title: Nicotinamide inhibits alkylating agent-induced apoptotic neurodegeneration in the developing rat brain.
abstract: BACKGROUND
  Exposure to the chemotherapeutic alkylating agent thiotepa during brain development leads to neurological complications arising from neurodegeneration and irreversible damage to the developing central nerve system (CNS). Administration of single dose of thiotepa in 7-d postnatal (P7) rat triggers activation of apoptotic cascade and widespread neuronal death. The present study was aimed to elucidate whether nicotinamide may prevent thiotepa-induced neurodegeneration in the developing rat brain.
  
  
  RESULTS
  Neuronal cell death induced by thiotepa was associated with the induction of Bax, release of cytochrome-c from mitochondria into the cytosol, activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP-1). Post-treatment of developing rats with nicotinamide suppressed thiotepa-induced upregulation of Bax, reduced cytochrome-c release into the cytosol and reduced expression of activated caspase-3 and cleavage of PARP-1. Cresyl violet staining showed numerous dead cells in the cortex hippocampus and thalamus; post-treatment with nicotinamide reduced the number of dead cells in these brain regions. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) and immunohistochemical analysis of caspase-3 show that thiotepa-induced cell death is apoptotic and that it is inhibited by nicotinamide treatment.
  
  
  CONCLUSIONS
  Nicotinamide (Nic) treatment with thiotepa significantly improved neuronal survival and alleviated neuronal cell death in the developing rat. These data demonstrate that nicotinamide shows promise as a therapeutic and neuroprotective agent for the treatment of neurodegenerative disorders in newborns and infants.
authors.affiliation: Division of Life Science, College of Natural Sciences (RINS) and Applied Life Science (Brain Korea 21), Gyeongsang National University, Chinju, Republic of Korea.
authors.forename: Najeeb
authors.initials: N
authors.lastname: Ullah
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Muhammad Imran
authors.initials: MI
authors.lastname: Naseer
authors.forename: Ikram
authors.initials: I
authors.lastname: Ullah
authors.forename: Joo Won
authors.initials: JW
authors.lastname: Suh
authors.forename: Myeong Ok
authors.initials: MO
authors.lastname: Kim
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000187:drug effects* / Q000196:embryology*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000517:prevention & control*; D009474:Neurons / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013852:Thiotepa / Q000494:pharmacology; D014803:Vitamin B Complex / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D000477:Alkylating Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D014803:Vitamin B Complex; D009536:Niacinamide; D045304:Cytochromes c; D013852:Thiotepa; D053148:Caspase 3