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Aggravated brain damage after hypoxic ischemia in immature adenosine A2A knockout mice
Ulrika Adén1, Linda Halldner, Hugo Lagercrantz
1Department of Physiology and Pharmacology, Karolinska Institutet, S-171 76 Stockholm, Sweden. ulrika.aden@fyfa.ki.se
Insights
Adenosine A2A receptors (A2AR) protect against neonatal hypoxic-ischemic brain injury. A2AR knockout mice showed worsened brain damage and long-term behavioral deficits after injury, highlighting A2AR
Area of Science:
- Neuroscience
- Neonatal Research
- Ischemic Injury
Background:
- Cerebral hypoxic-ischemia (HI) is a significant cause of brain damage in newborns.
- Adenosine receptors are implicated in neuroprotection, but their specific roles in young animals remain unclear.
Purpose of the Study:
- To investigate the role of adenosine A2A receptors (A2AR) in neonatal brain injury using a mouse model.
- To determine if A2AR influence the severity and long-term consequences of HI in young animals.
Main Methods:
- Neonatal mice (7-day-old) underwent induced hypoxic-ischemia (HI).
- Adenosine A2A receptor knockout (A2AR(-/-)) and wild-type (A2AR(+/+)) mice were compared.
- Histopathological scoring, behavioral tests, and cerebral blood flow measurements were performed.
Main Results:
- HI induced comparable reductions in cerebral blood flow and temperature in both knockout and wild-type mice.
- A2AR(-/-) mice exhibited significantly aggravated brain injury compared to wild-type controls.
- Long-term behavioral deficits, including impaired motor coordination, were more pronounced in A2AR(-/-) mice post-HI.
Conclusions:
- Adenosine A2A receptors play a crucial protective role against neonatal hypoxic-ischemic brain injury.
- Targeting A2AR may offer a therapeutic strategy for mitigating brain damage in newborns following HI.
Background And Purpose:
Cerebral hypoxic ischemia (HI) is an important cause of brain injury in the newborn infant. Adenosine is believed to protect against HI brain damage. However, the roles of the different adenosine receptors are unclear, particularly in young animals. We examined the role of adenosine A2A receptors (A2AR) using 7-day-old A2A knockout (A2AR(-/-)) mice in a model of HI.
Methods:
HI was induced in 7-day-old CD1 mice by exposure to 8% oxygen for 30 minutes after occlusion of the left common carotid artery. The resulting unilateral focal lesion was evaluated with the use of histopathological scoring and measurements of residual brain areas at 5 days, 3 weeks, and 3 months after HI. Behavioral evaluation of brain injury by locomotor activity, rotarod, and beam-walking test was made 3 weeks and 3 months after HI. Cortical cerebral blood flow, assessed by laser-Doppler flowmetry, and rectal temperature were measured during HI.
Results:
Reduction in cortical cerebral blood flow during HI and rectal temperature did not differ between wild-type (A2AR(+/+)) and knockout mice. In the A2AR(-/-) animals, brain injury was aggravated compared with wild-type mice. The A2AR(-/-) mice subjected to HI displayed increased forward locomotion and impaired rotarod performance in adulthood compared with A2AR(+/+) mice subjected to HI, whereas beam-walking performance was similarly defective in both groups.
Conclusions:
These results suggest that, in contrast to the situation in adult animals, A2AR play an important protective role in neonatal HI brain injury.