NSI-189 Phosphate is an experimental, orally active small molecule under investigation for its potential to address various neurological and psychiatric conditions. Research aims to explore its effects on brain function and its potential as a therapeutic agent for disorders with limited treatment options.
Origins and Development
NSI-189 Phosphate was developed by Neuralstem, Inc., as part of a research initiative focused on neurogenic compounds. It is chemically classified as a benzylpiperazine-aminopyridine derivative. The compound’s discovery involved systematically screening a chemical library to identify agents capable of promoting neurogenesis in human hippocampal neural stem cells. This aimed to identify novel approaches to treating brain disorders by stimulating the growth of new brain cells.
The compound’s development progressed from preclinical studies, where it demonstrated the ability to stimulate neurogenesis in murine (mouse) hippocampus in vivo. The phosphate salt form was developed to enhance its properties for oral administration.
Investigational Therapeutic Applications
NSI-189 Phosphate is primarily being investigated for its potential in treating major depressive disorder (MDD). This focus stems from hypotheses that deficits in neurogenesis, the process of generating new neurons, may contribute to depression. The compound has undergone clinical trials to assess its efficacy in mitigating depressive symptoms.
Beyond MDD, NSI-189 Phosphate has also shown potential in addressing cognitive impairment. Studies suggest it may improve cognitive function. Interest also exists for its possible use in post-traumatic stress disorder (PTSD), bipolar depression, and other neurodegenerative conditions like Alzheimer’s disease, brain injuries, and diabetic neuropathy.
How NSI-189 Phosphate Interacts with the Brain
NSI-189 Phosphate is believed to exert its effects primarily by promoting neurogenesis, the formation of new neurons, particularly in the hippocampus. This brain region is associated with learning, memory, and mood regulation. The compound has been shown to stimulate the proliferation and differentiation of neural stem cells into neurons.
The compound also appears to influence synaptic plasticity, the brain’s ability to strengthen or weaken connections between neurons. This process is crucial for learning and memory formation. Preclinical studies indicate that NSI-189 can enhance neurite outgrowth and upregulate factors such as brain-derived neurotrophic factor (BDNF) and stem cell factor (SCF). While it has shown to increase hippocampal volume in rodents, a similar effect has not been consistently observed in human clinical studies.
Current Research and Safety Profile
NSI-189 Phosphate has progressed through various phases of clinical research, including Phase 1 and Phase 2 trials. A Phase 1B study in patients with MDD found NSI-189 to be well tolerated across different doses. The half-life of NSI-189 ranged from approximately 17.4 to 20.5 hours.
A Phase 2 clinical trial involving 220 subjects with MDD evaluated daily doses of 40 mg and 80 mg over 12 weeks. While the primary outcome measure, the Montgomery-Asberg Depression Rating Scale (MADRS), did not show statistically significant reduction versus placebo for either dose, some secondary measures, such as the Symptoms of Depression Questionnaire (SDQ) and Cognitive and Physical Functioning Questionnaire (CPFQ), showed promising reductions, particularly with the 40 mg dose. The 40 mg dose also showed advantages on some objective cognitive measures. A post-hoc analysis of the Phase 2 study suggested that the 80 mg dose might offer significant benefit over placebo for moderately depressed patients (MADRS score less than 30).
NSI-189 Phosphate remains an experimental compound without broad regulatory approval. Anecdotal reports of side effects include anxiety and hyper-emotionality, though clinical trials generally reported it as well-tolerated. Development efforts continue for MDD, bipolar depression, and PTSD, under the new developmental code name ALTO-100.