Ischemic stroke is a devastating disease and one of the leading causes of mortality worldwide. Overproduction of reactive oxygen and nitrogen species (RONS) following ischemic insult is known as a key factor in exacerbating brain damage. Thus, RONS scavengers that can block excessive production of RONS have great therapeutic potential. Herein, we propose an efficient treatment strategy in which an artificial nanozyme with multienzyme activity drives neuroprotection against ischemic stroke primarily by scavenging RONS. Specifically, through a facile, Bi 3+ -assisted, template-free synthetic strategy, we developed hollow Prussian blue nanozymes (HPBZs) with multienzyme activity to scavenge RONS in a rat model of ischemic stroke. The comprehensive characteristics of HPBZs against RONS were explored. Apart from attenuating oxidative stress, HPBZs also suppressed apoptosis and counteracted inflammation both in vitro and in vivo, thereby contributing to increased brain tolerance of ischemic injury with minimal side effects. This study provides a proof of concept for a novel class of neuroprotective nanoagents that might be beneficial for treatment of ischemic stroke and other RONS-related disorders.

BackgroundSpinal root avulsion induces multiple pathophysiological events consisting of altered levels of specific genes and proteins related to inflammation, apoptosis, and oxidative stress, which collectively result in the death of the affected motoneurons. Recent studies have demonstrated that the gene changes involved in spinal cord injury can be regulated by microRNAs, which are a class of short non-coding RNA molecules that repress target mRNAs post-transcriptionally. With consideration for the time course of the avulsion-induced gene expression patterns within dying motoneurons, we employed microarray analysis to determine whether and how microRNAs are involved in the changes of gene expression induced by pathophysiological events in spinal cord motoneurons.ResultsThe expression of a total of 3,361 miRNAs in the spinal cord of adult rats was identified. Unilateral root-avulsion resulted in significant alterations in miRNA expression. In the ipsilateral half compared to the contralateral half of the spinal cord, on the 3rd day after the injury, 55 miRNAs were upregulated, and 24 were downregulated, and on the 14th day after the injury, 36 miRNAs were upregulated, and 23 were downregulated. The upregulation of miR-146b-5p and miR-31a-3p and the downregulation of miR-324-3p and miR-484 were observed. Eleven of the miRNAs, including miR-21-5p, demonstrated a sustained increase; however, only miR-466c-3p presented a sustained decrease 3 and 14 days after the injury. More interestingly, 4 of the miRNAs, including miR-18a, were upregulated on the 3rd day but were downregulated on the 14th day after injury.Some of these miRNAs target inflammatory-response genes in the early stage of injury, and others target neurotransmitter transport genes in the intermediate stages of injury. The altered miRNA expression pattern suggests that the MAPK and calcium signaling pathways are consistently involved in the injury response.ConclusionsThis analysis may facilitate the understanding of the time-specific altered expression of a large set of microRNAs in the spinal cord after brachial root avulsion.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2202-15-92) contains supplementary material, which is available to authorized users.

Although early exposure to sevoflurane increases activated caspase-3 expression and neuronal loss and decreases nNOS in the neonatal hippocampus, it does not affect subsequent neurobehavioural performances in juvenile rats.

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Posttraumatic stress disorder (PTSD) is an anxiety disorder that occurs after exposure to a traumatic event. This study aimed to investigate the neurobiologic changes before and after exposure-based therapy by PET in a rat model of PTSD. Methods: Serial 18 F-FDG PET imaging studies were performed under the control (tone presentation), fear-conditioning, and extinction retrieval phases. Neuroactivity marker c-Fos protein was used for immunostaining. Results: Increased glucose metabolism was observed in the bilateral amygdala after fearconditioning (P , 0.001) and in the right posterior insular cortex under extinction retrieval (P , 0.001) compared with the control phase. Increased c-Fos expression in the posterior insular cortex under extinction retrieval was positively correlated to the glucose metabolism (P , 0.01). Conclusion: Our results indicated that the amygdala plays a key role in fear memory formation and, most importantly, the insular cortex is related to the retrieval of extinction memory. 18 F-FDG PET may provide a promising in vivo approach for evaluating exposurebased therapy of PTSD. Post traumatic stress disorder (PTSD) is the most costly psychiatric disorder, affecting up to 40% of individuals over lifetime exposure to traumatic events (1,2). Over the past decades, considerable studies have explored how fear memories are encoded in the brain. A neurocircuitry model of PTSD emphasized the importance of the amygdala, as well as its interactions with the ventral/ medial prefrontal cortex (PFC) and hippocampus (3). In accord with this model, initial neuroimaging studies of PTSD provided evidence for exaggerated amygdala responses and attenuated ventral/ medial PFC responses during exposure to reminders of the traumatic event (3). In addition, Pavlovian fear-conditioning studies highlighted the key role of the amygdala in the acquisition and storage of conditioned fear memories (4,5). Electrophysiologic recording and inactivation studies in rats suggest that fear extinction depended on increased neuroactivity in the medial PFC under extinction training (6,7). Furthermore, the amygdala has been found activated during fear acquisition (8) and positively correlated with the severity of PTSD symptoms (9). Failure to recall fear extinction memory is associated with lower activation in the hippocampus and ventral/medial PFC in PTSD patients relative to trauma-exposed healthy subjects (10).Although exposure-based therapy (conceptually based on fear extinction) has been widely used in the treatment of PTSD (1), its underlying mechanism has not been completely elucidated. Because PET has been increasingly used to characterize neural activities, we hypothesized that 18 F-FDG PET could be applied for evaluating cerebral glucose metabolism before and after exposure-based therapy and could provide a potential translational tool for future clinical applications. Thus, the present study aimed to investigate the neurobiologic changes by 18 F-FDG PET in a rat model of PTSD. MATERIALS AND METHODS AnimalsMale Sprague-Da...

A growing number of studies have shown that commonly used anesthetic agents may cause neurohistopathological changes and persistent behavioral impairments in the developing brain. The effects of sevoflurane, a widely used substance in pediatric anesthesia, on the developing brain have not been thoroughly analyzed thus far. In this study, Sprague-Dawley rats at postnatal day (P)7 were exposed to 2.3% sevoflurane for 6 h continuously. Six hours after exposure, hematoxylin and eosin (H&E) staining was used to determine the morphological changes in the hippocampus. The expression levels of neuronal nitric oxide synthase (nNOS) and caspase-3 in the hippocampus of the pups were determined by immunofluorescence. A single 6-h sevoflurane exposure at P7 caused morphological changes in the hippocampus. Sevoflurane also significantly increased the expression of cleaved caspase-3 and reduced the expression of the nNOS protein. These results indicate that neonatal exposure to sevoflurane causes neurohistopathological changes, apoptosis and decreases nNOS protein levels in the rat hippocampus.

BackgroundDuring the clinical treatment of the brachial plexus root avulsion (BPRA), reimplantation surgery can not completely repair the motor function of the hand because the axonal growth velocity of the spinal motoneurons (MNs) is too slow to re-innervate the intrinsic hand muscles before muscle atrophy. Here, we investigated whether lithium can enhance the regenerative capacity of the spinal MNs in a rat model of BPRA.ResultsThe avulsion and immediate reimplantation of the C7 and C8 ventral roots were performed and followed with daily intraperitoneal administration of a therapeutic concentrationof LiCl. After a 20 week long-term rehabilitation, the motor function recovery of the injured forepaw was studied by a grasping test. The survival and regeneration of MNs were checked by choline acetyltransferase (ChAT) immunofluorescence and by Fluoro-Gold (FG) retrograde labeling through the median and ulnar nerves of the ventral horn MNs. The number and diameter of the nerve fibers in the median nerve were assessed by toluidine blue staining. Our results showed that lithium plus reimplantation therapy resulted in a significantly higher grasping strength of the digits of the injured forepaw. Lithium plus reimplantation allowed 45.1% ± 8.11% of ChAT-positive MNs to survive the injury and increased the number and diameter of nerve fibers in the median nerve. The number of FG-labeled regenerative MNs was significantly elevated in all of the reimplantation animals. Our present data proved that lithium can enhance the regenerative capacity of spinal MNs.ConclusionsThese results suggest that immediate administration of lithium could be used to assist reimplantation surgery in repairing BPRA injuries in clinical treatment.

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