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Preserved memories

New compounds reduce the damage done by Alzheimer's disease

Right from birth, the human brain shrinks a little every day with the death of almost 400,000 nerve cells that are not replaced. This is the normal level that, without being noticed, consumes some 10 billion of them until the end of life. Common in normal aging, the loss of these cells, known as neurons, becomes more evident when an illness, which is as sly as it is cruel, installs itself in the organism: Alzheimer, which brutally speeds up the death of cells in the nervous system.

Devastating, this disease announces itself in a subtle manner, in the form of small losses of memory, such as not remembering where one had placed one’s glasses or car keys, but, in a matter of a few years, it can lead a person still productive in his 70’s to progressive loss of intellectual capacity and to present levels of skills similar to those of a newly born baby the person becomes incapable of walking, feeding himself, recognizing family and friends and even speaking.

Described in 1906 by the German doctor Alois Alzheimer, this infirmity hits 5% of men and 6% of women over 60 years of age in a total of 40 million people in the world, around 1.5 million of them in Brazil, and as yet today it remains without a cure. Until last year, the only medicines available for treating this infirmity, which progressively destroys the central nervous system, acted only in a palliative manner: they helped to temporarily reduce the loss of memory but did not avoid the elimination of neurons.

However, recent studies point to the emergence of compounds with complementary action, capable of reducing or even impeding the death of the nerve cells. And an important part of this progress is due to the work of Brazilian researchers. Over the last three years at the Federal University of Rio de Janeiro (UFRJ), a team led by the biochemist Sérgio Teixeira Ferreira has identified nine substances some of them produced by the organism itself, such as melatonin and taurine which, in laboratory tests, have slowed down or even blocked the elimination of neurons.

At the São Paulo State University (Unesp) in Araraquara, in the interior of the state of Sao Paulo, the team led by the pharmacist Vanderlan da Silva Bolzani extracted from the Senna spectabilis, a tree of about six meters in height, with tiny green leaves and golden yellow flowers, known as Cassia or locally as tula-de-besouro a substance named spectaline, whose derivatives acts against Alzheimer’s disease.

More acetylcholine, although they do prevent the death of nerve cells, three compounds derived from spectaline bars the destruction of a substance that makes the communication between the neurons the neurotransmitter acetylcholine, associated with the formation of memory, increase its quantity in the nervous system. The advantage is that these compounds are non-toxic unlike tacrine and rivastigmine, two of the medicines still used in combating the damage done by Alzheimer. As they act upon the enzyme that degrades acetylcholine, these compounds may help in the treatment of other neurological illnesses, such as Parkinson’s disease.

“Alzheimer’s is a complex illness, whose treatment demands the use of multiple strategies. I don’t believe that it will be beaten by using a single medicine”, says Ferreira, the team’s coordinator, who over the last two years discovered the protecting role of taurine and unveiled how this compound and the hormone melatonin avoid the destruction of neurons: both combat the toxic action set off by a molecule manufactured in large quantities in the brain of people with Alzheimer’s, the beta-amyloid peptide.

In the most recent study, published last month in the Faseb Journal, the magazine of the American Federation of Societies of Experimental Biology, the team from Rio de Janeiro confirmed that taurine, an amino acid generally found in large quantities in the nervous system, inverts the chemical imbalance characteristic of this illness. It is an effect similar to that obtained with memantine a compound whose use against Alzheimer’s was liberated in 2003 in Europe, and only this year in the United States which, nevertheless, works in a different manner.

Essential for the absorption of fats in the intestine, taurine works on the nervous system as an antidote against the effects of the beta-amyloid peptide, which in very low quantities, apparently stimulates the growth of neurons, but, in the case of Alzheimer’s, its production runs out of control and generates damage that reaches thousands of nerve cells. Generated by the abnormal degradation of an important protein for the functioning of neurons amyloid precursor protein amyloid or simply APP, the peptide beta-amyloid links itself to other molecules similar to itself on the outside of the cells. From this union there initially emerge almost spherical groupings, the oligomers, and, in the following stage, long cords known as amyloid fibers.

In contact with the outside surface of the nerve cells, the fibers of beta-amyloid connect themselves to various proteins, one of them especially, the receptor of glutamate, associated to learning and memory formation. This is the start of a fatal chain reaction: this connection opens small canals in the walls of the neurons and allows calcium ions to enter these cells, with a positive electrical charge. This flood of positive particles alters for a prolonged period of time the electrical charge in the interior of the neurons (normally negative) thus killing them.

Faced with this cellular short circuit, Ferreira decided to look for compounds capable of reestablishing the balance of electrical charges of the neurons and found taurine, an amino acid component in sport drinks, in fashion over the last few years. Studies carried out in other countries had already suggested that taurine hooked up to another type of protein on the surface of the neurons: the receptors of gamma aminobutyric acid (GABA) that regulate the entrance into the cell of negatively charged particles, the chloride ions.

The group from Rio decided to find out how the theoretical predictions worked out in practice. Under the coordination of Ferreira, the researchers Paulo Louzada, Andréa Paula Lima, Dayde Silva, François Nöel and Fernando de Mello carried out a battery of laboratory tests with neurons from the retina of chicks, cultivated on small glass plates.

Their discoveries are stimulating: the toxic effects of beta-amyloid eliminated only 15% of the nerve cells treated with small doses of taurine, while 65% of the neurons that did not receive the amino acid died. This protecting action was also observed with the substitution of taurine for a drug used to treat epilepsy, named phenobarbitol, which has the disadvantage of bringing on dependency and undesirable side effects such as sleepiness and metal confusion.

It is clear that nobody is going to suggest drinking sports energy drinks in the expectation of preventing Alzheimer’s. It is still necessary to identify the adequate dosage and the best form of administering it in a series of studies on human beings, before the use of taurine would be indicated to combat this neurological disease. Even so, Ferreira is optimistic. “As taurine is not toxic for human beings, it will be possible to initiate clinical tests on a relatively short time, possibly next year”, the biochemist explains.

This is not the only alternative to counterbalancing the unbalance of electrical charge caused by beta-amyloid. In another paper published in December of 2003 in Neurotoxicity Research, the team from UFRJ demonstrated that melatonin the hormone responsible for inducing sleep, mainly released at night by the pineal gland and sold in some countries as a food supplement, or that is, without a medical prescription also avoids the death of neurons by acting in a similar manner to taurine.

Ferreira is also attempting complementary strategies that might slow down the progress of Alzheimer’s in other stages, before the beta-amyloid connects itself to the receptors of glutamate. In partnership with Fernanda De Felice, Jean-Christophe Houzel, José Garcia-Abreu, Vivaldo Moura Neto and Roberto Lent, the UFRJ biochemist revealed in 2001, also in the Faseb Journal, two organic compounds 2,4-dinitrophenol (DNP) and 3-nitrophenol (NP) that impede the death of neurons by blocking the formation of beta-amyloid fibers or even breaking them down after they have been formed.

Some three months ago the patents office in the United States awarded a patent for the use of one of them, 2, 4-dinitrophenol, to the UFRJ. The university has licensed the exploration of the patent to the national pharmaceutical laboratory Eurofarma, which is preparing to initiate an evaluation of the toxicity of this compound on animals. Over the next few months, the team from Rio intend to present another five compounds that show themselves capable of impeding the formation both of the long fibers of beta-amyloid and the oligomers, which, in spite of being smaller, are much more toxic.

The compounds identified by the team from Rio should in the future gain reinforcement from the molecules discovered by the Unesp team in Araraquara. Over the last five years, Vanderlan da Silva Bolzani’s team analyzed 1,677 extracts from 709 species of plants of the flora of the state of São Paulo, collected through a project that integrates into the Biota-FAPESP, the program that is carrying out a survey of the biodiversity in the state of Sao Paulo. Among the 150 substances already isolated are spectaline and its derivatives that, in laboratory experiments and in tests on rats, demonstrated very specific actions.

In the nervous system, two derivatives of spectaline impede the elimination of acetylcholine and as a consequence, improve the capacity of retaining information without interfering with other substances of the central nervous system a mechanism similar to that of another natural compound, galanthamine, isolated from Galanthus nirvalis, a plant of one meter in height and with white flowers, used today in the treatment of Alzheimer’s. Within the remainder of the organism, the molecules of Senna spectabilis function as a potent analgesic.

“The most interesting thing is that, as well as improving the memory, the spectaline derivatives are not toxic like tacrine, the medicine most widely used in the treatment of Alzheimer’s disease”, says Vanderlan. Recently, the Unesp team obtained the provisional registration of the patent in Brazil for the use of all spectaline derivatives. In conjunction with two teams from UFRJ, those of Eliezer Barreiros and Newton de Castro, Vanderlan is now working on the development of a medicine based on the derivatives of spectaline that can be tested on human beings.

The Projects
Innovative Therapeutic Approaches to Human Amyloidogenic Diseases; Coordinator Sérgio Teixeira Ferreira UFRJ; Investment US$ 350,000.00 (Howard Hughes Medical Institute); R$ 310,000.00 (Finep, Green-Yellow Fund, and Eurofarma); R$ 160,000.00 (CNPq), R$ 72,000.00 (Faperj)
2. Conservation and Sustainable Use of the Plant Biodiversity from the Cerrado and the Atlantic Rainforest: Chemical Diversity and Prospecting for Potential Drugs; Modality Biota Program; Coordinator Vanderlan da Silva Bolzani – Unesp; Investment R$ 1,659,568.47 (FAPESP)