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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Dipyridamole promotes changes in calbindin-D28k and tyrosine hydroxylase expression in neonatal rats
K E Hefner1, R Butler, A Ravindra
1Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1010, USA.
Insights
Perinatal hypoxia increases brain adenosine, impacting motor control regions. Targeting adenosine may prevent central nervous system damage in infants.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Perinatal Medicine
Background:
- Perinatal hypoxia alters brain neurochemicals, including adenosine.
- Hypoxia is linked to central nervous system (CNS) disorders in infants, such as periventricular leukomalacia and encephalopathy.
Purpose of the Study:
- Investigate the effects of sustained increases in brain adenosine on CNS regions involved in motor activity planning and execution.
- Utilize the postnatal rat as a model for perinatal human development.
Main Methods:
- Administered dipyridamole (adenosine uptake inhibitor) or N(6)-cyclopentyladenosine (A(1) adenosine receptor agonist) to rats from postnatal day 3 to 14.
- Performed immunohistochemical and morphological analyses to assess calbindin D-28k expression and external granule cell layer thickness in the cerebellum.
- Examined tyrosine hydroxylase expression in the caudate putamen and ventricular size.
Main Results:
- Both dipyridamole and N(6)-cyclopentyladenosine reduced calbindin D-28k positive Purkinje cells and external granule cell layer thickness in the cerebellum.
- Dipyridamole, but not N(6)-cyclopentyladenosine, decreased tyrosine hydroxylase expression in the caudate putamen.
- Neither agent significantly altered ventricular size.
Conclusions:
- Elevated brain adenosine, following hypoxia, induces neurochemical and cellular changes in motor control brain regions.
- Therapeutic strategies targeting adenosine-sensitive brain regions may prevent or mitigate CNS damage from perinatal hypoxia.
Background:
Perinatal hypoxia alters the concentration of many neurochemicals in the brain, including adenosine, and promotes central nervous system (CNS) disorders in human infants such as periventricular leukomalacia or encephalopathy.
Objective:
Using the postnatal rat as a model of perinatal human development, we examined the effects of sustained increases in brain adenosine on CNS regions thought to be involved with both planning and execution of motor activity.
Methods:
To simulate hypoxia-induced changes in adenosine, Sprague-Dawley rats were injected twice daily from postnatal day (P) 3 to P14, with the adenosine uptake inhibitor dipyridamole (DIP) or the A(1) adenosine receptor agonist N(6)-cyclopentyladenosine (CPA). Vehicle-injected animals served as controls. Immunohistochemical and morphological analyses were then performed to examine the expression of calbindin D-28k (CB) and the thickness of the external granule cell layer (eGL) in the cerebellum. Additionally tyrosine hydroxylase (TH) expression in the caudate putamen and ventricular size were also examined.
Results:
In the cerebellum, both DIP and CPA reduced the number of CB-positive Purkinje cells as well as decreased the thickness of the eGL compared to vehicle. In the caudate putamen we found that DIP but not CPA decreased TH expression when compared to vehicle. Neither agent significantly altered ventricular size when compared to vehicle.
Conclusions:
These observations suggest that elevations in brain adenosine, which can occur following hypoxia, leads to both neurochemical and cellular changes in regions of the brain which control the planning and execution of motor activity. Thus, therapeutic strategies that target brain regions most sensitive to adenosine may prevent or control at least some of the CNS damage observed following perinatal hypoxia.
