The expression of activity-dependent neuroprotective protein (ADNP) is regulated by brain damage and treatment of mice with the ADNP derived peptide, NAP, reduces the severity of traumatic head injury.
NAP is a short octapeptide sequence (single letter code, NAPVSIPQ) that protects neurons against a wide variety of insults. The NAP sequence was identified by peptide structure/function scanning of activity-dependent neuroprotective protein (ADNP), a gene product essential for brain formation. To further evaluate the in vivo efficacy of NAP neuroprotection we used a mouse model of head trauma; a condition that presents a risk factor for the development of Alzheimer's disease in injured patients. In the mouse model, NAP treatment (prophylactic or curative) indicated improvement in longitudinal clinical, biochemical and anatomical outcomes. Furthermore, closed head injury was associated with a delayed increase in the expression of the immune cell surface glycoprotein Mac-1 (CD11B antigen) at the injury site that was decreased in NAP-treated mice. Additional experiments with Mac-1-deficient mice suggested partial protection against death related to severe head injury. NAP protection in Mac-1-deficient mice against adverse clinical outcome was concomitant with the time period when increases in Mac-1 transcripts were observed in the Mac-1 expressing mice ( approximately four weeks after the injury). The expression of ADNP (the NAP parent protein) was also increased at the injured brain site four weeks after the traumatic event, only in Mac-1 expressing mice. Here, using immunocytochemistry, we localized the increase in ADNP to microglia and astrocyte-like cells. The increase in ADNP in injured brains is now suggested to be a part of an endogenous compensatory mechanism and NAP treatment provides an additional protection. Toxicology studies suggest NAP as safe for further clinical development.
Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. igozes@post.tau.ac.il
Illana
I
Gozes
Roy
R
Zaltzman
Janet
J
Hauser
Douglas E
DE
Brenneman
Esther
E
Shohami
Joanna M
JM
Hill
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*
C117632:Adnp protein, mouse; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; C425904:davunetide