Glial growth factor 2 treatment alleviates ischemia and reperfusion-damaged integrity of the blood-brain barrier through decreasing Mfsd2a/caveolin-1-mediated transcellular and Pdlim5/YAP/TAZ-mediated paracellular permeability.

The impairment of blood-brain barrier (BBB) integrity is the pathological basis of hemorrhage transformation and vasogenic edema following thrombolysis and endovascular therapy. There is no approved drug in the clinic to reduce BBB damage after acute ischemic stroke (AIS). Glial growth factor 2 (GGF2), a recombinant version of neuregulin-1ß that can stimulates glial cell proliferation and differentiation, has been shown to alleviate free radical release from activated microglial cells. We previously found that activated microglia and proinflammatory factors could disrupt BBB after AIS. In this study we investigated the effects of GGF2 on AIS-induced BBB damage as well as the underlying mechanisms. Mouse middle cerebral artery occlusion model was established: mice received a 90-min ischemia and 22.5 h reperfusion (I/R), and were treated with GGF2 (2.5, 12.5, 50 ng/kg, i.v.) before the reperfusion. We showed that GGF2 treatment dose-dependently decreased I/R-induced BBB damage detected by Evans blue (EB) and immunoglobulin G (IgG) leakage, and tight junction protein occludin degradation. In addition, we found that GGF2 dose-dependently reversed AIS-induced upregulation of vesicular transcytosis increase, caveolin-1 (Cav-1) as well as downregulation of major facilitator superfamily domain containing 2a (Mfsd2a). Moreover, GGF2 decreased I/R-induced upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that played an important role in BBB damage after AIS. In addition, GGF2 significantly alleviated I/R-induced reduction of YAP and TAZ, microglial cell activation and upregulation of inflammatory factors. Together, these results demonstrate that GGF2 treatment alleviates the I/R-compromised integrity of BBB by inhibiting Mfsd2a/Cav-1-mediated transcellular permeability and Pdlim5/YAP/TAZ-mediated paracellular permeability.

Nicotine pretreatment alleviates MK-801-induced behavioral and cognitive deficits in mice by regulating Pdlim5/CRTC1 in the PFC.

Increasing evidence shows that smoking-obtained nicotine is indicated to improve cognition and mitigate certain symptoms of schizophrenia. In this study, we investigated whether chronic nicotine treatment alleviated MK-801-induced schizophrenia-like symptoms and cognitive impairment in mice. Mice were injected with MK-801 (0.2 mg/kg, i.p.), and the behavioral deficits were assessed using prepulse inhibition (PPI) and T-maze tests. We showed that MK-801 caused cognitive impairment accompanied by increased expression of PDZ and LIM domain 5 (Pdlim5), an adaptor protein that is critically associated with schizophrenia, in the prefrontal cortex (PFC). Pretreatment with nicotine (0.2 mg · kg-1 · d-1, s.c., for 2 weeks) significantly ameliorated MK-801-induced schizophrenia-like symptoms and cognitive impairment by reversing the increased Pdlim5 expression levels in the PFC. In addition, pretreatment with nicotine prevented the MK-801-induced decrease in CREB-regulated transcription coactivator 1 (CRTC1), a coactivator of CREB that plays an important role in cognition. Furthermore, MK-801 neither induced schizophrenia-like behaviors nor decreased CRTC1 levels in the PFC of Pdlim5-/- mice. Overexpression of Pdlim5 in the PFC through intra-PFC infusion of an adreno-associated virus AAV-Pdlim5 induced significant schizophrenia-like symptoms and cognitive impairment. In conclusion, chronic nicotine treatment alleviates schizophrenia-induced memory deficits in mice by regulating Pdlim5 and CRTC1 expression in the PFC.

An Overview of Systematic Reviews of Chinese Herbal Medicine for Parkinson's Disease.

Parkinson's disease (PD) is a high prevalence neurodegenerative disorder without a disease-modifying therapy. Up to now, a number of systematic reviews have been conducted to evaluate efficacy and safety of Chinese herbal Medicine (CHM) for PD patients. Here, we aimed to assess the methodological quality and reporting quality of systematic reviews using an overview, and then synthesize and evaluate the available evidence level of CHM for PD. Six databases were searched from inception to September 2018. The literatures were selected and data were extracted according to prespecified criteria. A Measurement Tool to Assess Systematic Reviews (AMSTAR) was used to evaluate the quality of methodology, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to determine the evidence quality of the primary outcome measures. A total of 11 systematic reviews with 230 RCTs of CHM for PD were included. AMSTAR scores of the included reviews were range from 4 to 9. Compared with conventional western medicine (WCM), CHM paratherapy showed significant effect in improving UPDRS score, Webster scale score, PDQ-39, NMSQuest, CHM Syndrome Integral Scale, and PDSS. However, CHM monotherapy showed no difference relative to WCM according to various outcome measures. Adverse events were reported in 9 systematic reviews. The side effect in CHM paratherapy group was generally less than or lighter than that in WCM group. The quality of the evidence of primary outcomes was moderate (42%) to high (54%) according to the GRADE profiler. The present finding supported the use of CHM paratherapy for PD patients but we should treat the evidence cautiously because of the methodological flaws, whereas there is insufficient evidence of CHM monotherapy for PD.

Borneol Attenuates Ultrasound-Targeted Microbubble Destruction-Induced Blood-Brain Barrier Opening in Focal Cerebral Ischemia.

Ultrasound-targeted microbubble destruction (UTMD) and the herb medicine borneol can both facilitate the delivery of therapeutic agents to diseased brain regions and serve as promising adjuvant neuroprotective therapies. Our preliminary experiments showed that UTMD could exacerbate ischemic blood-brain barrier (BBB) opening, while borneol can protect the BBB. In this study, we tested the hypothesis that the combination of UTMD and borneol could attenuate UTMD-induced injury to the BBB under ischemic stroke conditions. Male albino mice were subjected to 60-min middle cerebral artery occlusion (MCAO) with reperfusion. Borneol and UTMD was given to mice 3 days before and 24 h after MCAO induction. BBB permeability, brain water contents, ultrastructural changes of the BBB and histopathological alterations were evaluated. Our data demonstrated that UTMD aggravated the leakage of Evans blue dye, ultrastructural alterations of cerebral microvasculature, brain edema, and even induced cerebral hemorrhage in ischemic stroke mice. Pretreatment with borneol significantly attenuated the above detrimental effects of UTMD on the BBB. This study indicates that under ischemic stroke conditions, the BBB becomes vulnerable to UTMD intervention, and the combination of borneol can help to maintain the integrity of the BBB.

Cocktail treatment, a promising strategy to treat acute cerebral ischemic stroke?

Up to now, over 1,000 experimental treatments found in cells and rodents have been difficult to translate to human ischemic stroke. Since ischemia and reperfusion, two separate stages of ischemic stroke, have different pathophysiological mechanisms leading to brain injury, a combination of protective agents targeting ischemia and reperfusion respectively may obtain substantially better results than a single agent. Normobaric hyperoxia (NBO) has been shown to exhibit neuro- and vaso-protective effects by improving tissue oxygenation when it is given during ischemia, however the effect of NBO would diminish when the duration of ischemia and reperfusion was extended. Therefore, during reperfusion drug treatment targeting inflammation, oxidative stress and free radical scavenger would be a useful adjuvant to extend the therapeutic window of tissue plasminogen activator, the only United States Food and Drug Administration (FDA) approved treatment for acute ischemic stroke. In this review, we discussed the neuro- and vaso-protective effects of NBO and recent finding of combining NBO with other drugs.

Oxygen or cooling, to make a decision after acute ischemia stroke.

The presence of a salvageable penumbra, a region of ischemic brain tissue with sufficient energy for short-term survival, has been widely agreed as the premise for thrombolytic therapy with tissue plasminogen activator (tPA), which remains the only United States Food and Drug Administration (FDA) approved treatment for acute ischemia stroke. However, the use of tPA has been profoundly constrained due to its narrow therapeutic time window and the increased risk of potentially deadly hemorrhagic transformation (HT). Blood brain barrier (BBB) damage within the thrombolytic time window is an indicator for tPA-induced HT and both normobaric hyperoxia (NBO) and hypothermia have been shown to protect the BBB from ischemia/reperfusion injury. Therefore, providing the O2 as soon as possible (NBO treatment), freezing the brain (hypothermia treatment) to slow down ischemia-induced BBB damage or their combined use may extend the time window for the treatment of tPA. In this review, we summarize the protective effects of NBO, hypothermia or their use combined with tPA on ischemia stroke, based on which, the combination of NBO and hypothermia may be an ideal early stroke treatment to preserve the ischemic penumbra. Given this, there is an urge for large randomized controlled trials to address the effect.

The α(2A)-adrenoceptor agonist guanfacine improves spatial learning but not fear conditioning in rats.

It is known that stimulation of the α(2A)-adrenoceptors (α(2A)-ARs) by the selective α(2A)-AR agonist guanfacine produces an important and beneficial influence on prefrontal cortical (PFC) cognitive functions such as spatial working memory and selective attention. However, it is unclear whether stimulation of the α(2A)-ARs has a similar effect on fear conditioning that involves the amygdala and hippocampus. Here, we show that systemically administered guanfacine significantly enhances spatial learning of rats in the Lashley maze: compared with controls, the rats treated with guanfacine required significantly fewer trials and made significantly fewer errors to reach learning criterion. However, guanfacine produced no effect on acquisition of contextual and auditory fear memories. The present study suggests that beneficial effect of α(2A)-AR stimulation is task-dependent: guanfacine improves spatial learning but not fear conditioning.

Glucocorticoid receptors in the basolateral nucleus of amygdala are required for postreactivation reconsolidation of auditory fear memory.

It is well known that initial consolidation requires de novo gene transcription and protein synthesis in order for memory to become stable. The consolidated memory again becomes labile and temporarily sensitive to disruption when retrieved, requiring a reconsolidation process to become permanent. Although it is well established that glucocorticoid receptors (GR) in the basolateral nucleus of amygdala (BLA) are required for consolidation of fear memory, little is known about their role in reconsolidation of fear memory. In the present study, we first examined the effect of a GR antagonist on postconditioning consolidation of auditory fear memory (AFM). Intra-BLA infusion of the GR antagonist RU486 0 h postconditioning impaired long-term AFM, leaving short-term AFM intact. RU486 had no effect if infusion was performed 6 h postconditioning. We then investigated the effect of the RU486 treatment on postretrieval reconsolidation of AFM. Severe amnesia took place when RU486 was infused into the BLA 0 h postretrieval (reactivation) of AFM, regardless of whether the retrieval was performed 1 day or 10 days postconditioning. RU486 produced no amnesia if the memory retrieval was omitted or if the drug was administered 6 h postretrieval. Treatment with RU486 0 h postretrieval produced no deficit in postretrieval short-term memory but impaired postretrieval long-term memory, and the amnesia exhibited no spontaneous recovery 6 days after retrieval. The present results provide strong evidence that glucocorticoid receptors in the BLA are required for reconsolidation as well as consolidation of AFM.