NSI-189 is a benzylphiperizine-aminiopyridine, nootropic and neurogenic research chemical created by Neuralstem, Inc. that was derived from pyrazine and nicotinamide. Studies have shown that it stimulates neurogenesis of human hippocampus-derived neural stem cells in vivo and vitro. In healthy adult mice, NSI-189 has been shown to increase the hippocampal volume by 20% and reverse behavioral symptoms in mouse depression models, meaning at the source it could address depression . The hippocampus is responsible for spatial navigation, along with the consolidation of information from short-term memory to long-term memory.
The chemical entity stimulates new neuron growth in the hippocampus, which is an area of the brain that is believed to be contributory in conditions such as post-traumatic stress disorder (PTSD), Alzheimer's disease, and major depressive disorder (MDD).
NSI-189 successfully completed a phase I clinical trial for MDD in 2011, where it was administered to 41 healthy volunteers. A phase Ib clinical trial for treating MDD in 24 patients started in 2012 and completed in July 2014, with results published in December 2015. Neuralstem is now preparing to initiate phase II clinical studies for MDD in the first quarter of 2016, with results expected in the second half of 2017. In the two clinical studies conducted thus far, NSI-189 has shown statistically significant effectiveness in reducing depressive symptoms, has been found to be safe and well-tolerated (with no major adverse effects observed), and has been found to improve cognitive deficits in depressed patients. In addition to MDD, Neuralstem intends to pursue clinical development of NSI-189 for a variety of other neurological conditions, including traumatic brain injury, Alzheimer's disease, post-traumatic stress disorder, stroke, and natural cognitive and memory decline in aging
Tests have shown that NSI-189 significantly improved behavioral responses that are associated with depression . In humans it may counter hippocampal atrophy which is seen in disorders such as MDD, reversing their symptoms. A phase 1B randomized, double-blind, placebo-controlled, multiple-dose escalation study conducted over a 28 day period showed behavioral efficacy in 24 patients who were orally administered NSI-189 . The efficacy measurements showed a clinically meaningful reduction in cognitive and depressive symptoms across all measures, and appeared to persist over time during follow up for the efficacy assessments which included the Clinical Global Impression - Improvement (CGI-I), Montgomery-Aserb Depression Rating Scale (MADRS), Cognitive and Physical Functioning Questionnaire (CPFQ, and the Symptoms of Depression Questionnaire (SDQ) .
Phase 1A tested escalating doses of the neurogenic compound NSI-189 in healthy patients, 1B tested the safety of escalating doses in 24 depressed patients over the course of 28 days . During phase 1B patients were administered 40 mg per day, and 80 mg per day, and at the highest dose 120 mg per day. No serious adverse events occurred during the time of the study and the drug was well tolerated. Reduction in cognitive and depressive symptoms were observed across all measures for the two lower doses 40 mg/day and 80 mg/day but not for the highest dose 120 mg/day .
How NSI-189 works
This drug was developed to address three important aspects of depression including hippocampal volume, neurogenesis and neurotransmission. NSI-189 increases the volume within the hippocampus. In so doing, hippocampal volume and healthy brain cell density is increased thereby improving mod and cognitive performance. Aside from increasing hippocampal volume, the drug also improves neuronal cell functionality. It works it promoting healthy neuronal cell growth whilst repair damaged areas in the brain.