Imagine being able to regenerate your brain cells by swallowing a pill. The potential treatment relies on a process known as neurogenesis—”neuro” meaning nerves and “genesis” meaning creation. Adults suffering from neurological diseases or brain disorders may one day benefit from small molecule activators to promote the birth of neurons in the brain.

Neurogenesis naturally occurs during fetal brain development and declines with age. Adult neurogenesis was assumed to be nonexistent until twenty years ago, when it was discovered that the hippocampus could in deed regenerate neurons.

A decrease in hippocampus neurons is associated with Parkinson’s and Alzheimer’s disease, and may be the cause of memory loss and disorientation commonly associated with both conditions. Recent studies also suggest chronic stress slows neurogenesis, indicating a possible association with clinical depression.

In this WEEKLY we’ll learn the nuances of drug discovery to get a realtime assessment of the current neurogenesis line up.

Checking out The Chemical Library

In drug discovery we often hear about companies using a chemical library—a collection of different chemical compounds, typically on the order of hundreds of thousands of different compounds. Each compound has associated information, such as chemical structure and characteristics, catalogued in a database.

Each compound in the library is screened or tested for its ability to have a particular effect in a cell-based assay (test). For example, different small molecule compounds could be screened for their ability to activate neurogenesis from neuronal stem cells grown in the lab. If a compound shows promise, it is called a “hit”; it is then modified further and its derivatives are tested to see if they show even greater efficacy. After several rounds of modification, scientists will present a lead candidate to advance into preclinical animal testing.

Chemical libraries may be customized for a particular company’s interests—for example, having structures likely to inhibit certain types of signaling pathways are of interest to companies focusing on oncology drug development. In the case of scientists developing neurogenesis compounds, the ability to cross the blood-brain barrier is paramount, because the protective network of blood vessels envelopes the brain and prevents the entry of most substances.

Mice as a Testing Device

Mouse models clue us in as to how a particular drug might work in a human patient and are more comprehensive than testing using lab grown cells.

Genetic engineering is used to alter a mouse to have genes that mimic genetically based human diseases. In the case of testing drugs for cystic fibrosis, one of the mutations associated with with the disease would be genetically engineered into the mouse and then tested accordingly.

Since genetic associations are not as clear cut for most diseases, mice used to study Alzheimer’s, for example, are elderly mice whose reduced hippocampal volume and cognitive decline mirror those of elderly human Alzheimer’s patients. A mouse model of Parkinson’s disease is created by treating mice with a chemical called MPTP that destroys dopaminergic neurons—a hallmark of the disease.

TERM OF THE WEEK: NEUROGENESIS

Neurogenesis is the process by which neurons are generated from neural stem cells and progenitor cellsAdult neurogenesis is the process of generating new neurons which integrate into existing circuits after fetal and early postnatal development has ceased.

IN THE CLINIC

Neuralstem (Germantown, MD) and Neuronascent (Clarksville, MD) are leading the charge in developing small molecule activators of neurogenesis. By screening large chemical libraries, they have identified various compounds showing promise in their ability to activate neurogenesis from adult neural stem cells, both in the lab and in mouse models of various neurodegenerative disorders.

Neuralstem’s lead neurogenesis candidate, NSI-189, increased the hippocampal region of mouse brains by as much as 20%. With Phase I trials for major depressive order recently completed, plans to enter Phase II clinical testing are expected by mid-2015.

Neuronascent is focusing on Alzheimer’s in their approach to neurogenesis drug development. In a mouse model of Alzheimer’s, lead compound NNI-362 promoted the growth of new hippocampal neurons that not only migrated to the correct functional location but also differentiated and survived long enough to reverse previously observed cognitive declines. Neuronascent is preparing for Phase I trials of NNI-362.

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