The P7C3 lead compound is bioavailable and protects newborn neurons from death
Our most advanced pro-neurogenic molecule has been termed ‘P7C3’, for ‘pool #7 compound #3’, in accordance with the discovery process that allowed its identification. P7C3 is orally bioavailable, readily able to cross the blood-brain barrier, and endowed with a plasma terminal half life of 7 hours after IP delivery. Dose response experiments of daily oral administration of P7C3 to adult mice showed that maximal pro-neurogenic efficacy was observed at oral doses of 5 mg/kg and above, with graded reductions in efficacy observed at doses of 2.5 mg/kg and 1 mg/kg.
Synthesis and analysis of both enantiomers of an active analog of P7C3 have subsequently shown that only the (+R)-enantiomer retains pro-neurogenic activity. Experiments in which newborn neurons were labeled immediately prior to prolonged administration of P7C3 have shown that P7C3 exerts its pro-neurogenic effect by protecting newborn cells from death along the arduous, month-long pathway taken between their birth and eventual functional incorporation into the dentate gyrus as properly wired neurons.
P7C3 protects neurons by inhibiting apoptosis
The gene for neuronal PAS domain protein 3 is disrupted in some patients with schizophrenia and bipolar disorder. Mice missing this gene, termed npas3-/- mice, are virtually devoid of functional hippocampal neurogenesis due to an abnormally high level of death of newborn hippocampal neurons. As a consequence, npas3-/- mice display malformation and dysfunction of the hippocampal dentate gyrus. As shown below in immunohistochemical staining for cleaved caspase-3, a marker of apoptotic cell death, the abnormally elevated rate of death of newborn neurons in npas3-/- mice is reduced to normal levels following one week of daily oral delivery of P7C3.
We have further demonstrated that P7C3 also protects cultured cortical neurons from cell death following exposure to beta-amyloid, a neurotoxin implicated in the pathogenesis of Alzheimer’s disease, and that P7C3 acts to preserve mitochondrial membrane permeability in the face of cellular insult. In these two cell culture assays of neuron death, only the (R)-enantiomer of P7C3 retains activity.