Caffeine prevents acute mortality after TBI in rats without increased morbidity

Abstract

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 25 mg/kg caffeine intraperitoneally within 1 minute of the injury. We assessed neuromotor function at 24 hours 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 24 hours 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.

Translating Drug-Induced Hibernation to Therapeutic Hypothermia

“…An increased level of adenosine signaling immediately after traumatic brain injury contributes to respiratory depression and death such that caffeine, a nonselective adenosine receptor antagonist, prevents acute mortality when administered immediately after traumatic brain injury. 18 Other studies show that a longer time lag between the return of spontaneous circulation (ROSC) and target T b is associated with a more favorable neurologic outcome in patients after cardiac arrest when compared to patients with a shorter time lag between ROSC and target T b . 17 Nonetheless, because the rate of CHA-induced cooling and minimum T b depend on the temperature differential, one is able to adjust the timing and depth of hypothermia through control of the temperature differential, i.e., the heat sink.…”

Adenosine Kinase: Exploitation for Therapeutic Gain

“…Astrogliosis and associated overexpression of ADK has also been identified in a rat model of severe traumatic brain injury (TBI) induced by a lateral fluid percussion injury. Interestingly, the injured animals developed epileptiform bursts associated with astrogliosis and overexpression of ADK well before the development of clinical epilepsy (Lusardi et al, 2012).…”

“…To determine whether excessive adenosine receptor activation contributed to lethal outcome, a subset of rats was treated with a 25 mg/kg concentration of the nonselective adenosine receptor antagonist caffeine intraperitoneally within 1 minute of the injury. Importantly, a single acute injection of caffeine was shown to completely prevent TBI-induced mortality when given immediately following the TBI, demonstrating that excessive adenosine contributed to lethal outcome (Lusardi et al, 2012). As in TBI, sudden unexpected death in epilepsy (SUDEP) has been associated with respiratory suppression (Langan, 2000;So, 2008).…”

Sleep, Sleep Disorders, and Mild Traumatic Brain Injury. What We Know and What We Need to Know: Findings from a National Working Group

“…The effects of caffeine shortly following injury have also been studied. In a rat model, high-dose (25 mg/kg) caffeine administered within 1 min of injury blocked the downstream effects of an adenosine surge that is thought to mediate death due to prolonged apnea [122]. Although caffeine may prove to be advantageous in an animal model during the acute phase of injury, its benefits in humans are currently unknown.…”