Inhibition of pathologically high cell death in npas3-/- mice enables P7C3 to correct structural and functional deficits in the hippocampus.
Daily administration of P7C3 to npas3-/- mice from embryonic day 13 through 3 months of age restores hippocampal neurogenesis in npas3-/- mice to normal levels by blocking the pathologically high level of cell death in these animals. This results in correction of morphological deficits in the dendritic branching of dentate gyrus neurons, as shown below. In addition, synaptic function in mutant mice was also corrected by daily administration of P7C3, as measured by electrophysiologic recording of whole field excitatory postsynaptic potentials in the dentate gyrus after stimulation of its neuronal input pathway.
P7C3 prevents cognitive decline in aging
Elevated levels of neuronal apoptosis seen in normal aging are associated with strong repression of adult hippocampal neurogenesis and inhibition of dendritic arborization of newborn hippocampal neurons in the aged brain. These physiologic changes with aging contribute to cognitive decline. Administration of a once daily dose of P7C3 to aged (18 month old) rats for 2 months significantly elevated hippocampal neurogenesis, inhibited cell death, and subsequently improved performance in the Morris water maze, a task that measures hippocampal learning and memory.
Unexpectedly, P7C3 also helped aged rats maintain stable body weight with aging, in contrast to vehicle treated rats whose weight declined steadily with age.
Future development of pro-neurogenic compounds
Our targeted screening approach using healthy physiologic activity in the living organism as the outcome measure, blind to mechanism, has enabled us to isolate eight chemically distinct, structurally unrelated small molecules that safely enhance hippocampal neurogenesis in vivo. Our most advanced molecule, P7C3, operates by inhibiting cell death, and safely improves hippocampal structure and function, as well as learning and memory, in rodents. Our medicinal chemistry program has generated hundreds of SAR variants of P7C3 to improve pharmacokinetic properties while also enhancing potency and eliciting a higher ceiling of pro-neurogenic efficacy. This SAR campaign also facilitated extensive composition of matter patent protection of large numbers of chemicals never before synthesized, assayed or claimed in the public domain or patent literature. As far as we know, our intellectual property position is devoid of any impediments to freedom to operate. We possess novel derivatives of P7C3 endowed with enhanced potency, efficacy and pharmacokinetic properties that are also devoid of undesirable activities, such as antihistamine activity, hERG channel inhibition or cytochrome p450 inhibition, and COGs are likely to be reasonable.
Our research program is actively engaged in improving the salient properties of P7C3, identifying its molecular target and evaluating efficacy in relevant animal models of neurologic disease.