title: Protective effect of pyruvate against ethanol-induced apoptotic neurodegeneration in the developing rat brain.
abstract: Exposure to alcohol during the early stages of brain development can lead to neurological disorders in the CNS. Apoptotic neurodegeneration due to ethanol exposure is a main feature of alcoholism. Exposure of developing animals to alcohol (during the growth spurt period in particular) elicits apoptotic neuronal death and causes fetal alcohol effects (FAE) or fetal alcohol syndrome (FAS). A single episode of ethanol intoxication (at 5 g/kg) in a seven-day-old developing rat can activate the apoptotic cascade, leading to widespread neuronal death in the brain. In the present study, we investigated the potential protective effect of pyruvate against ethanol-induced neuroapoptosis. After 4h, a single dose of ethanol induced upregulation of Bax, release of mitochondrial cytochrome-c into the cytosol, activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP-1), all of which promote apoptosis. These effects were all reversed by co-treatment with pyruvate at a well-tolerated dosage (1000 mg/kg). Histopathology performed at 24 and 48 h with Fluoro-Jade-B and cresyl violet stains showed that pyruvate significantly reduced the number of dead cells in the cerebral cortex, hippocampus and thalamus. Immunohistochemical analysis at 24h confirmed that ethanol-induced cell death is both apoptotic and inhibited by pyruvate. These findings suggest that pyruvate treatment attenuates ethanol-induced neuronal cell loss in the developing rat brain and holds promise as a safe therapeutic and neuroprotective agent in the treatment of neurodegenerative disorders in newborns and infants.
authors.affiliation: Division of Life Science, College of Natural Sciences (RINS) and Applied Life Sciences, Gyeongsang National University, Chinju 660-701, Republic of Korea.
authors.forename: Najeeb
authors.initials: N
authors.lastname: Ullah
authors.forename: Muhammad Imran
authors.initials: MI
authors.lastname: Naseer
authors.forename: Ikram
authors.initials: I
authors.lastname: Ullah
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Phil Ok
authors.initials: PO
authors.lastname: Koh
authors.forename: Myeong Ok
authors.initials: MO
authors.lastname: Kim
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D005452:Fluoresceins; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009930:Organic Chemicals; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019289:Pyruvic Acid / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D002492:Central Nervous System Depressants; D005452:Fluoresceins; D018696:Neuroprotective Agents; D009930:Organic Chemicals; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C435731:fluoro jade; D000431:Ethanol; D019289:Pyruvic Acid; D045304:Cytochromes c; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3