Research Article: Single Dose Caffeine Protects the Neonatal Mouse Brain against Hypoxia Ischemia

Date Published: January 27, 2017

Publisher: Public Library of Science

Author(s): Max Winerdal, Vijay Urmaliya, Malin E. Winerdal, Bertil B. Fredholm, Ola Winqvist, Ulrika Ådén, Valentin Ceña.


In this randomized blinded study, we investigated caffeine 5 mg/kg treatment given directly after neonatal brain hypoxia ischemia. Brain morphology, behavior and key brain infiltrating immune populations were examined. Caffeine treatment significantly improves outcome when compared to phosphate buffered saline. Flow cytometric analysis of immune responses revealed no persistent immunological alterations. Given its safety caffeine emerges as a candidate for neuroprotective intervention after neonatal brain injury.

Partial Text

Neuroprotective strategies are needed for neonatal hypoxia ischemia brain injury (HI). Mild hypothermia is currently the only available treatment in widespread clinical use [1], though difficult to achieve in low income countries. Thus, an affordable, technically uncomplicated alternative is highly desirable. When caffeine was given to treat apneas cerebral palsy significantly diminished [2], suggesting that caffeine might be a candidate for the treatment of brain HI.

All experiments were approved by the regional ethics committee, Stockholms norra djurförsöksetiska nämnd, in accordance with local institutional guidelines and the Directive 2010/63/EU.

A single dose caffeine 5 mg/kg administered directly after neonatal HI significantly decreased atrophy by 44% (p<0.05) defined by MAP-2 staining compared to PBS treatment (Fig 1A), paralleled by a borderline significant (p = 0.05) increase in time spent on the Rotarod (Fig 1B), indicating better balance and coordination. In addition, open field test activity significantly decreases after caffeine treatment compared to controls (p<0.01), signifying improved habituation (Fig 1C). Thus, caffeine given directly after HI is neuroprotective since improved neurological outcome was demonstrated in treated neonatal mice. Caffeine protects the neonatal mouse brain after HI, as observed by decreased brain atrophy and behavioral correlates in altered motor function and activation in the open field test. This confirms the neuroprotective properties of caffeine reported in humans [2] [9]. Of note, caffeine could potentially be administered trough breast feeding since prenatal continuous maternal caffeine intake reduces brain damage after neonatal HI in rats [10].   Source:


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