Terbutaline Is a Developmental Neurotoxicant: Effects on Neuroproteins and Morphology in Cerebellum, Hippocampus, and Somatosensory Cortex

Abstract

␤ 2 -Adrenoceptor agonists, especially terbutaline, are widely used to arrest preterm labor, but they also cross the placenta to stimulate fetal ␤-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.

Critical Prenatal and Postnatal Periods for Persistent Effects of Dexamethasone on Serotonergic and Dopaminergic Systems

“…Additionally, the use of multiple glucocorticoid courses is common (Crowther and Harding, 2003;Dammann and Matthews, 2001), despite the likelihood of subsequent metabolic, cardiovascular and behavioral anomalies (Barrington, 2001;Seckl, 2001;Shinwell et al, 2000;Trautman et al, 1995;Yeh et al, 2004). Recent reviews point out the long-term consequences of the use of antenatal steroids (Blackmon et al, 2002;Coe and Lubach, 2005;Newnham, 2001;Raff, 2004;Seckl, 2004) but isolating an explicit glucocorticoid effect in human populations is confounded by the comorbidities and interventions that are characteristic of preterm labor; as just one example, terbutaline, which is typically given to arrest uterine contractions (Lam et al, 1998) is itself a developmental neurotoxicant (Rhodes et al, 2004;Slotkin et al, 2003).…”

Neuroinflammation and Behavioral Abnormalities after Neonatal Terbutaline Treatment in Rats: Implications for Autism

“…Each model targets specific characteristics of behavior or neuroanatomy found in autism. Prenatal drug or chemical exposures have been suggested as potential contributors to the etiology of autism (Szpir, 2006a,b), including standard therapeutic interventions used in perinatal or pediatric medicine (Rhodes et al, 2004;Connors et al, 2005;Szpir, 2006b). Interestingly, one of these is terbutaline, a ␤2-adrenoceptor (␤2AR) agonist developed for asthma and frequently used for preterm labor as a tocolytic agent (Lam et al, 1998).…”

β2-Adrenergic receptor gene variants and risk for autism in the AGRE cohort

“…Overstimulation of the ADRB2 by agonists has been associated with apoptosis, and altered cell replication, differentiation, morphology and distribution. 5,6,[41][42][43] The Glu27 and Gly16 alleles that were associated with autism in the current study have been associated with increased responsiveness to b 2 -agonist and delayed desensitization and downregulation in vivo. These more responsive alleles may increase vulnerability to overstimulation and its associated effects, which in turn may increase risk for autism by altering neural architecture.…”

“…Neurotransmitters are thought to play a role as growth factors, with b-adrenergic agonists inhibiting proliferation while promoting differentiation. 2 Work with rodents shows that functional b-adrenergic receptors are expressed in the central nervous system during gestation, 3,4 and research on the effects of exposure to terbutaline, a b 2 -adrenergic receptor agonist, has produced evidence that pharmaceutical stimulation of the receptor in the fetus alters patterns of brain development [5][6][7][8] and could potentially increase risk for autism. 9 This suggests that other factors increasing stimulation of this receptor and the ensuing pathways, including functional polymorphisms in the receptor gene (ADRB2, also known as B2AR), may affect neurodevelopment and be associated with increased risk for autism.…”