Microtubules, schizophrenia and cognitive behavior: Preclinical development of davunetide (NAP) as a peptide-drug candidate

NAP (davunetide) is an active fragment of activity-dependent neuroprotective protein (ADNP). ADNP and the homologous protein ADNP2 provide cell protection. ADNP is essential for brain formation, proper development and neuronal plasticity, all reported to be impaired in schizophrenia. ADNP haploinsufficiecy inhibits social and cognitive functions, major hallmarks in schizophrenia. Imbalance in ADNP/ADNP2 expression in the schizophrenia brain may impact disease progression. NAP treatment partly ameliorates ADNP haploinsufficiecy. The microtubule, stable tubule-only polypeptide (STOP)-deficient mice were shown to provide a reliable model for schizophrenia. Daily intranasal NAP treatment significantly decreased hyperactivity in STOP-deficient mice and protected visual memory, supporting further clinical development.

Research highlights▶ Microtubule dysfunctions are associated with schizophrenia. ▶ STOP (MAP6)-deficiency models aspects of schizophrenia in mice. ▶ ADNP is deregulated in schizophrenia. ▶ Davunetide (NAP) is a drug candidate derived from ADNP. ▶ Davunetide (NAP) enhances cognitive functions in STOP-deficient mice.