Caffeine prevents acute mortality after TBI in rats without increased morbidity.
Severe traumatic brain injury (TBI) is associated with a high incidence of acute mortality followed by chronic alteration of homeostatic network activity that includes the emergence of posttraumatic seizures. We hypothesized that acute and chronic outcome after severe TBI critically depends on disrupted bioenergetic network homeostasis, which is governed by the availability of the brain's endogenous neuroprotectant adenosine. We used a rat lateral fluid percussion injury (FPI) model of severe TBI with an acute mortality rate of 46.7%. A subset of rats was treated with 25mg/kg caffeine intraperitoneally within 1 min of the injury. We assessed neuromotor function at 24h and 4 weeks, and video-EEG activity and histology at 4 weeks following injury. We first demonstrate that acute mortality is related to prolonged apnea and that a single acute injection of the adenosine receptor antagonist caffeine can completely prevent TBI-induced mortality when given immediately following the TBI. Second, we demonstrate that neuromotor function is not affected by caffeine treatment at either 24h or 4 weeks following injury. Third, we demonstrate development of epileptiform EEG bursts as early as 4 weeks post-injury that are significantly reduced in duration in the rats that received caffeine. Our data demonstrate that acute treatment with caffeine can prevent lethal apnea following fluid percussion injury, with no negative influence on motor function or histological outcome. Further, we show epileptiform bursting is reduced after caffeine treatment, suggesting a potential role in the modulation of epilepsy development after severe injury.
Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR 97232, USA.
Theresa A
TA
Lusardi
Nikki K
NK
Lytle
Cory
C
Szybala
Detlev
D
Boison
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000401:mortality* / Q000503:physiopathology; D002110:Caffeine / Q000627:therapeutic use*; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004827:Epilepsy / Q000209:etiology / Q000517:prevention & control; D005071:Evoked Potentials / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000697:Central Nervous System Stimulants; D002110:Caffeine