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New therapeutic targets for neurodegenerative diseases

The focus of work in the Neurosciences Department’s Neurobiology Laboratory at the University of the Basque Country’s Faculty of Medicine and Odontology is the investigation of the molecular and cellular bases of neurodegenerative illnesses – those that affect the brain and the spinal cord. Some of these neurodegenerative illnesses are well known and affect a significant part of the population, such as Alzheimer’s disease and multiple sclerosis.

Researchers at the University of the Basque Country (UPV-EHU) are studying the signals in the central nervous system - the brain and the spinal cord - that do not function well, in particular, those signals that cause the death of nerve cells. There are basically two types of cells in the central nervous system: neurones and the glial cells. Both types are sensitive to these functioning errors and both can die. In the case of Alzheimer’s disease, it is the neurones, above all, that die. However, in the case of multiple sclerosis, it is a class of glial cells – known as oligodendrocytes – that perish.

From in vitro cells to biological samples of human origin

The researchers at the Neurobiology Laboratory are investigating cells in cultures - neurones, oligodendrocytes or other cells of the nervous system -, and are trying to reproduce in vitro circumstances that are thought to be relevant in these ailments. That is to say, they are creating the conditions that cause the death of these cells, in order to determine what molecules intervene in the process – from the moment of the lethal signal to the point where the cells collapse. In this type of experimental work a series of molecules involved in the death process are identified, the aim being to come up with pharmaceutical medicines that will improve treatment.

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Apart from working with in vitro cells, they are also experimenting with animals that reproduce some of the elements involved in neurodegenerative illnesses under certain conditions, i.e. sensory symptoms, motor symptoms, etc. and that can be induced in these animals. And they are examining if these substances that have proved to be interesting with the in vitro cells are also efficacious in these experimental models of the diseases.

Moreover, over the past few years they have had the opportunity to study samples of brains of patients who have died of some neurodegenerative illness, such as, for example, multiple sclerosis. The illnesses leaves a mark in these samples and, although the brain has been at a terminal stage of the illness, they can investigate to see if there are signs of alterations to the molecules similar to those observed in the experiments, both with cells and with the animals. In this way it can be determined if the molecular targets discovered experimentally are relevant or not to the neurodegenerative processes and, if they are, develop pharmaceutical medicines that can neutralise these processes or the elements that enable them to progress, the goal being to halt the process of death.

In collaboration with neurologists they have also been able to access biological samples of patients who have given their consent and donated them to research. Biological samples such as, fundamentally, blood, given that changes in blood plasma that may indicate alterations at the brain level can be identified.

In search of biological samples

All this is a dynamic process that enables clues to be found and which are, in some cases, relevant for developing pharmaceutical drugs that can halt, or at least slow down, the course of a neurodegenerative illness. Apart from finding these molecules or targets that interact with pharmaceutical medicines, in order to stop the process of progressive deterioration, substances that favour the survival of the neurones and oligodendrocytes are also sought; substances such as, for example, antioxidants, given that, in many of the neurodegenerative illnesses the cells die because oxidative stress is produced. In recent years the Neurobiology Laboratory researchers have found a number of antioxidants that put a brake on the dying process and can act as a neuroprotector. Antioxidants of natural origin that are in our diet – fruit, vegetables, and so on – and which, in some way appear to alleviate the damage cause by these illnesses.

In short, the goal is to gain more knowledge about the molecular bases of these pathologies, define therapeutic targets (molecules of the cell that recognise a pharmaceutical drug and thus respond to it) and, in the last analysis, to come up with pharmaceutical medicines that improve treatment.

Notes


Research team:
C. Matute, A. Palomino, S. Mato, O. Oyanguren, A. Gutierrez, A. Pérez and E. Alberdi.

Department:
Neurosciences.

Faculty:
Medicine and Odontology Faculty (Leioa).

Chronic Illness and the Brain

If you or a loved one have been diagnosed with a brain-related chronic illness like depression, Parkinson's disease, or Alzheimer's disease, you may find yourself searching for information and answers to your questions.

You're not alone. These diseases affect millions upon millions of people in the U.S. Their effects are far-reaching, extending beyond those with chronic illnesses to include their families, friends, and colleagues. This is why it's important to address the concerns of people suffering from brain-related diseases as well as those who care about—and for—them.

Chronic, by definition, means long lasting or recurring. Chronic illnesses affecting the body include diabetes, heart disease, and arthritis. Examples of common chronic brain-related health conditions include depression, epilepsy, and stroke.

Some brain disorders, like stroke or head injury, are most commonly the result of damage to brain tissues. Other brain-related disorders are caused by progressive failure and death of nerve cells—this is known as "neurodegeneration," and occurs in Alzheimer's and Parkinson's diseases. As we age, our brain becomes more vulnerable to many brain disorders, and may be affected by problems elsewhere in the body.

The physical signs of some chronic illnesses begin gradually, and may not be noticeable for years. Symptoms may be mild or severe, frequent or infrequent, or they may not be evident at all on a day-to-day basis. Because so many factors affect the course of a chronic illness, it may be difficult to predict how we will feel from one day to the next.

As you read on, you will find answers to many of your questions about chronic brain-related illnesses, up-to-date information on the latest research on these diseases, and advice to help people with chronic illnesses and their caregivers.

Learning more about these diseases is important if you—or a loved one—have been diagnosed with, or are concerned about, chronic brain-related illness. As the saying goes, knowledge is power. In other words, understanding how best to cope with illness when it occurs can help you maintain a better quality of life. So let's continue, and learn more about chronic illness and the brain.

NEOTROFIN^TM - NeoTherapeutics, Inc.

NeoTherapeutics is developing NeotrofinT (AIT-082, leteprinim potassium) for Alzheimer's disease. The drug is currently in Phase 2b/3 clinical trials and has shown clinical benefit to patients in the trials completed to date. Based on the neurotrophic actions of NeotrofinT, this drug may provide benefit to patients with other neurodegenerative diseases. Pre-clinical studies are ongoing in animal models of spinal cord injury, peripheral neuropathy, ALS and other diseases. The results from the current pre-clinical studies will determine whether or not NeotrofinT will enter clinical trials in one or more of these indications.

On October 8, 1998 NeoTherapeutics, Inc. announced that the company has been issued a new U.S. patent on gene regulation technology involved in treating neurodegenerative diseases.

U.S. Patent No. 5,801,184 describes how purine derivatives, a class of drug compounds which includes NeoTherapeutics' lead compound NEOTROFIN(tm) (AIT-082, leteprinim potassium), can be used to selectively control "turning on or off of genes" for the protein molecules involved in nerve regeneration. This patent represents new step treatment of neurodegenerative diseases utilizing oral medication to replace or augment the presence of neurotrophic factors in the brain and spinal cord.

NeoTherapeutics reports that the company does not know if all types of nerve cells will react in the same manner to NEOTROFIN(tm). There is no evidence at this time that NEOTROFIN(tm) is effective for ALS. However, the company is conducting an exploratory, pre-clinical experiment in animals to determine if NEOTROFIN(tm) demonstrates effectiveness for ALS.

NEOTROFIN, AIT-082, regulates the genetic expression of several neurotrophic factors in various areas of the brain and spinal cord. In each area, the factors it induces are those naturally needed by the nerve cells in that region. AIT-082 is the first drug in human clinical trials, which acts by regulating the production of the naturally occurring neurotrophic growth factors.

Neurotrophic factors are essential for the growth, maturation and survival of nerve cells. When present in appropriate concentrations, these factors also protect nerve cells against damage in stroke, trauma, and many neurodegenerative disorders including Alzheimer's and Parkinson's diseases. These factors are not produced by the nervous system in sufficient quantities to be fully effective in those conditions, and, because neurotrophic factors are proteins, they cannot be orally administered. These problems are circumvented by NeoTherapeutics' orally active purine derivative that controls the genetic expression of neurotrophic factors in the nervous system to treat neurodegenerative diseases.

NeoTherapeutics' research program is focused on designing and developing small molecules capable of promoting nerve regeneration and repair for a range of neurological diseases and conditions such as Alzheimer's and Parkinson's diseases, stroke and spinal cord injury.