Prozac prevents onset of Huntington's disease in mice

A collaborative study by Australian and UK neuroscientists has shown that the anti-depressant fluoxetine (Prozac) prevents the onset of Huntington's disease (HD) in transgenic HD mice.

If fluoxetine and similar anti-depressants can also be shown to prevent or delay the onset of the devastating brain disease in humans, it could point towards treatment for a disorder long considered incurable.

The finding has emerged from earlier research by Prof Anthony Hannans' research team at Melbourne's Howard Florey Institute into the benefits of exercise and mental stimulation in delaying the onset of HD in transgenic mice expressing a virulent mutant allele of the human huntingtin gene.

Hannan's team and its collaborators at the Brain Research Institute at the University of Queensland, and Oxford University's Laboratory of Physiology, have confirmed that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), causes brain stem cells to differentiate and repopulate the hippocampus, the brain's memory 'engine', with new neurons.

The transgenic mice retain normal brain function and coordination as their untreated littermates begin to exhibit symptoms of depression, memory loss, cognitive decline and loss of coordination that typify human HD.

HD is a member of a class of dominant-gene disorders that exhibit a pattern of inheritance called 'anticipation' -- a parent will remain unaffected, while a child develops the disease because the DNA code of the huntingtin gene is mis-replicated in the egg or sperm, and produces a mutant protein that forms neurotoxic deposits in the brain.

In severe cases, the first symptoms may manifest in infancy, but typically the symptoms of memory loss, dementia and chorea -- loss of physical coordination -- develop in mid-life.

A genetic test for HD has been available since 1993, which also predicts approximately when a patient will develop the disorder. Because there has been no effective treatment, few at-risk family members opt to take it, preferring to live with uncertainty, and to remain childless.

Hannan said his team began experimenting with fluoxetine based on a study by US researchers that showed the drug stimulates the birth of new neurons in the brains of normal mice and rats, hypothesising that it might do the same in transgenic HD mice.

In Huntington's disease, the toxic amyloid causes a progressive loss of neurons in a region of the hippocampus called the dentate gyrus, and in a surrounding region of the brain called the striatum. Hannan said the onset of symptoms is due to the loss of neurons and failure of the mechanisms that normally generate new neurons to replace them.

Hannan said fluoxetine therapy completely rescued the HD mice from the mental and physical decline exhibited by their untreated HD littermates.

They exhibited normal behaviour and performance in tests of cognition, mood and physical coordination at 16 weeks, when untreated mice had developed severe symptoms of memory loss and dementia.

Hannan said fluoxetine seems to restore lost production of survival and growth factors, most notably, brain-derived neurotropic factor (BDNF), which promotes stem cell differentiation into neurons. BDNF also promotes the survival of new neurons as they integrate into the dentate gyrus and striatum.

Depression, a common symptom of HD, is usually accompanied by short-term memory loss. SSRI anti-depressants take up to two weeks to begin alleviating depression, which may reflect the time required for the drugs to initiate neurogenesis and repair of the hippocampus.

Hannan's team now plans to test fluoxitine therapy in HD volunteers. He said it is too early yet to recommend the treatment to alleviate or even prevent HD, on the basis of the mouse studies.

His team also plans to test other SSRI drugs to see if they produce similar or superior therapeutic benefits. US researchers are also experimenting with non-SSRI drugs that stimulate neurogenesis.

Hannan expects other researchers will now seek to determine whether SSRIs are useful in stimulating generalised brain repair in patients with other chronic neurodegenerative disorders like Alzheimer's disease, motor neuron disease and Parkinson's disease.