Ischemic preconditioning reduces ischemic brain injury by suppressing nuclear factor kappa B expression and neuronal apoptosis

Ischemic stroke induces a series of complex pathophysiological events including blood-brain barrier disruption, inflammatory response and neuronal apoptosis. Previous studies demonstrate that ischemic preconditioning attenuates ischemic brain damage via inhibiting blood-brain barrier disruption and the inflammatory response. Rats underwent transient (15 minutes) occlusion of the bilateral common carotid artery with 48 hours of reperfusion, and were subjected to permanent middle cerebral artery occlusion. This study explored whether ischemic preconditioning could reduce ischemic brain injury and relevant molecular mechanisms by inhibiting neuronal apoptosis. Results found that at 72 hours following cerebral ischemia, myeloperoxidase activity was enhanced, malondialdehyde levels increased, and neurological function was obviously damaged. Simultaneously, neuronal apoptosis increased, and nuclear factor-κB and cleaved caspase-3 expression was significantly increased in ischemic brain tissues. Ischemic preconditioning reduced the cerebral ischemia-induced inflammatory response, lipid peroxidation, and neurological function injury. In addition, ischemic preconditioning decreased nuclear factor-κB p65 and cleaved caspase-3 expression. These results suggested that ischemic preconditioning plays a protective effect against ischemic brain injury by suppressing the inflammatory response, reducing lipid peroxidation, and neuronal apoptosis via inhibition of nuclear factor-κB and cleaved caspase-3 expression.     

Endoplasmic reticulum stress-induced apoptosis in the penumbra aggravates secondary damage in rats with traumatic brain injur y

Neuronal apoptosis is mediated by intrinsic and extrinsic signaling pathways such as the membrane-mediated, mitochondrial, and endo-plasmic reticulum stress pathways. Few studies have examined the endoplasmic reticulum-mediated apoptosis pathway in the penumbra after traumatic brain injury, and it remains unclear whether endoplasmic reticulum stress can activate the caspase-12-dependent apoptotic pathway in the traumatic penumbra. Here, we established rat models of lfuid percussion-induced traumatic brain injury and found that protein expression of caspase-12, caspase-3 and the endoplasmic reticulum stress marker 78 kDa glucose-regulated protein increased in the traumatic penumbra 6 hours after injury and peaked at 24 hours. Furthermore, numbers of terminal deoxynucleotidyl transferase-mediat-ed dUTP nick end labeling-positive cells in the traumatic penumbra also reached peak levels 24 hours after injury. These ifndings suggest that caspase-12-mediated endoplasmic reticulum-related apoptosis is activated in the traumatic penumbra, and may play an important role in the pathophysiology of secondary brain injury.     

Neuroprotection by cattle encephalon glycoside and ignotin beyond the time window of thrombolysis in ischemic stroke

Cattle encephalon glycoside and ignotin(CEGI) injection is known as a multi-target neuroprotective drug that contains numerous liposoluble molecules, such as polypeptides, monosialotetrahexosyl ganglioside(GM-1), free amino acids, hypoxanthine and carnosine. CEGI has been approved by the Chinese State Food and Drug Administration and widely used in the treatments of various diseases, such as stroke and Alzheimer's disease. However, the neuroprotective effects of CEGI beyond the time window of thrombolysis(within 4.5 hours) on acute ischemic stroke remain unclear. This study constructed a rat middle cerebral artery occlusion model by suture-occluded method to simulate ischemic stroke. The first daily dose was intraperitoneally injected at 8 hours post-surgery and the CEGI treatments continued for 14 days. Results of the modified five-point Bederson scale, beam balance test and rotameric test showed the neurological function of ischemic stroke rats treated with 4 m L/kg/d CEGI improved significantly, but the mortality within 14 days did not change significantly. Brain MRI and 2,3,5-triphenyltetrazolium chloride staining confirmed that the infarct size in the 4 m L/kg/d CEGI-treated rats was significantly reduced compared with ischemic insult only. The results of transmission electron microscopy and double immunofluorescence staining showed that the hippocampal neuronal necrosis in the ischemic penumbra decreased whereas the immunopositivity of new neuronal-specific protein doublecortin and the percentage of Ki67/doublecortin positive cells increased in CEGI-treated rats compared with untreated rats. Our results suggest that CEGI has an effective neuroprotective effect on ischemic stroke when administered after the time window of thrombolysis. The study was approved by the Animal Ethics Committee of The Third Military Medical University, China.     

Inhibition of cerebral ischemia/reperfusion injury-induced apoptosis:nicotilforin and JAK2/STAT3 pathway

Nicotilforin is a lfavonoid extracted from Carthamus tinctorius. Previous studies have shown its cerebral protective effect, but the mecha-nism is undeifned. In this study, we aimed to determine whether nicotilforin protects against cerebral ischemia/reperfusion injury-induced apoptosis through the JAK2/STAT3 pathway. hTe cerebral ischemia/reperfusion injury model was established by middle cerebral artery occlusion/reperfusion. Nicotilforin (10 mg/kg) was administered by tail vein injection. Cell apoptosis in the ischemic cerebral cortex was examined by hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Bcl-2 and Bax expres-sion levels in ischemic cerebral cortex were examined by immunohistochemial staining. Additionally, p-JAK2, p-STAT3, Bcl-2, Bax, and caspase-3 levels in ischemic cerebral cortex were examined by western blot assay. Nicotilforin altered the shape and structure of injured neurons, decreased the number of apoptotic cells, down-regulates expression of p-JAK2, p-STAT3, caspase-3, and Bax, decreased Bax immunoredactivity, and increased Bcl-2 protein expression and immunoreactivity. hTese results suggest that nicotilforin protects against cerebral ischemia/reperfusion injury-induced apoptosis via the JAK2/STAT3 pathway.     

Computed tomography perfusion and computed tomography angiography for prediction of clinical outcomes in ischemic stroke patients atfer thrombolysis

Cerebral blood perfusion and cerebrovascular lesions are important factors that can affect the therapeutic effcacy of thrombolysis. At pres-ent, the majority of studies focus on assessing the accuracy of lesion location using imaging methods before treatment, with less attention to predictions of outcomes atfer thrombolysis. hTus, in the present study, we assessed the effcacy of combined computed tomography (CT) perfusion and CT angiography in predicting clinical outcomes atfer thrombolysis in ischemic stroke patients. hTe study included 52 patients who received both CT perfusion and CT angiography. Patients were grouped based on the following criteria to compare clinical outcomes:(1) thrombolytic and non-thrombolytic patients, (2) thrombolytic patients with CT angiography showing the presence or ab-sence of a vascular stenosis, (3) thrombolytic patients with CT perfusion showing the presence or absence of hemodynamic mismatch, and (4) different CT angiography and CT perfusion results. Short-term outcome was assessed by the 24-hour National Institution of Health Stroke Scale score change. Long-term outcome was assessed by the 3-month modiifed Rankin Scale score. Of 52 ischemic stroke patients, 29 were treated with thrombolysis and exhibited improved short-term outcomes compared with those without thrombolysis treatment (23 patients). Patients with both vascular stenosis and blood lfow mismatch (13 patients) exhibited the best short-term outcome, while there was no correlation of long-term outcome with CT angiography or CT perfusion ifndings. hTese data suggest that combined CT perfusion and CT angiography are useful for predicting short-term outcome, but not long-term outcome, atfer thrombolysis.