The role of neurotrophic factors, apoptosis-related proteins, and endogenous antioxidants in the differential temporal vulnerability of neonatal cerebellum to ethanol.
BACKGROUND
Ethanol produces abnormalities in the developing nervous system, with certain regions being vulnerable during well-defined periods. Neonatal rodent cerebellum is particularly susceptible to ethanol during the early postnatal period [on postnatal days 4-5 (P4-5)], while this region is resistant to ethanol at a slightly later time (P7-9). We assessed basal levels of several substances which may be involved in differential temporal ethanol vulnerability in neonatal cerebellum, and analyzed alterations in these substances after early ethanol exposure.


METHODS
Assessments were made of neurotrophic factors nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4; apoptosis-related proteins Bcl-2, Bcl-xl, Bax, Bcl-xs, Bad, phosphorylated-Bad, phosphorylated-Akt, and phosphorylated-c-Jun N-terminal kinase; and the antioxidants superoxide dismutase, glutathione reductase, and catalase. These analyses quantified basal levels (in controls), and sequential changes following acute ethanol exposure at the vulnerable and resistant cerebellar periods (P4, P7).


RESULTS
Comparisons of basal levels of the molecules assessed between P4 and P7 revealed higher levels of total proapoptotic Bad at p4, higher levels of the protective pAkt kinase at P7, and lower levels of proapoptotic pJNK at P7. Other basal levels did not differ. While ethanol-mediated alterations were found at both ages favoring both apoptosis and survival, the apoptosis-promoting changes produced on P4 exceeded those on P7, and most occurred within the first 2 hr after exposure, a critical survival/death period. The number of alterations favoring survival were similar at the two ages, but at P7 most occurred within the first 2 hr after exposure, possibly acting in a protective manner.


CONCLUSIONS
Differential temporal vulnerability to ethanol in the neonatal cerebellum appears to be paralleled by cellular alterations in neurotrophic factors, apoptosis-regulatory proteins, and/or antioxidant activities which generally favor apoptosis at the most sensitive age and survival at the resistant age.
Heaton
Marieta Barrow
MB
Department of Neuroscience, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, USA. heaton@ufbi.ufl.edu
Moore
D Blaine
DB
Paiva
Michael
M
Madorsky
Irina
I
Mayer
Joanne
J
Shaw
Gerry
G
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002531:Cerebellum / Q000187:drug effects* / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D008297:Male; D009414:Nerve Growth Factors / Q000502:physiology*; D011506:Proteins / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans
D000975:Antioxidants; D009414:Nerve Growth Factors; D011506:Proteins; D000431:Ethanol