The MT1 receptor as the target of ramelteon neuroprotection in ischemic stroke.

Stroke is the leading cause of death and disability worldwide. Novel and effective therapies for ischemic stroke are urgently needed. Here, we report that melatonin receptor 1A (MT1) agonist ramelteon is a neuroprotective drug candidate as demonstrated by comprehensive experimental models of ischemic stroke, including a middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia in vivo, organotypic hippocampal slice cultures ex vivo, and cultured neurons in vitro; the neuroprotective effects of ramelteon are diminished in MT1-knockout (KO) mice and MT1-KO cultured neurons. For the first time, we report that the MT1 receptor is significantly depleted in the brain of MCAO mice, and ramelteon treatment significantly recovers the brain MT1 losses in MCAO mice, which is further explained by the Connectivity Map L1000 bioinformatic analysis that shows gene-expression signatures of MCAO mice are negatively connected to melatonin receptor agonist like Ramelteon. We demonstrate that ramelteon improves the cerebral blood flow signals in ischemic stroke that is potentially mediated, at least, partly by mechanisms of activating endothelial nitric oxide synthase. Our results also show that the neuroprotection of ramelteon counteracts reactive oxygen species-induced oxidative stress and activates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Ramelteon inhibits the mitochondrial and autophagic death pathways in MCAO mice and cultured neurons, consistent with gene set enrichment analysis from a bioinformatics perspective angle. Our data suggest that Ramelteon is a potential neuroprotective drug candidate, and MT1 is the neuroprotective target for ischemic stroke, which provides new insights into stroke therapy. MT1-KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death.

Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor.

The function of melatonin as a protective agent against newborn hypoxic-ischemic (H-I) brain injury is not yet well studied, and the mechanisms by which melatonin causes neuroprotection in neurological diseases are still evolving. This study was designed to investigate whether expression of MT1 receptors is reduced in newborn H-I brain injury and whether the protective action of melatonin is by alterations of the MT1 receptors. We demonstrated that there was significant reduction in MT1 receptors in ischemic brain of mouse pups in vivo following H-I brain injury and that melatonin offers neuroprotection through upregulation of MT1 receptors. The role of MT1 receptors was further supported by observation of increased mortality in MT1 knockout mice following H-I brain injury and the reversal of the inhibitory role of melatonin on mitochondrial cell death pathways by the melatonin receptor antagonist, luzindole. These data demonstrate that melatonin mediates its neuroprotective effect in mouse models of newborn H-I brain injury, at least in part, by the restoration of MT1 receptors, the inhibition of mitochondrial cell death pathways and the suppression of astrocytic and microglial activation.

Changes in inpatient brain arteriovenous malformation management in the United States following the ARUBA trial: analysis of an interrupted time series design.

The November 2013 online publication of ARUBA, the first multi-institutional randomized controlled trial for unruptured brain arteriovenous malformations (AVMs), has sparked over 100 publications in protracted debates METHODS: This study sought to examine inpatient management patterns of brain AVMs from 2009 to 2016 and observe if changes in U.S. inpatient management were attributable to the ARUBA publication using interrupted time series of brain AVM studies from the National Inpatient Sample data 2009-2016. Outcomes of interest were use of embolization, surgery, combined embolization and microsurgery, radiotherapy, and observation during that admission. An interrupted time series design compared management trends before and after ARUBA. Segmented linear regression analysis tested for immediate and long-term impacts of ARUBA on management. RESULTS: Elective and asymptomatic patient admissions declined 2009-2016. In keeping with the ARUBA findings, observation for unruptured brain AVMs increased and microsurgery decreased. However, embolization, radiosurgery, and combined embolization and microsurgery also increased. For ruptured brain AVMs, treatment modality trends remained positive with even greater rates of observation, embolization, and combined embolization and microsurgery occurring after ARUBA (data on radiosurgery were scarce). None of the estimates for the change in trends were statistically significant. CONCLUSIONS: The publication of ARUBA was associated with a decrease in microsurgery and increase in observation for unruptured brain AVMs in the US. However, inpatient radiotherapy, embolization, and combined embolization and surgery also increased, suggesting trends moved counter to ARUBA's conclusions. This analysis suggested that ARUBA had a small impact as clinicians rejected ARUBA's findings in managing unruptured brain AVMs.

Use of immediate dermal fat graft for scalp contour defect following resection of arteriovenous malformation.

Arterial venous malformations (AVMs) are rare conditions that are difficult to manage. Therapeutic options include selective embolization with or without surgical excision. Recurrence, however, is high despite correction of the primary abnormality. Cosmetic concern is among the indications for treatment, particularly if the AVM occurs on the face or scalp. Historically, AVM excision and the residual defect correction have been performed separately. We present the first case reported of a successful embolization and interval excision with immediate reconstruction using a dermal fat graft, as a novel approach to correct soft tissue defect following the resection of an AVM. A 35-year-old man presented with a 20-year history of a nonpulsating mass posterior to the hairline in the right frontoparietal region, measuring 4.0 cm on its longest axis. Embolization of the AVM was achieved by injecting N-butyl cyanoacrylic acid and ethiodol. One month after embolization, surgical excision of the mass was performed. The resulting disfiguring contour defect was immediately corrected using a dermal fat graft harvested from the groin. At 4 months' follow-up, the graft was viable with no evidence of resorption or epidermal cyst formation. In addition, there was no recurrence of the AVM and no complications at the donor site. This case demonstrates the utility of a dermal fat grafts in correcting the impending defect in 1 stage avoiding a second-stage procedure and significant period of cosmetic disfigurement. This method should be considered as a treatment option for patients requiring moderately sized AVM excisions in cosmetically sensitive areas.

Monogenic, Polygenic, and MicroRNA Markers for Ischemic Stroke.

Ischemic stroke (IS) is a leading disease with high mortality and disability, as well as with limited therapeutic window. Biomarkers for earlier diagnosis of IS have long been pursued. Family and twin studies confirm that genetic variations play an important role in IS pathogenesis. Besides DNA mutations found previously by genetic linkage analysis for monogenic IS (Mendelian inheritance), recent studies using genome-wide associated study (GWAS) and microRNA expression profiling have resulted in a large number of DNA and microRNA biomarkers in polygenic IS (sporadic IS), especially in different IS subtypes and imaging phenotypes. The present review summarizes genetic markers discovered by clinical studies and discusses their pathogenic molecular mechanisms involved in developmental or regenerative anomalies of blood vessel walls, neuronal apoptosis, excitotoxic death, inflammation, neurogenesis, and angiogenesis. The possible impact of environment on genetics is addressed as well. We also include a perspective on further studies and clinical application of these IS biomarkers.

Preoperative tumor embolization.

In this article, the authors review general principles and technical details of preoperative embolization of various hypervascular head, neck, and spinal tumors encountered in contemporary neuroendovascular practice. Indications, treatment goals, techniques, outcomes, and complications are discussed, and illustrative case examples are presented.

Low morbidity associated with use of n-butyl cyanoacrylate liquid adhesive for preoperative transarterial embolization of central nervous system tumors.

OBJECTIVE: To determine the safety and efficacy of preoperative embolization of central nervous system tumors with n-butyl cyanoacrylate (NBCA) liquid adhesive. METHODS: Over a 6-year period, 35 consecutive patients (12 women, 23 men; mean age, 42 yr; range, 6 mo-75 yr) with a central nervous system tumor underwent preoperative embolization with NBCA. Tumor type, location, endovascular and surgical treatment, percent of tumor embolization, estimated blood loss, and neurological deficits related to embolization were evaluated retrospectively. RESULTS: One hundred feeding arteries were embolized (mean, 3 vessels/patient). In only one (3%) case was a normal artery inadvertently occluded by the embolization. During the follow-up period, the resulting neurological deficit resolved completely. There were no neurological deficits or inadvertent embolization events in the remaining 34 cases. The mean percent of tumor embolized was 68%, but this did not significantly correlate with operative blood loss (Pearson's correlation coefficient, r = 0.049). CONCLUSION: In experienced hands, central nervous system tumors can be embolized with NBCA liquid adhesive with a high degree of safety and efficacy. We think that adroit embolization technique with NBCA and other embolisates should be part of the contemporary neuroendovascular armamentarium.