Activity-dependent neuroprotective protein (ADNP) differentially interacts with chromatin to regulate essential genes. Because complete ADNP deficiency is embryonic lethal, the outcome of partial ADNP deficiency was examined. ADNP ϩ/Ϫ mice exhibited cognitive deficits, significant increases in phosphorylated tau, tangle-like structures, and neurodegeneration compared with ADNP ϩ/ϩ mice. Increased tau hyperphosphorylation is known to cause memory impairments in neurodegenerative diseases associated with tauopathies, including the most prevalent Alzheimer's disease. The current results suggest that ADNP is an essential protein for brain function and plays a role in normal cognitive performance. ADNP-deficient mice offer an ideal paradigm for evaluation of cognitive enhancers. NAP (NAPVSIPQ) is a peptide derived from ADNP that interacts with microtubules and provides potent neuroprotection. NAP treatment partially ameliorated cognitive deficits and reduced tau hyperphosphorylation in the ADNP ϩ/Ϫ mice. NAP is currently in phase II clinical trials assessing effects on mild cognitive impairment.

NAP (NAPVSIPQ, generic name, davunetide), a neuroprotective peptide in clinical development for neuroprotection against Alzheimer’s disease and other neurodegenerative indications, has been recently shown to provide protection against kainic acid excitotoxicity in hippocampal neuronal cultures. In vivo, kainic acid toxicity models status epilepticus that is associated with hippocampal cell death. Kainic acid toxicity has been previously suggested to involve the microtubule cytoskeleton and NAP is a microtubule‐interacting drug candidate. In the current study, kainic acid‐treated rats showed epileptic seizures and neuronal death. Injection of NAP into the dentate gyrus partially protected against kainic acid‐induced CA3 neuron death. Microarray analysis (composed of > 31 000 probe sets, analyzing over 30 000 transcripts and variants from over 25 000 well‐substantiated rat genes) in the kainic acid‐injured rat brain revealed multiple changes in gene expression, which were prevented, in part, by NAP treatment. Selected transcripts were further verified by reverse transcription coupled with quantitative real‐time polymerase chain reaction. Importantly, among the transcripts regulated by NAP were key genes associated with proconvulsant properties and with long‐lasting changes that underlie the epileptic state, including activin A receptor (associated with apoptosis), neurotensin (associated with proper neurotransmission) and the Wolfram syndrome 1 homolog (human, associated with neurodegeneration). These data suggest that NAP may provide neuroprotection in one of the most serious neurological conditions, epilepsy.