Experts At Anavex Offer A Primer On Promising 'Oxidative Stress' Theory

Main Category: Alzheimer's / Dementia
Also Included In: Neurology / Neuroscience
Article Date: 25 Jul 2008 - 1:00 PDT

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As trials on anti-amyloid vaccines continue to fail in the search for a viable Alzheimer's drug, a new approach - oxidative stress - is starting to emerge as a contender.

Anavex Life Sciences (AVXL.OB) is leading this promising avenue of research. It has developed an Alzheimer's drug candidate based on the theory that oxidative stress, not amyloid-beta plaques, is the cause of the disease. Oxidative stress is a type of damage to the body's tissues caused by the destructive action of certain forms of oxygen.

To help people better understand the science behind oxidative stress, Anavex offers this helpful primer:

What is Oxidative stress?

We are all familiar with processes like the rusting of iron, oil and butter turning rancid and fruits turning brown after prolonged exposure to air. All these phenomena are caused by exposure to oxygen in a process known as oxidation. Similar effects are known to happen inside our bodies in the molecular and cellular level, all because of the destructive action of a form of oxygen known as Reactive Oxygen Species (ROS). This destructive nature of oxygen comes in contrast to its unconditional necessity for the survival of all living aerobic organisms.

The term oxidative stress is used to describe a state in which the equilibrium between the production of ROS and the body's protective mechanisms (antioxidants and repair mechanisms) has been compromised, resulting in the oxidative damage of cells, tissues and organs. Moreover, ROS in the state of oxidative stress can impair several cellular signaling pathways that may result in the onset of age related diseases.

The Oxidative Stress And Alzheimer's Disease

A growing number of publications have supported the idea that oxidative stress may be the real cause of Alzheimer's. For example, in "Involvement of Oxidative Stress in Alzheimer's Disease," published in the Journal of Neuropathology and Experimental Neurology in 2006, study leader Dr. Akihiko Nunomura pointed to extensive evidence of mechanistic and chronological links between oxidative stress and a number of key characteristics of the disease.

Interestingly, this research also suggests that amyloid beta, which can act as an anti-oxidant, could in fact be initially produced by the body as it tries to combat the disease, only later turning toxic as the substance accumulates in large amounts. In other words, amyloid-beta could be the body's early protective reaction to the disease - suggesting that its removal from the brain during the early stages of Alzheimer's could in fact do more harm than good.

This theory is consistent with a number of factors for which the amyloid-beta hypothesis has been unable to account. There are reports, for instance, of individuals with amyloid-beta loads equivalent to Alzheimer's patients who do not suffer from the disease, as noted by R. J. Castellani et al in a 2006 article in the American Journal of Alzheimer's Disease and Other Dementias.

In addition, scientists have found a weak correlation between the amount of amyloid beta present in the brains of Alzheimer's sufferers and the severity of the illness. Furthermore, even though some test drugs reduce the amount of amyloid-beta in the brain, this is not correlated with substantial improvements in cognitive functioning.

Promising Pre-clinical Studies

Meanwhile, Anavex's alternative approach is showing great promise in early-stage testing. Anavex's drug candidate, known as ANAVEX 1-41, uses sigma receptors, a unique class of receptor molecules, to guard against oxidative stress and repair cells compromised by its effects. In advanced pre-clinical studies, ANAVEX 1-41 appeared to provide neurons with potent protection from oxidative stress. It also prevented amyloid beta from becoming toxic and causing any follow-on damage. Moreover, ANAVEX 1-41 reduced memory deficits in animal test subjects - a particularly notable finding, given the quest for a drug that can actively reverse the effects of the disease.

A program of further work is currently underway to further assess the compound, including ongoing pre-clinical studies being carried out in collaboration with the Université Montpellier in France. The company is moving forward aggressively with this work, which is designed to pave the way for a rapid move towards human testing, expected to commence in late 2008 or early 2009.

While much still needs to be done, Anavex is enormously pleased with its progress to date on this promising new approach to combating one of the world's most complex and devastating diseases.

About Anavex Life Sciences Corp.

Anavex Life Sciences Corp. is an emerging biopharmaceutical company engaged in the discovery and development of novel drug targets for the treatment of cancer and neurological diseases such as Alzheimer's and depression. The company's proprietary SIGMACEPTOR™ Discovery Platform involves the rational design of drug compounds that fulfill specific criteria based on unmet market needs and new scientific advances. Selected drug candidates demonstrate high, non-exclusive affinity for sigma receptors, which are involved in the modulation of multiple cellular biochemical signaling pathways. http://www.anavex.com

ANAVEX's SIGMACEPTOR™-N program involves the development of novel and original drug candidates that target neurological and neurodegenerative diseases (Alzheimer's disease, epilepsy, depression, etc.) The company's lead drug candidates exhibit high, non-exclusive affinity for sigma receptors with strong evidence for anti-amnesic, neuroprotective, anti-apoptotic, anti-oxidative, anti-inflammatory, anti-convulsive, anti-depressant and anxiolytic properties. The company believes that oxidative stress, not amyloid-beta, is the cause of Alzheimer's. ANAVEX 1-41, uses sigma receptors, a unique class of receptor molecules, to guard against oxidative stress and repair cells compromised by its effects. So far, through the advanced pre-clinical phase of development, the compound has performed extremely well in well-recognized animal models of Alzheimer's disease, underscoring the promise of this alternative approach to the disease.

ANAVEX SIGMACEPTOR™-C program involves the development of novel and original drug candidates targeting cancer. The company's lead drug candidates exhibit high, non-exclusive affinity for sigma receptors with strong evidence for selective pro-apoptotic, anti-metastatic and low toxicity properties in various types of solid cancers such as colon, prostate, breast and lung. ANAVEX 7-1037 has already demonstrated its ability to significantly delay the growth of cancerous tumors in patient-derived xenografts during advanced pre-clinical studies.

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