Chronic cerebral hypoperfusion leads to white matter injury (WMI), which subsequently causes neurodegeneration and even cognitive impairment. However, due to the lack of treatment specifically for WMI, novel recognized and effective therapeutic strategies are urgently needed. In this study, we found that honokiol and magnolol, two compounds derived from Magnolia officinalis, significantly facilitated the differentiation of primary oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes, with a more prominent effect of the former compound. Moreover, our results demonstrated that honokiol treatment improved myelin injury, induced mature oligodendrocyte protein expression, attenuated cognitive decline, promoted oligodendrocyte regeneration, and inhibited astrocytic activation in the bilateral carotid artery stenosis model. Mechanistically, honokiol increased the phosphorylation of serine/threonine kinase (Akt) and mammalian target of rapamycin (mTOR) by activating cannabinoid receptor 1 during OPC differentiation. Collectively, our study indicates that honokiol might serve as a potential treatment for WMI in chronic cerebral ischemia.
Magnolia ; White Matter ; Brain Ischemia/metabolism* ; Oligodendroglia/metabolism*

Cerebral metabolism can be divided into basal and active metabolism. Active electroencephalogram(EEG) represents electrophysiologic activity of the brain and become flat when such an activity is abolished. Hypothermia can protect ischemic cerebral damage by reducing cerebral metabolic rate. Profound hypothermia could induce a slow or flat EEG. It can be assumed that the cessation of brain electrical activity appear far faster in the case of cerebral ischemia combined with brain cooling than simple ischemia. To prove this assumption, we carried out this study to determine if selective brain cooling shortens time to onset of a flat electroencephalogram(EEG) after cerebral ischemia. Rabbits were anesthetized with halothane and oxygen. Brain was selectively cooled by intracarotid infusion with saline at 37degrees C (normothermic group) and 18degrees C (hypothermic group). Cerebral ischemia was induced for 2 minutes with a simultaneous clamping of contralateral carotid artery and induced hypatension. In 22 of 28(79%) episodes a flat EEG was identified, and occurred an average 10+/-1 sec in the hypothermic group, 14+/-I sec in the normothermic group. Time to onset of a flat EEG was significantly faster in the hypothermic group than normothermic group(p=0.02). These pattems may be recognized as an indication of metabolic suppression of hypothermia during cerebral ischemia.
Brain Ischemia ; Brain* ; Carotid Arteries ; Constriction ; Electroencephalography* ; Halothane ; Hypothermia ; Ischemia ; Metabolism ; Oxygen ; Rabbits

AIMTo observe the effect of nonselective nitro oxide synthase inhibitor N(G)-nitro-L-arginine(L-NA) on mitochondria injury in focal cerebral ischemia rats.

METHODSThe rats were randomly divided into sham, ischemia and L-NA treatment group. The model of focal cerebral ischemia was prepared with thread embolism in rats. L-NA was administrated respectively at 2 h, 6 h, 12 h after middle cerebral artery occlusion (MCAO). Rats were killed and the mitochondria of cerebral tissue were isolated by differential centrifugation after L-NA treatment for 3 days. The swelling and the activity of mitochondria, and the activities of ATPase, SOD, GSH-Px in mitochondria and the contents of NO, MDA in mitochondria were measured. Ultrastructure changes of neuronal mitochondria were examined by electronic microscope in ischemia and L-NA treatment group.

RESULTSThe swelling of mitochondria was markedly increased and the activity of mitochondria was decreased, and the contents of mitochondria NO and MDA were markedly increased, the activity of ATPase, SOD and GSH-Px in mitochondria were decreased significantly after MCAO. Compared with ischemia group, the contents of NO were decreased after ischemia 2h, 6h, 12h administered by L-NA, and the swelling of mitochondria was decreased and the activity of mitochondria was increased, and the activities of ATPase, SOD, GSH-Px in mitochondria were enhanced and the contents of MDA in mitochondria were decreased after ischemia 12 h administered by L-NA. The neuronal cytoplasm and the mitochondria swelled, the cristae were disrupted, dissolved or disappeared in MCAO rats. Administration of L-NA could reduce these changes induced by cerebral ischemia in rats.

CONCLUSIONIt could be concluded that L-NA could beneficially inhibit NO production. But it could't protect brain against damage in ischemia acute stage. It could improve mitochondria energy pump, ameliorate oxidative injury and increase the activities of mitochondria during postischemia, and then could effectively protect brain against damage induced by focal cerebral ischemia.

Animals ; Arginine ; pharmacology ; Brain ; metabolism ; Brain Ischemia ; metabolism ; pathology ; Male ; Mitochondria ; metabolism ; pathology ; Rats ; Rats, Wistar

Using a rat model, this study examined the cerebral protective effect of moderate hypothermia and evaluated the effect on early local metabolic change of permanent focal cerebral ischemia. The middle cerebral artery(MCA) of the rat was approached subtemporally and was occluded, and its surface was cooled. Cerebral infarct size was measured at 1, 4 and 7 days after MCA occlusion in non-treated(n=27), 2-hour hypothermia(n=27) and 3-hour hypothermia(n=27) group, respectively, and regional cerebral glucose uptake(rCGU) was determined at 1 and 4 hour after MCA occlusion in the non-treated(n=8) and 3-hour hypothermia(n=8) group, respectively. Infarct size measured at 1, 4 and 7 days after MCA occlusion was 22.2%+/-4.4%, 14.3%+/-6.6%, 13.7%+/-5.3% in the non-treated group, 19.6%+/-10.0%, 12.5%+/-6.2%, 12.0%+/-6.9% in the 2-hour hypothermia group and 12.9%+/-5.6%, 8.3%+/-3.3%, 8.2%+/-2.3% in the 3-hour hypothermia group. In the 2-hour hypothermia group, no significant size reduction was seen, but in the 3-hour hypothermia group, infarct size had decreased to half of that of the non-treated group(p<0.05). This protective effect was observed untill 1 week after MCA occlusion. rCGU in the non-treated group measured at 1 hour after MCA occlusion had increased in the periphery of the ischemic core, but at 4 hours, periischemic hypermetabolism had disappeared and the area of low metabolism in the center had become larger. rCGU in the 3-hour hypothermia group measured at 1 hour after MCA occlusion(BT 26degreesC) showed a uniform decrease in all regions, supressing temporary periischemic hypermetabolism, and at 4 hours(BT 37degreesC) after occlusion, hypermetabolism was not prominent and the area of low metabolism in the center had narrowed. This study indicates that 3 hour moderate hypothermia immediately after MCA occlusion significantly reduces infarct size, and that this protective effect was associated with suppression of periischemic hypermetabolism occurring around 1 hour after MCA occlusion.
Animals ; Brain Ischemia* ; Glucose* ; Hypothermia* ; Metabolism ; Models, Animal ; Rats*

This study investigated the effect of Xiaoxuming Decoction(XXMD) on the activation of astrocytes after cerebral ischemia/reperfusion(I/R) injury. The model of cerebral IR injury was established using the middle cerebral artery occlusion method. Fluorocitrate(FC), an inhibitor of astrocyte activation, was applied to inhibit astrocyte activation. Rats were randomly divided into a sham group, a model group, a XXMD group, a XXMD+FC group, and a XXMD+Vehicle group. Neurobehavioral changes at 24 hours after cerebral IR injury, cerebral infarction, histopathological changes observed through HE staining, submicroscopic structure of astrocytes observed through transmission electron microscopy, fluorescence intensity of glial fibrillary acidic protein(GFAP) and thrombospondin 1(TSP1) measured through immunofluorescence, and expression of GFAP and TSP1 in brain tissue measured through Western blot were evaluated in rats from each group. The experimental results showed that neurobehavioral scores and cerebral infarct area significantly increased in the model group. The XXMD group, the XXMD+FC group, and the XXMD+Vehicle group all alleviated neurobehavioral changes in rats. The pathological changes in the brain were evident in the model group, while the XXMD group, the XXMD+FC group, and the XXMD+Vehicle group exhibited milder cerebral IR injury in rats. The submicroscopic structure of astrocytes in the model group showed significant swelling, whereas the XXMD group, the XXMD+FC group, and XXMD+Vehicle group protected the submicroscopic structure of astrocytes. The fluorescence intensity and protein expression of GFAP and TSP1 increased in the model group compared with those in the sham group. However, the XXMD group, the XXMD+FC group, and XXMD+Vehicle group all down-regulated the expression of GFAP and TSP1. The combination of XXMD and FC showed a more pronounced effect. These results indicate that XXMD can improve cerebral IR injury, possibly by inhibiting astrocyte activation and down-regulating the expression of GFAP and TSP1.
Rats ; Animals ; Astrocytes ; Brain Ischemia/metabolism* ; Brain ; Reperfusion Injury/metabolism* ; Infarction, Middle Cerebral Artery

Immunohistochemistry and double immunofluorescent labeling techniques combined with confocal laser scanning microscope analysis were used to investigate the characteristic spatial induction profile of nestin following a transient middle cerebral artery occlusion in adult rat brain. The results showed that nestin was induced in ischemic core at 1 day after reperfusion. In addition to ischemic core, the expression of nestin increased in peri-ischemic I, II and III regions at 3 days and 1 week, then it decreased and narrowed along the rim of ischemic core 2 weeks after reperfusion. Double immunofluorescent labeling showed that nestin positive cells were mostly co-stained with GFAP,a astrocyte marker, in peri-ischemic I region 3 days after reperfusion. At 2 weeks, however nestin cells showed a long process and the cells double stained with nestin and NSE,a neuonal specific marker,increased in the ischemic brain. The results suggest that cerebral ischemia induces nestin expression in damaged neurons which might favor the neuroprotection against ischemic damage.
Animals ; Brain ; metabolism ; pathology ; Brain Ischemia ; metabolism ; pathology ; Immunohistochemistry ; Infarction, Middle Cerebral Artery ; metabolism ; pathology ; Nestin ; metabolism ; Neurons ; metabolism ; Rats

Based on the findings recently reported, cysteinyl leukotriene receptors, both CysLT (1) and CysLT(2) receptors, are involved in the ischemic and traumatic brain injury in vivo. CysLT(1)receptor regulates the increased permeability of blood-brain barrier and the related vasogenic brain edema, astrocyte proliferation, and inflammatory responses after brain ischemia; while CysLT(2)receptor regulates AQP4 expression and the related cytotoxic brain edema, and astrocyte injury. A new subtype of CysLT receptor, GPR17, is also involved in brain ischemic injury. The roles of CysLT receptors in brain injury or neuroprotection from the injury should be further understood. This understanding is necessary to accelerate the screening and development of the new drugs for the prevention and treatment of brain injury with the receptors as therapeutic targets.
Aquaporin 4 ; metabolism ; Brain Injuries ; metabolism ; Brain Ischemia ; metabolism ; Humans ; Receptors, G-Protein-Coupled ; metabolism ; Receptors, Leukotriene ; metabolism

OBJECTIVEThis study examined the changes of regional cerebral oxygen saturation (rSO2) by noninvasive near infrared spectrophotometry in neonates with meconium aspiration syndrome (MAS).

METHODSSeventy-three full neonates with MAS were divided into three groups by respiratory symptoms: asymptomatic group (group 1, n=38), common group (group 2, n=28) and severe group (group 3, n=7). Near infrared spectrophotometry was used to measure the cerebral rSO2 on days 1, 3, 5 and 7 after birth. Thirty healthy full-term newborns served as the Control group.

RESULTSThe cerebral rSO2 of group 1 decreased significantly compared with that of the Control group between days 1 and 3 (P < 0.05). The cerebral rSO2 of group 2 or group 3 was significantly lower than that of group 1 and the Control group on days 1, 3 and 5 (P < 0.05). The MAS patients with mild hypoxic-ischemic encephalopathy (HIE) had significantly higher brain rSO2 levels than those with medium or severe HIE on days 2, 3 and 5 (P < 0.05).

CONCLUSIONSThe cerebral rSO2 decreased in neonates with MAS. The values for rSO2 correlated with the severity of HIE in MAS patients.

Brain ; metabolism ; Female ; Humans ; Hypoxia-Ischemia, Brain ; metabolism ; Infant, Newborn ; Male ; Meconium Aspiration Syndrome ; metabolism ; Oxygen ; metabolism ; Spectroscopy, Near-Infrared

OBJECTIVETo investigate the mRNA expression of monocarboxylate transporter 8 (MCT8), a thyroid hormone transport protein, in the lateral ventricle of rats with cerebral ischemia.

METHODSImmunofluorescence staining was used to observe the expression of MCT8 in the lateral ventricle of 5 normal SD rats. Another 20 adult male SD rats were randomized into 4 groups and subject to permanent ligation of both the common carotid arteries (2-vessel occlusion, 2VO) for 3 days, 2 weeks, or 5 weeks, or no ligation (control). At the end of the experiment, the transcriptional level of MCT8 in the brain tissue of the rats were detected using fluorescent quantitative PCR.

RESULTSMCT8 mRNA levels in 3-day and 2-week 2VO groups were comparable with that in the control group (P=0.909; P=0.694), but increased significantly in 5-week 2VO group compared with that in the control and 3-day 2VO groups (P=0.029; P=0.023). No significance was found in MCT8 mRNA between the 2-week and 5-week 2VO groups (P=0.065).

CONCLUSIONProlonged cerebral ischemia causes compensatory increase of MCT8 mRNA expression on the capillary endothelial cell membranes in the lateral ventricle of rats.

Animals ; Brain ; metabolism ; Brain Ischemia ; metabolism ; Cerebral Infarction ; metabolism ; Male ; Monocarboxylic Acid Transporters ; metabolism ; Rats ; Rats, Sprague-Dawley

Animals ; Brain Chemistry ; Brain Ischemia ; metabolism ; physiopathology ; Cerebral Cortex ; metabolism ; Dementia ; metabolism ; physiopathology ; Humans ; Microdialysis ; Reperfusion Injury ; metabolism ; physiopathology