The microtubule interacting drug candidate NAP protects against kainic acid toxicity in a rat model of epilepsy.
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.
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Ilona
I
Zemlyak
Nathan
N
Manley
Inna
I
Vulih-Shultzman
Andrew B
AB
Cutler
Kevin
K
Graber
Robert M
RM
Sapolsky
Illana
I
Gozes
D000818:Animals; D004195:Disease Models, Animal; D004347:Drug Interactions; D004569:Electroencephalography / Q000379:methods; D004827:Epilepsy / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007608:Kainic Acid; D008297:Male; D008870:Microtubules / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D009842:Oligopeptides / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018696:Neuroprotective Agents; D009842:Oligopeptides; C425904:davunetide; D007608:Kainic Acid