fragile X patients, " he said.

" We are excited that our research has the potential to affect many

lives. "

Fragile X affects 1 in 4000 males and 1 in 6000 females of all races and

ethnic groups. About 1 in 259 women carry Fragile X and could pass it to

their children. About 1 in 800 men carry Fragile X; their daughters will

also be carriers.

Minocycline belongs to a group of antibiotics that has been used in

people for more than fifty years to treat Lyme disease, acne, and other

skin infections.

Minocycline may have beneficial effects in other disorders where

higher-than-normal brain levels of MMP-9 are found. It is currently

under study for treating rheumatoid arthritis, multiple sclerosis (MS),

Parkinson's disease, and several other neurodegenerative conditions.

" In the future, new compounds that more specifically target MMP-9 can be

developed and tested, " Ethell said.

Next in their research, the Ethells and their colleagues plan to refine

the therapeutic strategy in Fragile X mice to determine the optimal age,

if any, to administer minocycline. They will also explore other MMP

inhibitors that may be more effective than minocycline.

" We will investigate whether a combination of MMP inhibitors with other

drugs, such as fenobam, can help mature the synapses in Fragile X mice, "

Iryna Ethell said.

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