The biochemical factors related to moderation of secondary or delayed damage to the central nervous system (CNS) remain undefined. We have recently demonstrated that the weight- drop induced moderate diffuse axonal injury (mDAI) in rats causes a rapid decline in serum ionized magnesium (Mg2+) and a significant increase in the amount of serum ionized calcium (Ca2+) relative to Mg2+ (Ca2+/ Mg2+). For three hours, serum Mg2+ levels remained significantly depressed at 76% of preinjury values (p< 0.05), but total serum magnesium remained unchanged (tMg, p > 0.05). Head trauma resulted in a small decrease of Ca2+ (about 10%), but a significant increase in the amount of Ca2+/Mg2+ (mean value in control group: in injured group for 3 hours after trauma =4.65 +/-0.012 : 5.69 +/-0.015, p< 0.05) was observed. In order to further investigate the relationship between Mg2+ and brain injury, the effect of Mg2+ treatment on posttraumatic histological changes (apoptotic changes) was examined following the weight-drop induced brain injury. At 30 min postinjury, animals treated with MgSO4 (750micro Ml/kg) showed significant improvements of apoptotic changes when compared to the control group (54.8 +/- 1.7, 51.5 +/- 3.2 at 12, 24 h in control group, 24.8 +/- 2.6, 20.5 +/- 1.4 at 12, 24 h in treated group, p< 0.05). The early decline in serum Mg2+ and the increase in the amount of Ca2+/Mg2+ immediately following brain trauma uncovered by these findings suggest that they may be a critical factor in the development of irreversible tissue injury. If this proves to be the case, treatment with MgSO4 may be effective in improving histological findings following experimental traumatic brain injury in rats.
Animals ; Apoptosis/*drug effects ; Axons/*pathology ; Brain Injuries/blood/*drug therapy/pathology ; Calcium/blood ; Magnesium/blood/*therapeutic use ; Rats ; Rats, Sprague-Dawley

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

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