25 July 2002. Stockholm. Last Sunday at the 8th International Conference on Alzheimer’s Disease and Related Disorders here, Illana Gozes presented a poster with the latest data in her investigation of NAP. This intriguing peptide of eight amino acids lies within a glia-derived protein called activity-dependent neuroprotective protein, ADNP, which Gozes et al. first cloned in 1999. NAP protects neurons in vitro at femtomolar concentrations, said Gozes. Most currently prescribed drugs work in the nanomolar range at best. Gozes, who is at Tel Aviv University, did this work in collaboration with Douglas Brenneman at the National Institutes of Health in Bethesda, Maryland.
Studies published prior to the international conference in Stockholm showed that NAP is neuroprotective in different in-vitro systems against a variety of toxins, including Aβ, excitotocity, and gp120 of the HIV virus. NAP protects against oxidative stress by increasing glutathione levels in neurons, said Gozes. In a previous study, Gozes and colleagues rescued cultured cells that were dying following pre-treatment with a glutathione inhibitor. NAP also inhibits cell death following hydroxyperoxide treatment, and in 2000, the scientists reported glutathione increase and neuroprotection in a NAP-treated mouse model of severe oxidative stress, Gozes said.
At the Stockholm conference, Gozes et al. reported a preventive in-vivo inflammation experiment that was not specific to AD but is relevant to neurodegeneration. The scientists injected newborn mouse pups daily with NAP for three weeks, and at four months of age inflicted a head trauma, widely seen as a risk factor for dementia. NAP-treated mice recovered faster, and a five-day Morris water maze experiment with the injured mice showed that only those pre-treated with NAP found the submerged platform. In addition, NAP-treated mice had decreased mRNA levels of the inflammatory marker Mac-1. Alternatively, injecting a single dose of NAP 15 hours after injury into mice that had not received it postnatally also kept Mac-1 expression low, Gozes said.
Last April, Gozes and her colleagues published that NAP is neuroprotective in a rat model of stroke when injected four hours after the insult. And last year, they reported that administering NAP through the nose protected mice into whose cerebral ventricles the researchers had previously injected a toxin that slowly kills cholinergic neurons. The researchers again saw a difference in water maze performance.
"In the toxicology we have done until now, we found no side effects, though we still need to do pharmacokinetic and other studies," said Gozes. In general, peptides make poor drugs because they are degraded by proteases and do not penetrate their target cells sufficiently well at safe concentrations. Gozes said, however, that this peptide is unusually stable and appears to penetrate the brain well when administered intranasally. No clinical trial is imminent, though the ADCS in San Diego is considering the approach. Even if all went smoothly in future trials, (which is rare), this peptide would take years before becoming widely available.-Gabrielle Strobel.