In mouse and cell studies, drugs shut down damaging stress response, protected brain.
|Oh, there's that cure I was looking for.|
Tried, true, and FDA-approved drugs for cancer and depression—already in medicine cabinets—may also be long-sought treatments for devastating brain diseases such as Alzheimer’s, Parkinson’s, and other forms of dementia, according to a new study in Brain, a Journal of Neurology.
The research is still in early stages; it only involved mouse and cell experiments, which are frequently not predictive of how things will go in humans. Nevertheless, the preliminary findings are strong, and scientists are optimistic that the drugs could one day help patients with progressive brain disease. Researchers are moving toward human trials. And this process would be streamlined because the drugs have already cleared safety tests. But even if the early findings hold up, it would still take years to reach patients.
In the preliminary tests, the two drugs—trazodone hydrochloride, used to treat depression and anxiety, and dibenzoylmethane (DBM), effective against prostate and breast tumors—could shut down a devastating stress response in brain cells, known to be critical for the progression of brain diseases. The drugs both protected brain cells and restored memory in mice suffering from brain diseases.
"We're excited by the potential of these findings from this well-conducted and robust study,” Doug Brown, of the Alzheimer's Society, told the BBC.
David Dexter, from Parkinson's UK, added that “if these studies were replicated in human clinical trials, both trazodone and DBM could represent a major step forward.”
Stressful stress response
For years, researchers have known that a stress response in cells, called “unfolded protein response,” or UPR, is involved in a bunch of neurodegenerative diseases. The response kicks in when there’s a buildup of unfolded or misfolded proteins. Typically, protein chains are folded into specific 3D structures that are often critical for their function in the body. But this folding goes awry in some neurodegenerative conditions, such as prion diseases, Alzheimer's disease, Parkinson's disease, and other forms of dementia.
When this happens, UPR kicks in. It shuts down protein production, tries to junk the botched proteins, and gets protein production machinery back in order. If all goes well, the cell can resume normal protein production. But if it doesn’t, UPR initiates apoptosis, aka cell suicide.
In neurodegenerative diseases, things don’t go well; UPR is over-activated, and brain cells start dying off. Scientists know that hampering UPR can protect brain cells and restore memory in mice engineered to mimic having Alzheimer's disease. But so far, all the compounds found to knock back UPR were highly toxic or highly insoluble (they don’t work as medicine).
Cut to the drugs
For a drug discovery shortcut, researchers at the University of Cambridge wondered: do we already have drugs that can interfere with UPR but just don’t know it? They screened a library of 1,040 FDA-approved drugs to find out.
Because UPR is highly conserved across animals, the researchers could use worms to screen the drugs. They initially found 20 drugs that seemed to have UPR-dampening effects. Upon further testing, they whittled down the list to five, then to two.
In further cell experiments, both trazodone and DBM inhibited a specific step in UPR and restored protein production. In mice, the drugs traversed the blood-brain barrier. When the researchers infected mice with a prion disease, clinically relevant doses of either drug held back neurological symptoms, boosted survival, and substantially reduced loss of brain cells in most of the infected mice. In mice that modeled a type of dementia, called frontotemporal dementia, both drugs could rescue the rodents’ memory and restore protein synthesis in brain cells.
“The two drugs were markedly neuroprotective,” the authors conclude. “These drugs therefore represent an important step forward in the pursuit of disease-modifying treatments for Alzheimer’s and related disorders.”
Trazodone, the authors note, is even already approved for use in the elderly. Clinical trials are the next step.