Ceftriaxone Treatment after Traumatic Brain Injury Restores Expression of the Glutamate Transporter, GLT-1, Reduces Regional Gliosis, and Reduces Post-Traumatic Seizures in the Rat

Abstract

Excessive extracellular glutamate after traumatic brain injury (TBI) contributes to excitotoxic cell death and likely to posttraumatic epilepsy. Glutamate transport is the only known mechanism of extracellular glutamate clearance, and glutamate transporter 1 (GLT-1) is the major glutamate transporter of the mammalian brain. We tested, by immunoblot, in the rat lateral fluid percussion injury TBI model whether GLT-1 expression is depressed in the cortex after TBI, and whether GLT-1 expression after TBI is restored after treatment with ceftriaxone, a well-tolerated b-lactam antibiotic previously shown to enhance GLT-1 expression in noninjured animals. We then tested whether treatment with ceftriaxone mitigates the associated regional astrogliosis, as reflected by glial fibrillary acid protein (GFAP) expression, and also whether ceftriaxone treatment mitigates the severity of post-traumatic epilepsy. We found that 7 days after TBI, GLT-1 expression in the ipsilesional cortex was reduced by 29% (n = 7/group; p < 0.01), relative to the contralesional cortex. However, the loss of GLT-1 expression was reversed by treatment with ceftriaxone (200 mg/kg, daily, intraperitoneally). We found that ceftriaxone treatment also decreased the level of regional GFAP expression by 43% in the lesioned cortex, relative to control treatment with saline (n = 7 per group; p < 0.05), and, 12 weeks after injury, reduced cumulative post-traumatic seizure duration (n = 6 rats in the ceftriaxone treatment group and n = 5 rats in the saline control group; p < 0.001). We cautiously conclude that our data suggest a potential role for ceftriaxone in treatment of epileptogenic TBI.

Attenuation of Ethanol Withdrawal by Ceftriaxone-Induced Upregulation of Glutamate Transporter EAAT2

“…Our findings are in agreement with the large body of evidence that supports the hypothesis that ethanol withdrawal results from a rebound hyperglutamatergic state unmasked by the abrupt termination of ethanol intake (Chandler et al, 2006;Crews et al, 1996;De Witte et al, 2003;Grant and Lovinger, 1995). Furthermore, our results are in agreement with previous reports showing that ceftriaxone administration displayed anti-seizure properties in an invertebrate assay (Rawls et al, 2010a), reduced the frequency of seizure in a mouse model of tuberous sclerosis complex (Zeng et al, 2010), and reduced cumulative posttraumatic seizure duration in rats (Goodrich et al, 2013). In addition, ceftriaxone (150, 200 mg/kg) injected once daily during chronic morphine exposure inhibited each naloxone-precipitated withdrawal sign (Rawls et al, 2010b), improved mechanical allodynia and attenuated morphine tolerance in an animal model of neuropathic pain (Rawls et al, 2010c), and reduced opioid-induced hyperalgesia in mice (Chen et al, 2012).…”

Elevated glutamate and lactate predict brain death after severe head trauma

“…For instance, secondary mechanisms associated with the brain tissue deformation including global ischemia, sustained increased intracranial pressure and focal contusions11, 13, and spontaneous brain hypothermia (<36°C)26 have been implicated in the increase in glutamate levels and acute neuronal death. Also, increased extracellular brain glutamate concentration after TBI is also influenced by decreased astrocytic glutamate uptake 27. This might indicate that different players associated to the tripartite glutamatergic synapse, likely contribute for the deterioration of brain function after severe TBI, such as disrupted energy support rapidly triggering neuronal death.…”

Glutamate Neurotransmission in Rodent Models of Traumatic Brain Injury

“…88,90,91 Moreover, decreases may be in a specific splice variant for EAAT2, suggesting a shift in the cellular or subcellular localization of this transporter in TBI. 91 These findings in animal models replicate analyses of human postmortem brain in which protein levels of the astrocytic glutamate transporters may be decreased.…”

“…For example, the b-lactam antibody ceftriaxone reversed the loss of EAAT2 expression in the ipsilateral frontal cortex of TBI mice 7 days post-injury and resulted in lower levels of pro-inflammatory mediators. 90,119 A number of additional compounds, including riluzole, the tricyclic antidepressant amitriptyline (which upregulates EAAT expression), and the beta-carboline alkaloid harmine (which stimulates EAAT2 activity), show promise in multiple models of CNS injury and neurodegeneration. 120 By focusing on neuronal protection, pharmacological intervention may be ignoring the crucial role of astrocytes in the propagation and sustainment of the disease state.…”