TY - JOUR
T1 - NAP protects against cytochrome c release
T2 - Inhibition of the initiation of apoptosis
AU - Zemlyak, Ilona
AU - Sapolsky, Robert
AU - Gozes, Illana
N1 - Funding Information:
These studies are in partial fulfillment of the Ph.D. requirements for Mrs. Ilona Zemlyak at the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Professor Illana Gozes is the incumbent of Lily and Avraham Gildor Chair for the Investigation of Growth Factors and serves as the Director of the Adams Super Center for Brain Studies, the Edersheim Levie-Gitter Institute for Functional Brain Imaging and the Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology. Professor Illana Gozes serves as the Chief Scientific Officer of Allon Therapeutics Inc. and the President of the Israel Society for Neuroscience. Professor Robert Sapolsky is the John A. and Cynthia Fry Gunn Professor at Stanford University. We thank Dr. Leonid Mittelman for his help with the confocal microscopy experiments and the Allon Therapeutics team for excellent discussions. This study was supported in part by the US–Israel Binational Science Foundation and by Allon Therapeutics Inc. The clinical effect of NAP (generic name, davunetide, intranasal formulation, AL-108) on cognition has been evaluated in patients with mild cognitive impairment. In that study, significant improvement was observed in 2 measures of memory, although significant improvement was not observed on the primary endpoint or secondary endpoints evaluating other cognitive domains. While headache and nasopharyngeal events were reported more frequently by NAP-treated subjects, overall, the incidence of adverse events was similar between placebo- and NAP-treated groups. In short, in phase IIa clinical trials, AL-108 showed cognitive protection in patients with amnestic mild cognitive impairment (prodromal to Alzheimer's disease) ( Schmechel et al., ICAD 2008 ; www.allontherapeutics.com ).
PY - 2009/9/15
Y1 - 2009/9/15
N2 - NAPVSIPQ (NAP), an 8 amino acid peptide derived from activity-dependent neuroprotective protein (ADNP), provides neuroprotection through interaction with microtubules. Previous results have demonstrated NAP protection against oxygen-glucose deprivation in hippocampal cells in culture. Furthermore, in vivo studies have shown that NAP reduces caspase 3 activation in rats subjected to permanent mid-cerebral artery occlusion (a rat model of stroke). Oxygen-glucose deprivation (ischemia) has been associated with microtubule breakdown and cytochrome c release from mitochondria leading to apoptosis. Here, NAP in concentrations ranging from 10- 14 M to 10- 8 M completely blocked cytochrome c release in cortical neurons subjected to oxygen-glucose deprivation. Furthermore, quantitative microscopy coupled to microtubule immunocytochemistry suggested that NAP prevented microtubule degradation under oxidative stress. As cytochrome c release is a known initiator of the apoptotic pathway, it is suggested that NAP inhibits the early events of apoptosis.
AB - NAPVSIPQ (NAP), an 8 amino acid peptide derived from activity-dependent neuroprotective protein (ADNP), provides neuroprotection through interaction with microtubules. Previous results have demonstrated NAP protection against oxygen-glucose deprivation in hippocampal cells in culture. Furthermore, in vivo studies have shown that NAP reduces caspase 3 activation in rats subjected to permanent mid-cerebral artery occlusion (a rat model of stroke). Oxygen-glucose deprivation (ischemia) has been associated with microtubule breakdown and cytochrome c release from mitochondria leading to apoptosis. Here, NAP in concentrations ranging from 10- 14 M to 10- 8 M completely blocked cytochrome c release in cortical neurons subjected to oxygen-glucose deprivation. Furthermore, quantitative microscopy coupled to microtubule immunocytochemistry suggested that NAP prevented microtubule degradation under oxidative stress. As cytochrome c release is a known initiator of the apoptotic pathway, it is suggested that NAP inhibits the early events of apoptosis.
KW - Cortical neuron
KW - Cytochrome c
KW - Microtubule
KW - Neuroprotection
KW - Neuroprotective peptide
KW - Oxygen-glucose deprivation
UR - http://www.scopus.com/inward/record.url?scp=68949176990&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2009.07.013
DO - 10.1016/j.ejphar.2009.07.013
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AN - SCOPUS:68949176990
SN - 0014-2999
VL - 618
SP - 9
EP - 14
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -