Caffeine prevents acute mortality after TBI in rats without increased morbidity

Article (PDF Available)inExperimental Neurology 234(1):161-8 · March 2012with36 Reads
DOI: 10.1016/j.expneurol.2011.12.026 · Source: PubMed
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.

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Available from: Cory Szybala, Jan 21, 2016
    • "Studying the mechanisms underlying post-traumatic epilepsy is complicated by its long latency, often occurring months or years after a traumatic event (Lusardi et al., 2012). Early pharmacological intervention following traumatic brain injury is especially important for preventing post-traumatic epilepsy. "
    [Show abstract] [Hide abstract] ABSTRACT: The activity of the Schaffer collaterals of hippocampal CA3 neurons and hippocampal CA1 neurons has been shown to increase after fluid percussion injury. Diazepam can inhibit the hyperexcitability of rat hippocampal neurons after injury, but the mechanism by which it affects excitatory synaptic transmission remains poorly understood. Our results showed that diazepam treatment significantly increased the slope of input-output curves in rat neurons after fluid percussion injury. Diazepam significantly decreased the numbers of spikes evoked by super stimuli in the presence of 15 μmol/L bicuculline, indicating the existence of inhibitory pathways in the injured rat hippocampus. Diazepam effectively increased the paired-pulse facilitation ratio in the hippocampal CA1 region following fluid percussion injury, reduced miniature excitatory postsynaptic potentials, decreased action-potential-dependent glutamine release, and reversed spontaneous glutamine release. These data suggest that diazepam could decrease the fluid percussion injury-induced enhancement of excitatory synaptic transmission in the rat hippocampal CA1 area.
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    • "The neuronal modulation of Ngb after ischemia [6] is similar to the positive modulation of Ngb occurring after graded TBI recorded in our experiments; however, the data referring to the oxidant/antioxidant balance recorded in both mTBI-and sTBIinjured rats, and connected to ROS and RNS overproduction, do not seem to corroborate the notion that an increase in Ngb equates to reduced brain injury. Although the severe level of TBI is associated with irreversible brain injury [27,28,49], mTBI causes only transient alterations in the absence of visible histological damage [27,50]. Therefore, mTBI would have been a suitable grade of injury to observe a time course of eventual Ngb overexpression mirroring the recovery period from the transitory oxidant/antioxidant imbalance. "
    [Show abstract] [Hide abstract] ABSTRACT: Neuroglobin is a neuron specific hexacoordinated globin capable of binding various ligands, including O2, NO, and CO, the biological function of which is still uncertain. Various studies seem to indicate that neuroglobin is a neuroprotective agent when overexpressed, acting as a potent inhibitor of oxidative and nitrosative stress. In this study, we evaluated the pathophysiological response of the neuroglobin gene and protein expression in the cerebral tissue of rats sustaining a traumatic brain injury of different severity, whilst simultaneously measuring the oxidants/antioxidants balance. Two levels of trauma (mild and severe) were induced in anesthetized animals using the weight-drop model of diffuse axonal injury. Rats were then sacrificed at 6, 12, 24, 48 and 120 hours after traumatic brain injury, and the gene and protein expression of neuroglobin and the concentrations of malondialdehyde (as a parameter representative of ROS mediated damage), nitrite+nitrate (indicative of NO metabolism), ascorbate and GSH were determined in the brain tissue. Results indicated that mild traumatic brain injury, while causing a reversible increase in oxidative/nitrosative stress (increase in malondialdehyde and nitrite+nitrate) and imbalance in antioxidants (decrease in ascorbate and GSH), did not induce any change in neuroglobin. Conversely, severe traumatic brain injury caused an over 9-fold and 5-fold increase in neuroglobin gene and protein expressions respectively, as well as a remarkable increase in oxidative/nitrosative stress and depletion of antioxidants. The results of the present study, showing a lack of effect in mild traumatic brain injury, as well as an asynchronous time course changes of neuroglobin expression, oxidative/nitrosative stress and antioxidants in severe traumatic brain injury, do not seem to support the role of neuroglobin as an endogenous neuroprotective antioxidant agent, at least under pathophysiological conditions.
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