Traumatic brain injury (TBI) is a main cause of death and disability worldwide, posing a serious threat to public health. But currently, the diagnosis and treatments for TBI are still very limited. Exosomes are a group of extracellular vesicles and participate in multiple physiological processes including intercellular communication and substance transport. Non-coding RNAs (ncRNA) are of great abundancy as cargo of exosomes. Previous studies have shown that ncRNAs are involved in several pathophysiological processes of TBI. However, the concrete mechanisms involved in the effects induced by exosome-derived ncRNA remain largely unknown. As an important component of exosomes, ncRNA is of great significance for diagnosis, precise treatment, response evaluation, prognosis prediction, and complication management after TBI.
Brain Injuries, Traumatic/genetics* ; Cell Communication ; Exosomes/genetics* ; Extracellular Vesicles ; Humans ; RNA, Untranslated/genetics*

PURPOSEIt is becoming increasingly clear that genetic factors play a role in traumatic brain injury (TBI), whether in modifying clinical outcome after TBI or determining susceptibility to it. MicroRNAs are small RNA molecules involved in various pathophysiological processes by repressing target genes at the post- transcriptional level, and TBI alters microRNA expression levels in the hippocampus and cortex. This study was designed to detect differentially expressed microRNAs in the cerebrospinal fluid (CSF) of TBI patients remaining unconscious two weeks after initial injury and to explore related single nucleotide polymorphisms (SNPs).

METHODSWe used a microarray platform to detect differential microRNA expression levels in CSF samples from patients with post-traumatic coma compared with samples from controls. A bioinformatic scan was performed covering microRNA gene promoter regions to identify potential functional SNPs.

RESULTSTotally 26 coma patients and 21 controls were included in this study, with similar distribution of age and gender between the two groups. Microarray showed that fourteen microRNAs were differentially expressed, ten at higher and four at lower expression levels in CSF of traumatic coma patients compared with controls (p<0.05). One SNP (rs11851174 allele: C/T) was identified in the motif area of the microRNA hsa-miR-431-3P gene promoter region.

CONCLUSIONThe altered microRNA expression levels in CSF after brain injury together with SNP identified within the microRNA gene promoter area provide a new perspective on the mechanism of impaired consciousness after TBI. Further studies are needed to explore the association between the specific microRNAs and their related SNPs with post-traumatic unconsciousness.

Adult ; Brain Injuries, Traumatic ; cerebrospinal fluid ; genetics ; Computational Biology ; Humans ; Male ; MicroRNAs ; cerebrospinal fluid ; genetics ; Middle Aged ; Polymorphism, Single Nucleotide ; Unconscious (Psychology)

OBJECTIVETo investigate the effects of three different ways of chronic caffeine administration on blast- induced memory dysfunction and to explore the underlying mechanisms.

METHODSAdult male C57BL/6 mice were used and randomly divided into five groups: control: without blast exposure, con-water: administrated with water continuously before and after blast-induced traumatic brain injury (bTBI), con-caffeine: administrated with caffeine continuously for 1 month before and after bTBI, pre-caffeine: chronically administrated with caffeine for 1 month before bTBI and withdrawal after bTBI, post-caffeine: chronically administrated with caffeine after bTBI. After being subjected to moderate intensity of blast injury, mice were recorded for learning and memory performance using Morris water maze (MWM) paradigms at 1, 4, and 8 weeks post-blast injury. Neurological deficit scoring, glutamate concentration, proinflammatory cytokines production, and neuropathological changes at 24 h, 1, 4, and 8 weeks post-bTBI were examined to evaluate the brain injury in early and prolonged stages. Adenosine A1 receptor expression was detected using qPCR.

RESULTSAll of the three ways of chronic caffeine exposure ameliorated blast-induced memory deficit, which is correlated with the neuroprotective effects against excitotoxicity, inflammation, astrogliosis and neuronal loss at different stages of injury. Continuous caffeine treatment played positive roles in both early and prolonged stages of bTBI; pre-bTBI and post-bTBI treatment of caffeine tended to exert neuroprotective effects at early and prolonged stages of bTBI respectively. Up-regulation of adenosine A1 receptor expression might contribute to the favorable effects of chronic caffeine consumption.

CONCLUSIONSince caffeinated beverages are widely consumed in both civilian and military personnel and are convenient to get, the results may provide a promising prophylactic strategy for blast-induced neurotrauma and the consequent cognitive impairment.

Animals ; Blast Injuries ; complications ; Brain Injuries, Traumatic ; complications ; Caffeine ; pharmacology ; Cerebral Cortex ; pathology ; Hippocampus ; pathology ; Male ; Memory Disorders ; etiology ; prevention & control ; Mice ; Mice, Inbred C57BL ; RNA, Messenger ; analysis ; Receptor, Adenosine A1 ; genetics

OBJECTIVETo examine the effect of icariin (ICA) on the cognitive impairment induced by traumatic brain injury (TBI) in mice and the underlying mechanisms related to changes in hippocampal acetylation level.

METHODSThe modifified free-fall method was used to establish the TBI mouse model. Mice with post-TBI cognitive impairment were randomly divided into 3 groups using the randomised block method (n=7): TBI (vehicle-treated), low-dose (75 mg/kg) and high-dose (150 mg/kg) of ICA groups. An additional sham-operated group (vehicle-treated) was employed. The vehicle or ICA was administrated by gavage for 28 consecutive days. The Morris water maze (MWM) test was conducted. Acetylcholine (ACh) content, mRNA and protein levels of choline acetyltransferase (ChAT), and protein levels of acetylated H3 (Ac-H3) and Ac-H4 were detected in the hippocampus.

RESULTSCompared with the sham-operated group, the MWM performance, hippocampal ACh content, mRNA and protein levels of ChAT, and protein levels of Ac-H3 and Ac-H4 were signifificantly decreased in the TBI group (P<0.05). High-dose of ICA signifificantly ameliorated the TBI-induced weak MWM performance, increased hippocampal ACh content, and mRNA and protein levels of ChAT, as well as Ac-H3 protein level compared with the TBI group (P<0.05).

CONCLUSIONICA improved post-TBI cognitive impairment in mice by enhancing hippocampal acetylation, which improved hippocampal cholinergic function and ultimately improved cognition.

Acetylation ; Acetylcholine ; metabolism ; Animals ; Brain Injuries, Traumatic ; complications ; Choline O-Acetyltransferase ; genetics ; metabolism ; Cognitive Dysfunction ; drug therapy ; etiology ; Flavonoids ; chemistry ; pharmacology ; therapeutic use ; Hippocampus ; pathology ; Histones ; metabolism ; Homeostasis ; drug effects ; Male ; Maze Learning ; drug effects ; Mice ; RNA, Messenger ; genetics ; metabolism

The aim of this study was to investigate the possible beneficial role of telmisartan in cerebral edema after traumatic brain injury (TBI) and the potential mechanisms related to the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) pyrin domain-containing 3 (NLRP3) inflammasome activation. TBI model was established by cold-induced brain injury. Male C57BL/6 mice were randomly assigned into 3, 6, 12, 24, 48 and 72 h survival groups to investigate cerebral edema development with time and received 0, 5, 10, 20 and 40 mg/kg telmisartan by oral gavage, 1 h prior to TBI to determine the efficient anti-edemic dose. The therapeutic window was identified by post-treating 30 min, 1 h, 2 h and 4 h after TBI. Blood-brain barrier (BBB) integrity, the neurological function and histological injury were assessed, at the same time, the mRNA and protein expression levels of NLRP3 inflammasome, IL-1β and IL-18 concentrations in peri-contused brain tissue were measured 24 h post TBI. The results showed that the traumatic cerebral edema occurred from 6 h, reached the peak at 24 h and recovered to the baseline 72 h after TBI. A single oral dose of 5, 10 and 20 mg/kg telmisartan could reduce cerebral edema. Post-treatment up to 2 h effectively limited the edema development. Furthermore, prophylactic administration of telmisartan markedly inhibited BBB impairment, NLRP3, apoptotic speck-containing protein (ASC) and Caspase-1 activation, as well as IL-1β and IL-18 maturation, subsequently improved the neurological outcomes. In conclusion, telmisartan can reduce traumatic cerebral edema by inhibiting the NLRP3 inflammasome-regulated IL-1β and IL-18 accumulation.
Animals ; Benzimidazoles ; administration & dosage ; Benzoates ; administration & dosage ; Blood-Brain Barrier ; drug effects ; Brain Edema ; drug therapy ; genetics ; pathology ; Brain Injuries, Traumatic ; drug therapy ; genetics ; pathology ; Caspase 1 ; biosynthesis ; Gene Expression Regulation ; drug effects ; Humans ; Inflammasomes ; adverse effects ; genetics ; Interleukin-18 ; biosynthesis ; Interleukin-1beta ; biosynthesis ; Male ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein ; biosynthesis ; genetics ; Signal Transduction ; drug effects

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. The finding that cellular microparticles (MPs) generated by injured cells profoundly impact on pathological courses of TBI has paved the way for new diagnostic and therapeutic strategies. MPs are subcellular fragments or organelles that serve as carriers of lipids, adhesive receptors, cytokines, nucleic acids, and tissue-degrading enzymes that are unique to the parental cells. Their sub-micron sizes allow MPs to travel to areas that parental cells are unable to reach to exercise diverse biological functions. In this review, we summarize recent developments in identifying a casual role of MPs in the pathologies of TBI and suggest that MPs serve as a new class of therapeutic targets for the prevention and treatment of TBI and associated systemic complications.
Animals ; Astrocytes ; metabolism ; pathology ; Biological Transport ; Blood Coagulation Factors ; genetics ; metabolism ; Brain ; metabolism ; pathology ; physiopathology ; Brain Injuries, Traumatic ; genetics ; metabolism ; pathology ; physiopathology ; Cell-Derived Microparticles ; chemistry ; metabolism ; pathology ; Cytokines ; blood ; genetics ; Disease Models, Animal ; Disseminated Intravascular Coagulation ; genetics ; metabolism ; pathology ; physiopathology ; Gene Expression Regulation ; Humans ; Microglia ; metabolism ; pathology ; Neurons ; metabolism ; pathology ; Signal Transduction

The purpose of the present study was to investigate the effect of glutamate scavenger oxaloacetate (OA) combined with CGS21680, an adenosine A2A receptor (A2AR) agonist, on acute traumatic brain injury (TBI), and to elucidate the underlying mechanisms. C57BL/6J mice were subjected to moderate-level TBI by controlled cortical impact, and then were treated with OA, CGS21680, or OA combined with CGS21680 at acute stage of TBI. At 24 h post TBI, neurological severity score, brain water content, glutamate concentration in cerebrospinal fluid (CSF), mRNA and protein levels of IL-1β and TNF-α, mRNA level and activity of glutamate oxaloacetate aminotransferase (GOT), and ATP level of brain tissue were detected. The results showed that neurological deficit, brain water content, glutamate concentration in CSF, and the inflammatory cytokine IL-1β and TNF-α production were exacerbated in CGS21680 treated mice. Administrating OA suppressed the rise of both glutamate concentration in CSF and brain water content, and elevated the ATP level of cerebral tissue. More interestingly, neurological deficit, brain edema, glutamate concentration, IL-1β and TNF-α levels were ameliorated significantly in mice treated with OA combined with CGS21680. The combined treatment exhibited better therapeutic effects than single OA treatment. We also observed that GOT activity was enhanced in single CGS21680 treatment group, and both the GOT mRNA level and GOT activity were up-regulated in early-stage combined treatment group. These results suggest that A2AR can improve the efficiency of GOT and potentiate the ability of OA to metabolize glutamate. This may be the mechanism that A2AR activation in combination group augmented the neuroprotective effect of OA rather than aggravated the brain damages. Taken together, the present study provides a new insight for the clinical treatment of TBI with A2AR agonists and OA.
Adenosine A2 Receptor Agonists/therapeutic use* ; Adenosine Triphosphate ; Animals ; Brain Injuries/metabolism* ; Brain Injuries, Traumatic/metabolism* ; Glutamic Acid ; Mice ; Mice, Inbred C57BL ; Neuroprotective Agents/therapeutic use* ; Oxaloacetic Acid/therapeutic use* ; RNA, Messenger ; Receptor, Adenosine A2A/metabolism* ; Tumor Necrosis Factor-alpha/genetics* ; Water

OBJECTIVE: To investigate the effects of blocking the activation of ERK pathway on the expression of matrix metalloproteinase-9 (MMP-9) and the formation of cerebral edema in SD rats after brain injury. METHODS: Ninety SD rats were randomly divided into 3 equal groups, including a sham-operated group, modified Feeney's traumatic brain injury model group, and ERK inhibition group where the ERK inhibitor SCH772984 (500 μg/kg) was injected via the femoral vein 15 min before brain trauma. At 2 h and 2 days after brain trauma, the permeability of blood-brain barrier was assessed by Evans blue method, the water content of the brain tissue was determined, and the phosphorylation level of ERK and the expression level of MMP-9 mRNA and protein were measured by RT-PCR and Western blotting. RESULTS: Compared with the sham-operated group, the rats with brain trauma exhibited significantly increased level of ERK phosphorylation at 2 h and significantly increased expression of MMP-9 mRNA and protein 2 days after the injury ( < 0.01). Treatment with the ERK inhibitor significantly decreased the phosphorylation level of ERK after the injury ( < 0.01), suppressed over-expression of MMP-9 mRNA and protein 2 days after the injury ( < 0.01). The permeability of blood-brain barrier increased significantly 2 h after brain trauma ( < 0.05) and increased further at 2 days ( < 0.01); the water content of the brain did not change significantly at 2 h ( > 0.05) but increased significantly 2 d after the injury ( < 0.01). Treatment with the ERK inhibitor significantly lowered the permeability of blood-brain barrier and brain water content after brain trauma ( < 0.01). CONCLUSIONS Blocking the activation of ERK pathway significantly reduced the over-expression of MMP-9 and alleviates the damage of blood-brain barrier and traumatic brain edema, suggesting that ERK signaling pathway plays an important role in traumatic brain edema by regulating the expression of MMP-9.
Animals ; Brain Edema ; drug therapy ; etiology ; Brain Injuries, Traumatic ; complications ; drug therapy ; Gene Expression Regulation, Enzymologic ; drug effects ; Indazoles ; pharmacology ; therapeutic use ; MAP Kinase Signaling System ; drug effects ; Matrix Metalloproteinase 9 ; genetics ; Piperazines ; pharmacology ; therapeutic use ; Protein Kinase Inhibitors ; pharmacology ; therapeutic use ; Random Allocation ; Rats ; Rats, Sprague-Dawley