Terbutaline is a developmental neurotoxicant: effects on neuroproteins and morphology in cerebellum, hippocampus, and somatosensory cortex.
Beta(2)-adrenoceptor agonists, especially terbutaline, are widely used to arrest preterm labor, but they also cross the placenta to stimulate fetal beta-adrenoceptors that control neural cell differentiation. We evaluated the effects of terbutaline administration in neonatal rats, a stage of neurodevelopment corresponding to human fetal development. Terbutaline administered on postnatal days PN2 to 5 elicited neurochemical changes indicative of neuronal injury and reactive gliosis: immediate increases in glial fibrillary acidic protein and subsequent induction of the 68-kDa neurofilament protein. Quantitative morphological evaluations carried out on PN30 indicated structural abnormalities in the cerebellum, hippocampus, and somatosensory cortex. In the cerebellum, PN2 to 5 terbutaline treatment reduced the number of Purkinje cells and elicited thinning of the granular and molecular layers. The hippocampal CA3 region also displayed thinning, along with marked gliosis, effects that were restricted to females. In the somatosensory cortex, terbutaline evoked a reduction in the proportion of pyramidal cells and an increase in smaller, nonpyramidal cells; again, females were affected more than males. Although abnormalities were obtained with later terbutaline treatment (PN11 to 14), in general the effects were smaller than those seen with PN2 to 5 exposure. Our results indicate that terbutaline is a neurotoxicant that elicits biochemical alterations and structural damage in the immature brain during a critical period. These effects point to a causal relationship between fetal terbutaline exposure and the higher incidence of cognitive and neuropsychiatric disorders reported for the offspring of women receiving terbutaline therapy for preterm labor.
Rhodes
Melissa C
MC
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Seidler
Frederic J
FJ
Abdel-Rahman
Ali
A
Tate
Charlotte A
CA
Nyska
Abraham
A
Rincavage
Heather L
HL
Slotkin
Theodore A
TA
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002531:Cerebellum / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D008297:Male; D016900:Neurofilament Proteins / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013003:Somatosensory Cortex / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D013726:Terbutaline / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D005904:Glial Fibrillary Acidic Protein; D016900:Neurofilament Proteins; D013726:Terbutaline