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, indeed, 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 article, we’ll learn the nuances of drug discovery to get a real-time 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, cataloged 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 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.
IMPORTANT TERM: NEUROGENESIS
Neurogenesis is the process by which neurons are generated from neural stem cells and progenitor cells. Adult 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%. After successfully completing Phase I trials for major depressive disorder, NSI-189 is currently in Phase II clinical testing.
Neuronascent focuses on Alzheimer’s in its 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 currently developing NNI-362 in clinical trials for the treatment of Alzheimer’s patients.
The frontier of neurogenesis offers a tantalizing glimpse into the future of medicine, where pills could potentially regenerate brain cells and combat neurodegenerative diseases. Companies like Neuralstem and Neuronascent are pioneering this space, with promising compounds like NSI-189 and NNI-362 showing significant results in preclinical and clinical trials. While science is still in its nascent stages, the implications are profound. The ability to stimulate the birth of neurons in adults could revolutionize the treatment of diseases like Alzheimer’s, Parkinson’s, and even clinical depression. As we continue to explore the chemical libraries and refine our mouse models, we inch closer to turning this science fiction into scientific fact.
FREQUENTLY ASKED QUESTIONS
1. What is neurogenesis, and why is it important?
Neurogenesis is the process of generating new neurons from neural stem cells. It Is crucial for understanding how to treat neurodegenerative diseases like Alzheimer’s and Parkinson’s, as well as conditions like depression.
2. How do chemical libraries contribute to drug discovery in neurogenesis?
Chemical libraries are collections of various compounds that are screened for their ability to activate neurogenesis. Promising compounds, known as “hits,” are then further modified and tested for efficacy.
3. Why are mouse models used in testing neurogenesis compounds?
Mouse models provide insights into how a drug might work in humans. They are genetically engineered to mimic human diseases, offering a more comprehensive testing ground than lab-grown cells.
4. What is the significance of the blood-brain barrier in neurogenesis drug development?
The blood-brain barrier is a protective network that prevents most substances from entering the brain. For neurogenesis drugs to be effective, they must be able to cross this barrier.
5. Can you tell us about some companies leading in this area?
Neuralstem and Neuronascent are at the forefront. Neuralstem’s NSI-189 is in Phase II clinical testing for major depressive disorders, while Neuronascent is preparing for Phase I trials of NNI-362 for Alzheimer’s treatment.
6. What are the current challenges in neurogenesis drug development?
The challenges include understanding the precise mechanisms of neurogenesis, ensuring that compounds can cross the blood-brain barrier, and the long and rigorous process of clinical trials to prove efficacy and safety.