ABSTRACT
Synaptic inhibition in the adult brain is primarily mediated by the γ-aminobutyric acid (GABA) type A receptor (GABA(A)R). The distribution, properties, and dynamics of these receptors are largely determined by their subunit composition. Alteration of subunit composition after a traumatic brain injury (TBI) may result in abnormal increased synaptic firing and possibly contribute to injury-related pathology. Several studies have shown that the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway can alter GABA(A)R subunit expression. The present study investigated changes in JAK/STAT pathway activation after two different severities of experimental TBI in the mouse using the controlled cortical impact (CCI) model. It also investigated whether modulating the activation of the JAK/STAT pathway after severe controlled cortical impact (CCI-S) with a JAK/STAT inhibitor (WP1066) alters post-traumatic epilepsy development and/or neurological recovery after injury. Our results demonstrated differential changes in both the activation of STAT3 and the expression of the GABA(A)R α1 and γ2 subunit levels that were dependent on the severity of the injury. The change in the GABA(A)R α1 subunit levels appeared to be at least partly transcriptionally mediated. We were able to selectively reverse the decrease in GABA(A)R α1 protein levels with WP1066 treatment after CCI injury. WP1066 treatment also improved the degree of recovery of vestibular motor function after injury. These findings suggest that the magnitude of JAK/STAT pathway activation and GABA(A)R α1 subunit level decrease is dependent on injury severity in this mouse model of TBI. In addition, reducing JAK/STAT pathway activation after severe experimental TBI reverses the decrease in the GABA(A)R α1 protein levels and improves vestibular motor recovery.
Subject(s)
Brain Injuries/metabolism , Brain Injuries/physiopathology , Janus Kinases/metabolism , Receptors, GABA-A/metabolism , STAT Transcription Factors/metabolism , Signal Transduction/physiology , Analysis of Variance , Animals , Disease Models, Animal , Electroencephalography , Exploratory Behavior , Gene Expression Regulation/physiology , Janus Kinases/genetics , Male , Mice , Motor Activity/physiology , RNA, Messenger/metabolism , Receptors, GABA-A/genetics , Recognition, Psychology , STAT Transcription Factors/genetics , Time FactorsABSTRACT
We have previously observed that the non-opioid morphine metabolite, morphine-3-glucuronide, enhances pain via a toll-like receptor 4 (TLR4) dependent mechanism. The present studies were undertaken to determine whether TLR4-dependent pain enhancement generalizes to other classes of glucuronide metabolites. In silico modeling predicted that glucuronic acid alone and ethyl glucuronide, a minor but long-lasting ethanol metabolite, would dock to the same MD-2 portion of the TLR4 receptor complex previously characterized as the docking site for morphine-3-glucuronide. Glucuronic acid, ethyl glucuronide and ethanol all caused an increase in TLR4-dependent reporter protein expression in a cell line transfected with TLR4 and associated co-signaling molecules. Glucuronic acid-, ethyl glucuronide-, and ethanol-induced increases in TLR4 signaling were blocked by the TLR4 antagonists LPS-RS and (+)-naloxone. Glucuronic acid and ethyl glucuronide both caused allodynia following intrathecal injection in rats, which was blocked by intrathecal co-administration of the TLR4 antagonist LPS-RS. The finding that ethyl glucuronide can cause TLR4-dependent pain could have implications for human conditions such as hangover headache and alcohol withdrawal hyperalgesia, as well as suggesting that other classes of glucuronide metabolites could have similar effects.
Subject(s)
Ethanol/pharmacology , Glucuronic Acid/pharmacology , Glucuronides/pharmacology , Pain/chemically induced , Signal Transduction/drug effects , Toll-Like Receptor 4/metabolism , Animals , Ethanol/metabolism , HEK293 Cells , Humans , Hyperalgesia/chemically induced , Hyperalgesia/metabolism , Male , Pain/metabolism , Pain Measurement , Physical Stimulation , Rats , Rats, Sprague-DawleyABSTRACT
OBJECTIVES: We sought to determine joint outcomes relative to impact level of athletic participation among school-aged children who had hemophilia and were taking prophylactic factor replacement, as well as to investigate prognostic factors for joint outcomes. METHODS: School-aged boys with severe hemophilia A or B at a single center were included in the study. Clinical data on baseline joint status, BMI, hemophilia treatment, bleeding episodes, joint assessments, athletic participation, and injuries were retrospectively reviewed. Data on athletic participation were supplemented, when incomplete in the medical record, via structured telephone interview. RESULTS: Among 37 children with severe hemophilia A or B receiving factor prophylaxis, 73% participated in high-impact activities, whereas 27% participated in exclusively low-impact activities. The frequency of joint hemorrhages and new injuries did not appreciably differ between high- and low-impact athletics. In most instances, children developed <1 bleed or injury per season. A new target joint developed in 1 (3%) child. Sixteen percent of children met established BMI criteria for overweight, and 3% were obese. In logistic regression analyses with adjustment for prophylaxis frequency, level of athletic participation was not a significant prognostic factor for joint hemorrhage. CONCLUSIONS: In the setting of regular prophylaxis and adult coaching and supervision, significant bleeding complications were uncommon and level of impact of athletic participation was not a prognostic factor for joint outcomes. Athletic participation with appropriate supervision and precautions should be encouraged in children with hemophilia receiving prophylaxis, given potential health benefits in an increasingly overweight pediatric population.
