Caffeine inhibits hypoxia-induced nuclear accumulation in HIF-1α and promotes neonatal neuronal survival

Hsiu Ling Li, Nahla Zaghloul, Ijaz Ahmed, Anton Omelchenko, Bonnie L. Firestein, Hai Huang, Latoya Collins

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Apnea of prematurity (AOP) defined as cessation of breathing for 15–20 s, is commonly seen in preterm infants. Caffeine is widely used to treat AOP due to its safety and effectiveness. Caffeine releases respiratory arrest by competing with adenosine for binding to adenosine A 1 and A 2A receptors (A 1 R and A 2A R). Long before its use in treating AOP, caffeine has been used as a psychostimulant in adult brains. However, the effect of caffeine on developing brains remains unclear. We found that A 1 R proteins for caffeine binding were expressed in the brains of neonatal rodents and preterm infants (26–27 weeks). Neonatal A 1 R proteins colocalized with PSD-95, suggesting its synaptic localization. In contrast, our finding on A 2 R expression in neonatal neurons was restricted to the mRNA level as detected by single cell RT/PCR due to the lack of specific A 2A R antibody. Furthermore, caffeine (200 μM) at a dose twice higher than the clinically relevant dose (36–130 μM) had minor or no effects on several basic neuronal functions, such as neurite outgrowth, synapse formation, expression of A 1 R and transcription of CREB-1 and c-Fos, further supporting the safety of caffeine for clinical use. We found that treatment with CoCl 2 (125 μM), a hypoxia mimetic agent, for 24 h triggered neuronal death and nuclear accumulation of HIF-1α in primary neuronal cultures. Subsequent treatment with caffeine at a concentration of 100 μM alleviated CoCl 2 -induced cell death and prevented nuclear accumulation of HIF-1α. Consistently, caffeine treatment in early postnatal life of neonatal mice (P4-P7) also prevented subsequent hypoxia-induced nuclear increase of HIF-1α. Together, our data support the utility of caffeine in alleviating hypoxia-induced damages in developing neurons.

Original languageEnglish (US)
Pages (from-to)66-77
Number of pages12
JournalExperimental Neurology
StatePublished - Jul 2019
Externally publishedYes

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience


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