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

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*

Ischemia is the most common and important cause of injury to cardiomyocytes. Acute ischemia causes profound derangement of the cellular energetics and metabolism, and this ultimately leads to cell death. Experimental studies have demonstrated the presence of an endogenous protective mechanism that can diminish or delay cell death from ischemic insult; this is known as ischemic preconditioning. In this review, we summarize the recent knowledge of the cellular biology of acute ischemic injury and also signaling mechanisms of cardioprotection that are involved in preconditioning. Further, we briefly discuss the clinical implications.
Cell Death ; Ischemia* ; Ischemic Preconditioning ; Metabolism ; Myocytes, Cardiac*

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

OBJECTIVETo observe the electroacupuncture (EA) pretreatment at Baihui (GV20) on the concentration of adenosine deaminase (ADA) and adenosine, and to evaluate its effects on the neurologic function score and the infarction volume after middle cerebral artery occlusion (MCAO) ischemia/reperfusion (I/R), thus exploring its mechanisms for relieving the ischemia/reperfusion injury.

METHODSTotally 54 male SD rats were randomly divided into 3 groups, the sham-EA group, the EA group, and the control group, 18 in each group. Rats in the control group were not intervened after anesthesia. Rats in the EA group were needled at Baihui (GV20) for 30 min. Rats in the sham-EA group received the same procedure as those performed in the EA group without electricity connected. The changes of adenosine and ADA contents were detected at 30, 60, and 120 min after EA respectively. The I/R model was established. Totally 48 male SD rats were randomly divided into 6 groups, i.e., the model group (Group A), the EA group (Group B), the EA +8-Cyclopentyl-1,3-dipropylxanthine (DPCPX) group (Group C), the EA + DMSO group (Group D), the Deoxycoformycin (Deo) group (Group E), and the normal saline group (Group F). Rats in Group B, C, and D received EA for 30 min before modeling. Rats in Group C and D were peritoneally injected with DPCPX (1 mg/kg) and DMSO (1 mL/kg) at 30 min before EA. The neurologic function score was evaluated and the infarct volumes were detected after 24-h reperfusion.

RESULTSCompared with the sham-EA group, there was no statistical difference in the contents of the adenosine or ADA in the control group at each time point (P > 0.05). Compared with the control group at the same time point, the content of ADA significantly decreased at 60 min in the EA group [(315.0 +/- 22.9 U/L), P < 0.05], and restored to the normal level at 120 min after EA. The content of adenosine increased in the EA group at 120 min [(20.4 +/- 2.2) ng/microL, P < 0.05]. Compared with the model group, the neurologic function score decreased (P < 0.05) and the infarct volumes were obviously reduced (P < 0.01) in Group B, D and E. There was no statistical difference in the neurologic function score or the infarct volumes in other groups, when compared with the model group (P > 0.05)

CONCLUSIONEA at Baihui (GV20) showed protective effects on the cerebral I/R rats, which might be achieved through lowering the ADA concentration and elevating the adenosine content, and further activating adenosine A1 receptor.

Adenosine Deaminase ; metabolism ; Animals ; Brain Ischemia ; metabolism ; Electroacupuncture ; Male ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; metabolism

Mitochondria play a key role in various cell processes including ATP production, Ca homeostasis, reactive oxygen species (ROS) generation, and apoptosis. The selective removal of impaired mitochondria by autophagosome is known as mitophagy. Cerebral ischemia is a common form of stroke caused by insufficient blood supply to the brain. Emerging evidence suggests that mitophagy plays important roles in the pathophysiological process of cerebral ischemia. This review focuses on the relationship between ischemic brain injury and mitophagy. Based on the latest research, it describes how the signaling pathways of mitophagy appear to be involved in cerebral ischemia.
Animals ; Brain Ischemia ; metabolism ; pathology ; Humans ; Mitochondrial Degradation ; Reactive Oxygen Species ; metabolism ; Stroke ; metabolism ; pathology

OBJECTIVE: To explore the effect of Kuanxiong Aerosol (KXA) on isoproterenol (ISO)-induced myocardial injury in rat models. METHODS: Totally 24 rats were radomly divided into control, ISO, KXA low-dose and high-dose groups according to the randomized block design method, and were administered by intragastric administration for 10 consecutive days, and on the 9th and 10th days, rats were injected with ISO for 2 consecutive days to construct an acute myocardial ischemia model to evaluate the improvement of myocardial ischemia by KXA. In addition, the diastolic effect of KXA on rat thoracic aorta and its regulation of ion channels were tested by in vitro vascular tension test. The influence of KXA on the expression of calcium-CaM-dependent protein kinase II (CaMK II)/extracellular regulated protein kinases (ERK) signaling pathway has also been tested. RESULTS: KXA significantly reduced the ISO-induced increase in ST-segment, interventricular septal thickness, cardiac mass index and cardiac tissue pathological changes in rats. Moreover, the relaxation of isolated thoracic arterial rings that had been precontracted using norepinephrine (NE) or potassium chloride (KCl) was increased after KXA treatment in an endothelium-independent manner, and was attenuated by preincubation with verapamil, but not with tetraethylammonium chloride, 4-aminopyridine, glibenclamide, or barium chloride. KXA pretreatment attenuated vasoconstriction induced by CaCl₂ in Ca²⁺-free solutions containing K⁺ or NE. In addition, KXA pretreatment inhibited accumulation of Ca²⁺ in A7r5 cells mediated by KCl and NE and significantly decreased p-CaMK II and p-ERK levels. CONCLUSION KXA may inhibit influx and release of calcium and activate the CaMK II/ERK signaling pathway to produce vasodilatory effects, thereby improving myocardial injury.
Aerosols ; Animals ; Aorta, Thoracic ; Calcium/metabolism* ; Endothelium, Vascular/metabolism* ; Myocardial Ischemia/metabolism* ; Rats ; Vasodilation

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