OBJECTIVE: To determine whether Schisandrin B (Sch B) attenuates early brain injury (EBI) in rats with subarachnoid hemorrhage (SAH). METHODS: Sprague-Dawley rats were divided into sham (sham operation), SAH, SAH+vehicle, and SAH+Sch B groups using a random number table. Rats underwent SAH by endovascular perforation and received Sch B (100 mg/kg) or normal saline after 2 and 12 h of SAH. SAH grading, neurological scores, brain water content, Evan's blue extravasation, and terminal transferase-mediated dUTP nick end-labeling (TUNEL) staining were carried out 24 h after SAH. Immunofluorescent staining was performed to detect the expressions of ionized calcium binding adapter molecule 1 (Iba-1) and myeloperoxidase (MPO) in the rat brain, while the expressions of B-cell lymphoma 2 (Bcl-2), Bax, Caspase-3, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated specklike protein containing the caspase-1 activator domain (ASC), Caspase-1, interleukin (IL)-1β, and IL-18 in the rat brains were detected by Western blot. RESULTS: Compared with the SAH group, Sch B significantly improved the neurological function, reduced brain water content, Evan's blue content, and apoptotic cells number in the brain of rats (P<0.05 or P<0.01). Moreover, Sch B decreased SAH-induced expressions of Iba-1 and MPO (P<0.01). SAH caused the elevated expressions of Bax, Caspase-3, NLRP3, ASC, Caspase-1, IL-1β, and IL-18 in the rat brain (P<0.01), all of which were inhibited by Sch B (P<0.01). In addition, Sch B increased the Bcl-2 expression (P<0.01). CONCLUSION Sch B attenuated SAH-induced EBI, which might be associated with the inhibition of neuroinflammation, neuronal apoptosis, and the NLRP3 inflammatory signaling pathway.
Animals ; Apoptosis ; Brain/pathology* ; Brain Injuries/pathology* ; Caspase 3/metabolism* ; Cyclooctanes ; Evans Blue ; Inflammasomes/metabolism* ; Interleukin-18/metabolism* ; Lignans ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Polycyclic Compounds ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Rats ; Rats, Sprague-Dawley ; Subarachnoid Hemorrhage/drug therapy* ; Water ; bcl-2-Associated X Protein/metabolism*

Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic (HI) insult in the neonatal brain. AD-16 is a novel anti-inflammatory compound, recently found to exert potent inhibition of the lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators. In this study, we evaluated the effect of AD-16 on primary astrocytes and neurons under oxygen-glucose deprivation (OGD) in vitro and in mice with neonatal HI brain injury in vivo. We demonstrated that AD-16 protected against OGD-induced astrocytic and neuronal cell injury. Single dose post-treatment with AD-16 (1 mg/kg) improved the neurobehavioral outcome and reduced the infarct volume with a therapeutic window of up to 6 h. Chronic administration reduced the mortality rate and preserved whole-brain morphology following neonatal HI. The in vitro and in vivo effects suggest that AD-16 offers promising therapeutic efficacy in attenuating the progression of HI brain injury and protecting against the associated mortality and morbidity.
Animals ; Animals, Newborn ; Astrocytes/pathology* ; Brain/pathology* ; Brain Injuries/pathology* ; Glucose ; Hypoxia ; Hypoxia-Ischemia, Brain/drug therapy* ; Mice ; Neuroinflammatory Diseases ; Neuroprotective Agents/therapeutic use* ; Oxygen/therapeutic use*

PURPOSETo investigate the effects of estrogen G protein-coupled receptor 30 (GPR30) agonist G1 on hippocampal neuronal apoptosis and microglial polarization in rat traumatic brain injury (TBI).

METHODSMale SD rats were randomly divided into sham group, TBI + vehicle group, TBI + G1 group. Experimental moderate TBI was induced using Feeney's weigh-drop method. G1 (100μg/kg) or vehicle was intravenously injected from femoral vein at 30 min post-injury. Rats were sacrificed at 24 h after injury for detection of neuronal apoptosis and microglia polarization. Neuronal apoptosis was assayed by immunofluorescent staining of active caspase-3. M1 type microglia markers (iNOS and IL-1β) and M2 type markers (Arg1 and IL-4) were examined by immunoblotting or ELISA. Total protein level of Akt and phosphorylated Akt were assayed by immunoblotting.

RESULTSG1 significantly reduced active caspase-3 positive neurons in hippocampus. Meanwhile G1 increased the ratio of Arg1/iNOS. IL-1β production was decreased but IL-4 was increased after G1 treatment. G1 treatment also increased the active form of Akt.

CONCLUSIONSGPR30 agonist G1 inhibited neuronal apoptosis and favored microglia polarization to M2 type.

Animals ; Apoptosis ; drug effects ; Brain Injuries, Traumatic ; drug therapy ; pathology ; Cell Polarity ; Hippocampus ; drug effects ; Interleukin-1beta ; biosynthesis ; Male ; Microglia ; drug effects ; Neurons ; drug effects ; Proto-Oncogene Proteins c-akt ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled ; agonists

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 associated with poor neurological outcome, including necrosis and brain edema. In this study, we investigated whether agmatine treatment reduces edema and apoptotic cell death after TBI. TBI was produced by cold injury to the cerebral primary motor cortex of rats. Agmatine was administered 30 min after injury and once daily until the end of the experiment. Animals were sacrificed for analysis at 1, 2, or 7 days after the injury. Various neurological analyses were performed to investigate disruption of the blood-brain barrier (BBB) and neurological dysfunction after TBI. To examine the extent of brain edema after TBI, the expression of aquaporins (AQPs), phosphorylation of mitogen-activated protein kinases (MAPKs), and nuclear translocation of nuclear factor-kappaB (NF-kappaB) were investigated. Our findings demonstrated that agmatine treatment significantly reduces brain edema after TBI by suppressing the expression of AQP1, 4, and 9. In addition, agmatine treatment significantly reduced apoptotic cell death by suppressing the phosphorylation of MAPKs and by increasing the nuclear translocation of NF-kappaB after TBI. These results suggest that agmatine treatment may have therapeutic potential for brain edema and neural cell death in various central nervous system diseases.
Active Transport, Cell Nucleus/drug effects ; Agmatine/*therapeutic use ; Animals ; Apoptosis/*drug effects ; Aquaporins/metabolism ; Blood-Brain Barrier/physiopathology ; Brain Edema/*drug therapy ; Brain Injuries/*pathology ; Male ; Mitogen-Activated Protein Kinases/metabolism ; Motor Cortex/*pathology ; NF-kappa B/metabolism ; Phosphorylation/drug effects ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo detect absorbed bioactive compounds of the water extract whose pharmacodynamic effect was craniocerebral protection for quality control assessment.

METHODSAnthraquinones in water extract of rhubarb (WER), in cerebrospinal fluid (CSF) of patients with traumatic brain injury (TBI) and in ipsilateral cortex of TBI rats following oral WER were respectively explored by ultra performance liquid chromatography with photodiode array detector (UPLC-PDA) method developed in the present study. The effects of anthraquinones absorbed into injured cortex on superoxidase dismutase (SOD) activity in TBI rats were detected. The antioxidative anthraquinones absorbed into target organ were evaluated for quality control of WER.

RESULTSAnthraquinones in WER were aloe-emodin, rhein, emodin, chrysophanol, and physcion. Only the last anthraquinone was found in CSF and in ipsilateral cortex under this chromatographic condition. Physcion increased SOD activity in TBI rats significantly.

CONCLUSIONSPhyscion was the main active compound of rhubarb against craniocerebral injury via antioxidant pathway. According to our strategy, the exploration of physcion suggested the possibility of a novel quality control of WER in treating TBI injury.

Absorption ; drug effects ; Animals ; Anthraquinones ; cerebrospinal fluid ; chemistry ; Biological Products ; analysis ; cerebrospinal fluid ; chemistry ; Brain Injuries ; drug therapy ; pathology ; Chromatography, Liquid ; instrumentation ; methods ; Emodin ; administration & dosage ; analogs & derivatives ; pharmacology ; therapeutic use ; Humans ; Limit of Detection ; Linear Models ; Male ; Plant Extracts ; chemistry ; Quality Control ; Rats ; Rats, Sprague-Dawley ; Reference Standards ; Reproducibility of Results ; Rheum ; chemistry ; Water ; chemistry

OBJECTIVETo explore the effects of Xingnaojing injection on cerebral edema and blood-brain barrier (BBB) in rats following traumatic brain injury (TBI).

METHODSA total of 108 adult male Sprague-Dawley rats were used as subjects and randomly assigned to three groups: sham-operation, TBI and Xingnaojing injection groups (10 ml/kg/d, intraperitoneal injection). TBI in rats was set up by the improved device of Feeney's weight-dropping model with the impact of 600 g.cm. Brain water content and BBB permeability expressed as Evans blue content were measured at 1, 3, 5 and 7 days after surgery.

RESULTSIn sham-operation group, brain water content and Evans blue content in brain tissue were 78.97%+/-1.22% and 5.13 microgram+/-0.71 microgram. Following TBI, water content in brain tissue was increased significantly at 1, 3, 5 and 7 days (83.49%+/-0.54%, 82.74%+/-0.72%, 80.22%+/-0.68%, 79.21%+/-0.60%), being significantly higher than that in sham operation group (P less than 0.05). Evans blue content was increased in TBI group (16.54 microgram+/-0.60 microgram, 14.92 microgram+/-0.71 microgram, 12.44 microgram+/-0.92 microgram, 10.14 microgram+/-0.52 microgram) as compared with sham-operation group(P less than 0.05). After treatment with Xingnaojing injection, brain water content decreased as compared with TBI group (81.91%+/-1.04%, 80.38%+/-0.72%, 79.54%+/-0.58%, 78.60%+/-0.77%, P less than 0.05). Xingnaojing injection also reduced the leakage of BBB as compared with TBI group (15.11 microgram+/-0.63 microgram, 13.62 microgram+/-0.85 microgram, 10.06microgram+/-0.67 microgram, 9.54 microgram+/-0.41 microgram, P less than 0.05).

CONCLUSIONXingnaojing injection could alleviate cerebral edema following TBI via reducing permeability of BBB.

Animals ; Blood-Brain Barrier ; drug effects ; Brain ; pathology ; Brain Edema ; drug therapy ; Brain Injuries ; drug therapy ; pathology ; Drugs, Chinese Herbal ; administration & dosage ; Injections ; Male ; Medicine, Chinese Traditional ; Permeability ; Rats ; Rats, Sprague-Dawley

A 37-year-old female, who had received modified radical mastectomy for cancer of her right breast, presented with decreased visual acuity in the left eye after radiation therapy for the management of the metastasis to her right brain 14 months ago. After ocular examination, we diagnosed her as radiation retinopathy. At the time of the first visit, the corrected best visual acuity was 0.4 in the left eye, and fundus examination revealed cotton wool spots and cystoid macular edema (CME). The findings in the right eye were normal except for cotton wool spots in the superior major arch. Fluorescein angiography (FA) showed marked telangiectasia and microaneurysms in her left eye but tiny microaneurysms in her right eye. Subsequent optical coherent tomography (OCT) showed CME. We injected intravitreal triamcinolone acetonide (TA). Two weeks after treatment, the visual acuity was improved to 0.6 and the retinal thickness was decreased. Three months later, the visual acuity in the left eye was dropped to 0.3 due to the recurrence of CME, so we injected intravitreal TA again. Five months later, visual acuity was improved to 0.5 and OCT revealed the improvement of CME. The incidence of radiation retinopathy is higher in the side nearer to radiation, but careful radiation blocking is also required on the opposite side of irradiation site considering the possibility of radiation retinopathy and careful observation is required on both sides of the eyes when performing fundus examination.
Adult ; Brain Neoplasms/*radiotherapy/secondary ; Breast Neoplasms/pathology/radiotherapy/surgery ; Diagnosis, Differential ; Female ; Fluorescein Angiography ; Follow-Up Studies ; Fundus Oculi ; Glucocorticoids/administration & dosage ; Humans ; Radiation Injuries/diagnosis/drug therapy/*etiology ; Retina/pathology/*radiation effects ; Retinal Diseases/diagnosis/drug therapy/*etiology ; Tomography, Optical Coherence ; Triamcinolone Acetonide/administration & dosage

OBJECTIVETraumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in young people. Inflammatory cytokines play an important part in the pathophysiology of TBI. Recent studies demonstrate that progesterone significantly reduces cerebral edema and enhances functional recovery from TBI and stroke in several animal models. This study was designed to investigate the inhibitory effect of progesterone on inflammatory response after traumatic brain injury.

METHODSProgesterone was injected intraperitoneally using rats as a model of traumatic brain injury, and Western blot technique was applied to detect the expression of three inflammation-related factors: nuclear factor kappa B p65 (NFkappaB p65), glial fibrillary acidic protein (GFAP), and tumor necrosis factor-alpha (TNF-alpha). The water content of injured brain was also examined. A neurological severity score was recorded to evaluate the effect of progesterone on neurodeficit recovery.

RESULTSNFkappaB p65, GFAP, and TNF-alpha were increased in all injured animals. In rats treated with progesterone, the expression level of NFkappaB p65 and TNF-alpha were reduced significantly in comparison with vehicle-treated rats. However, progesterone did not alter the expression of GFAP in the injured rats. Progesterone also reduced the water content of injured brain and the lesion volume. In addition, progesterone-treated injured rats showed significant improvements in the Neurological Severity Score test, compared with vehicle-treated ones.

CONCLUSIONSProgesterone inhibits the inflammatory response after experimental traumatic brain injury and mitigates the severity of brain damage.

Actins ; genetics ; metabolism ; Animals ; Brain ; metabolism ; pathology ; Brain Edema ; prevention & control ; Brain Injuries ; drug therapy ; metabolism ; Gene Expression Regulation ; drug effects ; Male ; NF-kappa B ; genetics ; metabolism ; Neuroprotective Agents ; pharmacology ; Progesterone ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; genetics ; metabolism