By Anna Wexler
Dr Silvia Mandel
Dr Silvia Mandel always begins the first lecture of the semester by asking her Technion students the same question: “Why do we need to protect our brain cells?”
The answer, according to Mandel, who is the Vice Director of the Eve Topf Neurodegenerative Diseases Research and Teaching Center at the Technion, is that we are constantly losing brain cells, starting from the moment we are born, or possibly even earlier. “That is why we have to keep them in a very good state,” she says.
Much of Mandel’s research has revolved around exactly how to accomplish just this. Mandel, who immigrated with her family from Uruguay to Israel at 18, studied biochemistry as an undergraduate at Ben-Gurion University. At the Technion, she obtained her master’s in pharmacology, her PhD in neuropharmacology, and completed her postdoc at the Faculty of Biology.
In the nineties, Mandel began to work with Prof. Moussa Youdim on a variety of neuropharmacology studies, and joined him when the Eve Topf Center officially launched. Back then, the most accepted hypothesis regarding neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, was that a state of oxidative stress and an excess of metals in the brain-especially iron and copper-could cause one’s brain to “rust.”
By chance, Mandel came across a paper that investigated the effects of green tea on a number of diseases. Green tea was known to be an antioxidant, a molecule that can inhibit the process of oxidation, and it was thought to possess the capabilities to trap iron and other metals. But the paper that Mandel read dealt with blood cells, not brain cells.
Mandel and her colleagues thought that green tea, with its antioxidant and iron-trapping properties, might be helpful in treating neurological diseases. “So we began to work on green tea,” she says.
Her initial experiments showed that a two- to four-week treatment of green tea extract could prevent the development of the symptoms of Parkinson’s disease (PD) in mice. These effects were also found when the mice were administered only the main molecular component in green tea, epigallocatechin gallate (EGCG), which indicated that it was EGCG that was trapping the excess iron.
But Mandel was not satisfied with discovering just the preventative effects of green tea, because by the time patients affected by neurodegenerative disorders come to the doctor, they are seeking treatment, not prevention. So Mandel and her colleagues took the research one step further. This time, they used a different paradigm: they administered EGCG to mice that already displayed symptoms of PD.
Then, by staining brain slices and examining the neurons, and by measuring the levels of dopamine, the main neurotransmitter that is lost in PD, the researchers saw that there had been a complete restoration of neurons. Their experiments showed, for the first time, that EGCG could work to “rescue” neurons.
However, Mandel knew that no single drug could be 100 percent effective in treating a neurodegenerative disease. “Parkinson’s and Alzheimer’s are very complex, there are several factors involved, which is why they are called multifactorial diseases,” she says, comparing treatment of these neurodegenerative diseases to the treatment of cardiovascular diseases and AIDS, where patients take not a single drug, but a “cocktail” of drugs.
“The next step was to apply a cocktail paradigm,” says Mandel, “where we take tea and another drug that has a completely different mechanism of action.” Mandel’s PhD student, Lydia Reznichenko, began to mix doses of green tea and rasagiline, a drug developed at the Eve Topf Center for the treatment of PD. She reduced the dosage on both EGCG and rasagiline so that neither drug would be effective on its own, and administered the cocktail to mice with PD.
“What Lydia got was a complete restoration of neurons, from 50 percent to almost 100 percent,” says Mandel. The results, published in 2010 in the publication Neurodegenerative Diseases, indicated that either the damaged neurons were being recovered or that new neurons were being regenerated.
Exactly how EGCG is working to restore neurons is not yet clear. Mandel believes that the antioxidant properties of green tea do not represent the full story, since the peak effect of antioxidants declines after a few hours while the effects of green tea are powerful and long-lasting. To further understand how EGCG is working, her lab is now focusing on cell survival pathways, especially on the interaction between EGCG and mitochondria, the cell organelle that provides it with energy.
One thing, however, is certain: drinking green tea is good for your health. Mandel drinks two to four cups each day, taking two spoonfuls of leaves, stirring gently, and letting the tea steep for several minutes. While it would also be possible to take EGCG in a pill form, Mandel doesn’t see the point in this. “In my opinion, it’s better to drink it from the leaves. If you can drink such a pleasant beverage and enjoy it, why not?”