NEW YORK—Anavex Life Sciences Corp. is encouraged by the findings of a new report in the latest issue of the peer-reviewed scientific journal Neuroscience Letters, which demonstrates for the first time through real-time in-vivo imaging how microglial inflammation, which is involved in devastating neurodegenerative diseases, can be resolved by sigma-1 receptor activation.
The role of sigma-1 receptor activation is to reduce the negative response caused by chronic microglia over-activation, which leads to widespread cell death and multiple neurodegenerative diseases, from brain injury to Alzheimer's disease.
Microglia are the immune cells of the central nervous system (CNS). Upon the event of a brain injury, the microglia move towards and clear the damaged area by engulfing dying neurons. However, in the context of many neurological disorders, chronic microglial responses are exaggerated and responsible for neurodegeneration. The study concludes that the sigma-1 receptor efficiently "switches off" this damaging chronic microglial reaction. Additionally, the action of the sigma-1 receptor on microglia was found to be specific to damage responses as the response did not affect the normal microglia activity within the brain.
"These findings are very encouraging and appear to further confirm the therapeutic potential of our sigma-1 receptor agonists, including ANAVEX 2-73, which is currently in a Phase 2a clinical study in Alzheimer's disease," said Christopher U. Missling, Ph.D., president and CEO of Anavex. "Thus, increasing sigma-1 receptor activity through agonists could reduce the devastating impact of neuroinflammation and exaggerated microglial response in the context of many neurodegenerative diseases. These findings point to a clear role for the sigma-1 receptor in modulating microglial responses to damage. We are pleased to see the potential for our sigma-1 agonist drug therapeutics to prevent chronic inflammation in the pathology of Alzheimer's and also in other CNS diseases."
The report, titled "Live imaging reveals a new role for the sigma-1 receptor in allowing microglia to leave brain injuries," was authored by C. Moritz, F. Berardi, C. Abate and F. Peri from EMBL in Heidelberg, Germany and Dipartimento di Farmacia in Bari, Italy. In the abstract, the authors point out that “Microglial cells are responsible for clearing and maintaining the central nervous system (CNS) microenvironment. Upon brain damage, they move toward injuries to clear the area by engulfing dying neurons. However, in the context of many neurological disorders chronic microglial responses are responsible for neurodegeneration. Therefore, it is important to understand how these cells can be “switched-off” and regain their ramified state. Current research suggests that microglial inflammatory responses can be inhibited by sigma receptor activation. Here, we take advantage of the optical transparency of the zebrafish embryo to study the role of sigma-1 receptor in microglia in an intact living brain. By combining chemical approaches with real time imaging we found that treatment with PB190, a sigma-1 agonist, blocks microglial migration toward injuries leaving cellular baseline motility and the engulfment of apoptotic neurons unaffected. Most importantly, by taking a reverse genetic approach, we discovered that the role of sigma-1 in vivo is to “switch-off” microglia after they responded to an injury allowing for these cells to leave the site of damage. This indicates that pharmacological manipulation of sigma-1 receptor modulates microglial responses providing new approaches to reduce the devastating impact that microglia have in neurodegenerative diseases.”
Anavex Life Sciences Corp. is a publicly traded biopharmaceutical company dedicated to the development of novel drug candidates to treat central nervous system (CNS) diseases, pain and various types of cancer. The Company's lead drug candidates, ANAVEX 2-73 and ANAVEX PLUS, the combination of ANAVEX 2-73 and donepezil (Aricept), are currently being evaluated in a Phase 2a clinical trial for Alzheimer's disease. ANAVEX 2-73 is an orally available drug candidate that targets sigma-1 and muscarinic receptors and has successfully completed a Phase 1 study with a clean data profile. Preclinical studies demonstrate its potential to halt and/or reverse the course of Alzheimer's disease. The drug combination, ANAVEX PLUS, produced up to 80 percent greater reversal of memory loss in Alzheimer's disease models versus when the drugs were used individually. Recent positive preclinical data indicates that ANAVEX 2-73 also exhibits anticonvulsant, anti-amnesic, neuroprotective and anti-depressant properties, indicating its potential to treat additional CNS disorders, including epilepsy and others.