Among the molecules that regulate microglial activation is the chemokine CX3CL1 (fractalkine), which is constitu- tively expressed by normal neurons. CX3CL1 signals to microglia by binding to only one receptor, CX3CR1, whose function is to inhibit microglial activity [8,9]. In the brain, the CX3CR1 receptor is exclusively expressed by microglia  and when neuronal damage occurs, fractalk- ine levels decrease in the immediate hours after injury, which then decreases CX3CR1 receptor signaling result- ing in the recruitment and activation of microglia . Over the last few years, there has been increasing interest in the role of fractalkine in central nervous system injury. For example, the importance of the fractalkine/CX3CR1 pathway in neurological disorders has been assessed using an animal model wherein the cx3cr1 gene is substituted with the gene for the green fluorescent protein (GFP) pro- ducing a defective receptor for fractalkine . Using this animal model, studies on lateral amyotrophic sclerosis , Parkinson’s disease , and Alzheimer’s disease  report that the absence of CX3CR1 is associated with a worse outcome possibly due to the lack of fractalkine con- trol of microglial activation leading to chronic proinflam- matory function . However, others also report that in transient and permanent ischemia as well as spinal cord injury, absence of CX3CR1 result in favorable outcome after injury [16-18]. These conflicting data to date do not provide a coherent picture on the role of fractalkine in brain injury and disease. Moreover, little information is available on fractalkine/CX3CR1 signaling in the context of persistent neuroinflammation as a chronic consequence of transient globalcerebralischemia. We hypothesize the direct involvement of CX3CR1 functioning in ischemia- induced persistent neuroinflammation and cognitive im- pairment. Here, we study the role of CX3CR1 on transient globalcerebralischemia-induced chronic neuroinflamma- tion and cognitive function using small interfering RNA (siRNA).
Induction of GlobalCerebralIschemia: Mice were anesthetized by using chloral hydrate (400 mg/kg, i.p). A midline ventral incision was made in the neck to expose the right and left common carotid arteries, which were isolated from surrounding tissue and vagus nerve. A cotton thread was passed below both the carotid arteries. Globalcerebralischemia was induced by occluding the carotid arteries. After 17 min of globalcerebralischemia, reperfusion was allowed for 24 h. The incision was sutured back in layers. The sutured area was cleaned with 70% ethanol and was sprayed with antiseptic dusting powder.
with BCCAO for different time intervals makes it difficult to identify the optimum duration of experimental ischemia required in this model to cause significant cerebral injury without causing very high mortality. This also makes it difficult to compare and evaluate the effectiveness of various interventional research studies on cerebralischemia since the effect produced by such interventions is subjectively dependent on the neuronal damage caused by the model in the first place. The present study was therefore designed to study the influence of time dependent ischemic duration on cerebral injury caused by experimentally induced transient globalcerebralischemia using BCCAO in Wistar rats.
Transient GlobalCerebralIschemia (GCI) is a cerebrovascular condition dramatically reducing cerebral blood flow leading to a selective and delayed pyramidal neuronal death in the hippocampal CA1 area. Herbal medications and their active ingredients are a potential source for finding new remedies to improve cognitive and neurological deficits that occur following GCI. Several studies supported the anti-inflammatory, antioxidant, and neuroprotective effects of curcumin as an active constituent of turmeric. Because of its biological properties, curcumin is an appropriate can- didate for improving injuries after brain ischemia. This study is an attempt to assess the acute and chronic effects of curcumin on the spatial neuronal distribution in CA1 area and on the neurological symptoms and memory impairment after GCI. Experiments were conducted on 56 adult male Sprague Dawley rats. Based on the results, a high dose of curcumin (100 mg/kg) and its long-term administration (28 days) showed a greater effect on memory function, neuro- logical deficits, and regular neuronal aggregation in the CA1 hippocampal region after GCI.
The results of the therapeutic effects of policosanol and FO on neurological symptoms assessed at 1, 3 and 7 days of induced globalcerebralischemia in Mongolian gerbils are shown in Table 1. Bilateral occlusion of both carotid arteries for 5 min and 24 h of reperfusion produced neurological symptoms in the positive control group with a score that was significantly higher than the negative control group, which had no symptoms at all times evaluated. Oral administration with aspirin (60 mg/kg), the reference substance, markedly and significantly reduced the neurological symptoms score (92.1, 90.4 and 90% inhibition, respectively) at 1, 3 and 7 days respectively, which demonstrates the validity of the model in our experimental conditions.
Ischemia and reperfusion in the brain brings a inflammating reaction that is possibly exacerbating primary stages of tissue wound. This study has been undertaken to inspect the potential neuroprotective action of cineol in the improvement of inclusive analytical I/R injury in rat model via interfering with inflammation. Twenty four adult Swiss albino rats had been chosen randomly in groups. For 1 st group (sham group), rats endured the similar surgical and anesthesia processes as the controller group with no bilateral common carotid artery occlusion (BCCAO). While for 2 nd control group (induced-untreated), rats endured half hour of globalcerebralischemia via BCCAO and then one hour of reperfusion. For 3 rd group (Control – Vehicle), as controller collection but rats are taken day-to-day the vehicle of 1.8-cineol (10 mL/kg of 2% Tween 80 solution), p.o., then anesthesia and surgery with BCCAO for half hour followed by reperfusion for 1 hr were done. For 4 th Group (1,8-cineol treated group), the rats received 1,8-cineol. The dose of 1,8- cineole was 100 mg/kg per oral (po) 1 h before induction ischemia. Then, anesthesia and surgery with BCCAO for 30 min, followed by reperfusion for 1 hr were done. Compared with the sham group, levels of IL-6 and TNF-α increased significantly (p< 0.05). The study results disclose that pretreating process with cineol possibly will enhance the overall cerebralischemia-reperfusion injury by anti-inflammatory influence. We concluded that inflammatory cytokines are involved in globalcerebralischemia due to BCCAO effect. Cerebralischemia reperfusion injury can be modified by cineol via its anti inflammatory effect.
It is increasingly clear that physiological doses of isoflavones, which can behave as phytoestrogens, can mimic some of the neuroprotective effects of estrogens. [16-18]. In vitro some soy isoflavones can protect pri- mary neurons from glutamate toxicity , thapsigar- gin-induced apoptosis , and -amyloid toxicity . Several studies have indicated that genistein admini- stration prevents delayed neuronal death after transient globalcerebralischemia , inhibits the lipid peroxi- dation induced by pro-oxidant agents in cultured corti- cal neurons  and attenuates the oxidative stress and neuronal damage following cerebralischemia in rat hippocampus . However, the mechanisms underly- ing protection from ischemic injury remain unclear. Recently, Schreihofera and Redmond,  have shown that pre-treatment with dietary levels of soy phytoes- trogens can mimic neuroprotective effects observed with estrogen. Nevertheless, in all these works estrogen and phytoestrogens have been studied as neuroprotec- tive agents but it has not been studied their possible effects on neurorepair in post-ischemic period, in spite that it is in this time when protection is necessary after an ischemical event. The present study was performed to test the ability of the phytoestrogen genistein to in- hibit neuronal death in the post-ischemic period and to obtain further evidence about the molecular mecha- nisms by which phytoestrogens exercise these potential neuroprotective and neurorepairing effects. The study has been performed by using cortical neurons in pri- mary cultures subjected to oxygen-glucose deprivation (OGD), since this has been proved to be a good model to test the mechanisms of neuroprotective agents in brain ischemia. Our results suggest that genistein may protect neurons from OGD in the post-ischemic period by attenuating oxidative stress, lipid peroxidation, and necrotic and autophagic cell death.
called "first line of defense" against reaction- active free oxygen forms . Previously con- ducted experiments allowed to determine po- tential cerebral-protective effects produced by a new pyrimidine derivative with a laboratory cipher PIR-10 when globalcerebralischemia was simulated . Experts have also examined influences exerted by some substances belong- ing to pyrimidine group on the AOP system [9, 10]. Hence we can assume that this derivative of pyrimidine-4(1H)-on has some antioxida- tion properties as a possible action mechanism that can help to considerably improve the epi- demiologic situation as regards pathologies related to cerebral circulation disorders as well as substantially facilitate management of ische- mic stroke risks.
Ischemia is defined as diminution of cerebral blood flow to a critical threshold that propagates brain damage involving the entire brain or a selective region. Globalcerebralischemia entails diminution in cerebral blood flow over the entire brain, encountered clinically as sequelae during extracorporeal circulation following cardiac arrest from ventricular fibrillation or asystole that lasts 5 to 10 min. Globalischemia from cardiac arrest results in a predictable pattern of histologic injury in which specific neuronal populations are affected (selective ischemic necrosis). Although reperfusion restores cerebral blood flow, it can lead to secondary brain injury from influx of neutrophils and to increases in ROS, cerebral edema and hemorrhage. Elevated levels of ROS may lead to damage of intracellular proteins and DNA by way of oxidation and by activating a number of pathways that lead to cell death .
required for effective antioxidant intervention and for enlarging our knowledge of the pathophysiological mechanisms of cerebralischemia. The temporal profile of histopathological changes in the gerbil brain following globalischemia has been extensively characterized, showing no neuronal loss up to 2-3 days of reperfusion but an extensive delayed neuronal loss at 5-7 days of reperfusion in the hippocampal CA1 region (Kirino, 1982; Rao et al., 2000; Martínez et al., 2001; Candelario-Jalil et al., unpublished data). Although ROS have been postulated to play an important role in the progression of reperfusion injury, the time course of oxidative damage following transient forebrain ischemia has been poorly characterized. In the present study, we have examined the time course of oxidative injury in different brain regions following transient globalcerebralischemia in gerbils. Further, the antioxidant capacity in each brain area was studied at different sampling times after the ischemic insult in view that oxidative stress may result not only from an increase in free radical production but also from a decrease in cellular antioxidant mechanisms. To our knowledge, the time course of the activity of glutathione- related enzymes as well as the content of both GSH and GSSG following transient forebrain ischemia in gerbils had not been previously characterized.
unconscious, then placed in supine position and exposed to light source to keep it worm. After that a midline ventral small skin incision in the neck was made and the paratracheal muscles and fascia were splitted and pulled by stay sutures to expose the trachea, carotid arteries and vagal nerves. Both common carotid arteries were exposed, with special attention paid to separate and preserve the vagus nerve fibers and globalcerebralischemia was induced by BCCAO 16 by using vascular clamps for 30 min.
Globalcerebralischemia in rat model used in this study resembles one of the heterogeneous groups of processes in ischemic stroke which is accounted for 85% of all strokes. Other category of strokes such as intracerebral bleeding (hemorrhagic stroke) accounts for the remainder (Beal et al., 2010). In the present study Gymnemic acid was evaluated for neuroprotective activity in bilateral common carotid artery occlusion induced globalcerebralischemia. In order to support neuroprotective property various biochemical parameters were evaluated. It has showed in literature that globalcerebralischemia produced of carotid artery occlusion and histopathological observations were made, the marked destruction of different lobes and cells of brain were seen (Oisson et al., 2003). The ischemic parts were confirmed by staining different regions of brain with hematoxylin and eosin stains.
In these six patients, the appearance demonstrated on DW images is analogous to the “superscan” in the nuclear medicine literature that describes an appear- ance of diffuse skeletal metastases on a radionuclide bone scan where the skeletal signal is prominent when compared with the soft tissue and kidney up- take (24). Conceptually, this imaging appearance is similar to the cases presented in this study, in which globalcerebralischemia causes diffuse injury to the cerebral cortex, and the cortical gray–white matter differentiation is accentuated on the T2-weighted and FLAIR images (in the early subacute phase), but is much more visually apparent on properly windowed DW images. Hence, the brain can appear deceptively normal to the unaware observer on improperly win- dowed DW images (due to the uniform and symmet- ric cortical hyperintensity); although even in the sce- nario of improper windowing, the observer should note that the gray–white matter differentiation is ab- normally accentuated. Arbelaez et al (3) previously speculated that this potential imaging pitfall could occur in the transition between the late acute and subacute stages. In particular, in the early subacute phase after the anoxic event (likely around 24 –72 hours, based on the current study), there may be a paucity of findings on CT scans or even on other MR images, and the DW imaging appearance described herein may be predictive of diffuse cortical laminar necrosis in the setting of HIE and, hence, predictive of the clinical outcome of either permanent vegeta- tive state or brain death.
activated protein kinases, and to improve neurological deficits in models of both focal and globalcerebralischemia [6,44,45]. Most experimental studies have documented improved functional performance when neuroprotective agents were given before the insult. In patients with cardiac arrest, however, pretreatment is virtually impossible because of the unpredictable onset of ischemia. Therefore, as in our study, potential protec- tive interventions should be initiated during or after experimental ischemia to affect reperfusion injury. In this context, pharmacological postconditioning with volatile anesthetics in addition to mild hypothermia may offer an attractive opportunity to further ameliorate brain damage and inflammation in the post-resuscitation period. The effects of volatile agents on the inflamma- tory response after cardiac arrest have not yet been elu- cidated. In endotoxemic rats, inhalation of sevoflurane significantly attenuated plasma levels of TNFa and IL- 1b . In addition, sevoflurane post-conditioning showed anti-inflammatory and anti-necrotic effects in cultured kidney proximal tubule cells , and sevoflur- ane attenuated the inflammatory response upon stimula- tion of alveolar macrophages with endotoxin in vitro . In our study, however, sevoflurane administered instead of propofol during reperfusion after successful CPR did not further attenuate local cerebral inflamma- tory response. These observations are comparable to those obtained in a study by Fries et al. where the vola- tile anesthetic isoflurane did not reduce neurological dysfunction and histopathological alterations induced by cardiac arrest . However, it is conceivable that hypothermia alone has such potent anti-inflammatory properties compared to normothermia, that an addi- tional effect of sevoflurane could not be revealed in the present study. Moreover, potential protective effects of volatile anesthetics depend on energy-dependent signal transduction, for example, protein synthesis and phos- phorylation , that may be affected by hypothermia- induced decrease of metabolic rate as well as suppres- sion of protein synthesis.
appears that during severe hemorrhagic shock cerebral energy metabolism is severely compromised exhibiting a biochemical pattern typical of ischemia. Further, if hypotension is protracted and severe enough, cerebral energy metabolism may not be restored after transfusion. In the present experimental study, the biochemical pattern and the progressive increase of ICP indicated permanent cerebral lesions. The present experimental model was chosen because it creates reproducible severe globalcerebralischemia. However, the chosen hypotensive level of MAP around 35 mmHg is some- what lower that the recommendations by the European Society for Intensive Care Medicine expert panel . It is therefore important to stress that the present study cannot be used to determine the optimal level of MAP after hemorrhagic shock. The purpose of the present study was solely to establish a technique for “non-cranial” inva- sive monitoring of cerebral energy state. As shown in Table 2, there is a quantitative discrepancy in the LP ratio between the cerebral microdialysis probe and the one placed in the sinus. This suggests a “washout” effect. The degree of metabolic derange- ment in the present study was severe. In a clinical setting, e.g., after cardiac standstill, a less pronounced metabolic derangement will be expected. Accordingly, it might not be possible to detect minor metabolic derangements in the venous jugular bulb due to the washout effect. Future clinical studies are needed to determine this.
The recognition that crucial events in the pathogenesis of ischemic brain injury are set into motion at critical thresholds of reduced ce- rebral blood flow (CBF) constitutes a seminal conceptual advance with broad ramifications (see Hossman  for a recent review). In pa- tients undergoing carotid endarterectomy, it was first observed that CBF reductions to ap- proximately one third of normal (from about 0.5 to 0.16 or 0.17 mL/g per minute) led to elec- troencephalographic flattening (2, 3). Studies in baboons with acute middle cerebral artery (MCA) occlusion substantiated that cortical so- matosensory evoked potentials ceased when CBF fell to 0.15 to 0.20 mL/g per minute (4). Microelectrode measurements, however, re- vealed that this suppression of evoked re- sponses was not caused by altered extracellular [K 1 ] or [H 1 ] levels, because massive elevations of extracellular [K 1 ] were observed only at much lower CBF (approximately 0.06 to 0.10 mL/g per minute). These findings thus pointed toward dual thresholds in ischemia: the higher one (approximately 35% of normal CBF) for functional suppression (ie, failure of synaptic transmission), and the lower one (at approxi- mately 15% to 20% of normal CBF) for major
NEUROTOXICITY OF ZINC IN ISCHEMIA Tonder and colleagues (9) conducted the first study providing indirect evi- dence for the toxic translocation of zinc from presynaptic neurons into selective postsynaptic neurons during the experi- mental paradigm of globalischemia. TSQ (N-[6-methoxy-8-quinolyl]-P- toluenesulfonamide) and acid fuschin staining were used in conjunction to compare changes in zinc staining with the occurrence of degenerating or aci- dophilic cells between 2 and 24 h post- ischemia. Although degeneration of the cornu ammonis 1 (CA1) subfield was not observed due to the acute survival pe- riod of this study, the distribution of TSQ-cell stained bodies of CA4, which were observed as soon as 2 h post- ischemia, corresponded with the distri- bution of degenerating neurons observed beginning at 18 h post-ischemia. The concomitant decrease in TSQ fluores- cence of the mossy fiber terminals and the intracellular accumulation in the CA4 neurons strongly implicated the toxic translocation of zinc.
Abstract: Objective: Decocted turtle shell pill is a traditional Chinese medicine used for promoting blood circulation and removing blood stasis. The effect of decocted turtle shell pills on acute cerebral thrombosis was examined in 30 cases of cerebral ischemic infraction patients. Method: Sixty patients confirmed with cerebral thrombosis by clinical and imaging examinations were randomly divided into test group (n=30) and control group (n=30). Patients in con- trol group were treated with standard procedure according to guidelines; while patients in test group took decocted turtle shell pills in addition to the standard procedure basis. Treatment efficiency was compared between the two groups at 1 week, 1 month and 3 months after stroke onset; neurological deficit (ND) score and activities of daily living (ADL) score after treatment for 3 months, and laboratory indicators after 1 month of treatment. Results: No significant difference was observed after 1 week of treatment (P>0.05, for all observed indicators). After treatment for 3 months, ND score and ADL score of patients receiving decocted turtle shell pill were significantly improved than control. Triglyceride, cholesterol and fibrinogen level were significantly decreased compared with control group. Conclusion: Addition of decocted turtle shell pills based on standard procedure helps acute stoke patients recover by relieving neurological deficit and improving daily living activities.
Catalpol and puerarin are active ingredients isolated from Rehmannia glutinosa Libosch and Radix Puerariae, respectively. They are popular in research for their poly-pharmacological effects. This research focused on effect of anti-stroke by lyophilized powder of catalpol and puerarin (C-P) and potential mechanisms. At the beginning of research, C-P was identified and analyzed by HPLC. Neurological function was evaluated by Longa score, neurological complex function score and beam balance score after permanent middle cerebral artery occlusion (PMCAO) in mice. Infarct volume and water content were evaluated after treatment of C-P. Anti-oxidative stress, an- ti-apoptosis, angiogenesis and neurogenesis were investigated by ELISA, WB and immunohisto- chemical stain respectively. With treatment of C-P, neurological deficiency of PMCAO mice was ameliorated. Morphologically, infarct volume and water content in ischemic hemisphere were significantly reduced by C-P. In vivo and in vitro, oxidative stress injury was extenuated by C-P. Meanwhile, Caspase-3 was down-regulated and Bxl-2 was up-regulated by C-P in vivo. In addition, C-P enhanced angiogenesis around the infarct of cortex and neurogenesis in the Hippocampal Dentate Gyrus (DG). Hence, C-P ameliorated stroke-induced neurological deficiency through its multiple neuroprotections. What’s more, this article provides us a novel formula of active ingre- dients for stroke.