Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling

Whom the hell is going to follow up this research and create a stroke protocol? No one will because we having NO fucking strategy and NO fucking stroke leadership. You're screwed.
http://onlinelibrary.wiley.com/doi/10.1111/jpi.12300/abstract

1. Yushu Dong^1,†,
2. Chongxi Fan^2,3,†,
3. Wei Hu^2,†,
4. Shuai Jiang⁴,
5. Zhiqiang Ma³,
6. Xiaolong Yan³,
7. Chao Deng⁵,
8. Shouyin Di³,
9. Zhenlong Xin²,
10. Guiling Wu²,
11. Yang Yang^2,*,
12. Russel J. Reiter^6,* and
13. Guobiao Liang^1,*

DOI: 10.1111/jpi.12300

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Journal of Pineal Research

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

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1. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jpi.12300

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Keywords:

• Melatonin;
• Subarachnoid hemorrhage;
• Early brain injury;
• Inflammasome;
• Nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3

Abstract

Subarachnoid hemorrhage (SAH) is a devastating condition with high morbidity and mortality rates due to the lack of effective therapy. Nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation associated with the upregulation of apoptotic signaling pathway has been implicated in various inflammatory diseases including hemorrhagic insults. Melatonin is reported to possess substantial anti-inflammatory properties, which is beneficial for early brain injury (EBI) after SAH. However, the molecular mechanisms have not been clearly identified. The current study was designed to investigate the protective effects of melatonin against EBI induced by SAH and to elucidate the potential mechanisms. The adult mice were subjected to SAH. Melatonin or vehicle was injected intraperitoneally 2 h after SAH. Melatonin was neuroprotective, as shown by increased survival rate, as well as elevated neurological score, greater survival of neurons, preserved brain glutathione levels and reduced brain edema, malondialdehyde concentrations, apoptotic ratio, and blood brain barrier (BBB) disruption. Melatonin also attenuated the expressions of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase-1, interleukin-1β (IL-1β), and interleukin-6 (IL-6); these changes were also associated with an increase in the anti-apoptotic factor (Bcl2) and reduction in the pro-apoptotic factor (Bim). In summary, our results demonstrate that melatonin treatment attenuates the EBI following SAH by inhibiting NLRP3 inflammasome-associated apoptosis.

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Systemic Proteasome Inhibition Induces Sustained Post-stroke Neurological Recovery and Neuroprotection via Mechanisms Involving Reversal of Peripheral Immunosuppression and Preservation of Blood–Brain–Barrier Integrity

This sounds like something that needs further research into translating into a hyperacute stroke protocol. But it won't occur because we have no strategy and no person in charge of executing that strategy. So we will be screwed for another 50 years at least. 

Systemic Proteasome Inhibition Induces Sustained Post-stroke Neurological Recovery and Neuroprotection via Mechanisms Involving Reversal of Peripheral Immunosuppression and Preservation of Blood–Brain–Barrier Integrity

• Thorsten R. Doeppner 
• , Britta Kaltwasser
• , Ulrike Kuckelkorn
• , Petra Henkelein
• , Eva Bretschneider
• , Ertugrul Kilic
• , Dirk M. Hermann

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Abstract

In view of its profound effect on cell survival and function, the modulation of the ubiquitin-proteasome-system has recently been shown to promote neurological recovery and brain remodeling after focal cerebral ischemia. Hitherto, local intracerebral delivery strategies were used, which can hardly be translated to human patients. We herein analyzed effects of systemic intraperitoneal delivery of the proteasome inhibitor BSc2118 on neurological recovery, brain injury, peripheral and cerebral immune responses, neurovascular integrity, as well as cerebral neurogenesis and angiogenesis in a mouse model of transient intraluminal middle cerebral artery occlusion. Systemic delivery of BSc2118 induced acute neuroprotection reflected by reduced infarct volume when delivered up to 9 h post-stroke. The latter was associated with reduced brain edema and stabilization of blood–brain–barrier integrity, albeit cerebral proteasome activity was only mildly reduced. Neuronal survival persisted in the post-acute stroke phase up to 28 days post-stroke and was associated with improved neurological recovery when the proteasome inhibitor was continuously delivered over 7 days. Systemic proteasome inhibition prevented stroke-induced acute leukocytosis in peripheral blood and reversed the subsequent immunosuppression, namely, the reduction of blood lymphocyte and granulocyte counts. On the contrary, post-ischemic brain inflammation, cerebral HIF-1α abundance, cell proliferation, neurogenesis, and angiogenesis were not influenced by the proteasome inhibitor. The modulation of peripheral immune responses might thus represent an attractive target for the clinical translation of proteasome inhibitors.