Autophagy in ischemic stroke.

Background and Purpose— The proinflammatory cytokine IL-1 (interleukin-1) has a deleterious role in cerebral ischemia, which is attenuated by IL-1 receptor antagonist (IL-1Ra). IL-1 induces peripheral inflammatory mediators, such as interleukin-6, which are associated with worse prognosis after ischemic stroke. We investigated whether subcutaneous IL-1Ra reduces the peripheral inflammatory response in acute ischemic stroke. Methods— SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke) was a single-center, double-blind, randomized, placebo-controlled phase 2 trial of subcutaneous IL-1Ra (100 mg administered twice daily for 3 days) in patients presenting within 5 hours of ischemic stroke onset. Randomization was stratified for baseline National Institutes of Health Stroke Scale score and thrombolysis. Measurement of plasma interleukin-6 and other peripheral inflammatory markers was undertaken at 5 time points. The primary outcome was difference in concentration of log(interleukin-6) as area under the curve to day 3. Secondary outcomes included exploratory effect of IL-1Ra on 3-month outcome with the modified Rankin Scale. Results— We recruited 80 patients (mean age, 72 years; median National Institutes of Health Stroke Scale, 12) of whom 73% received intravenous thrombolysis with alteplase. IL-1Ra significantly reduced plasma interleukin-6 ( P P P =0.34. Exploratory mediation analysis suggested that IL-1Ra improved clinical outcome by reducing inflammation, but there was a statistically significant, alternative mechanism countering this benefit. Conclusions— IL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischemic stroke. Subcutaneous IL-1Ra is safe and well tolerated. Further experimental studies are required to investigate efficacy and possible interactions of IL-1Ra with thrombolysis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN74236229

/pdf/scil-stroke-subcutaneous-interleukin-1-receptor-antagonist-214mgcjch0.pdf

SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke): A Randomized Controlled Phase 2 Trial

Autophagy is a conserved process to maintains homeostasis via the degradation of toxic cell contents, which can either promote cell survival or accelerate cellular demise. Ferroptosis is a recently discovered iron-dependent cell death pathway associated with the accumulation of lethal reactive lipid species. In the past few years, an increasing number of studies have suggested the crosstalk between autophagy and ferroptosis. Ischemic stroke is a complex brain disease regulated by several cell death pathways, including autophagy and ferroptosis. However, the potential links between autophagy and ferroptosis in ischemic stroke have not yet been explored. In this review, we briefly overview the mechanisms of ferroptosis and autophagy, as well as their possible connections in ischemic stroke. The elucidation of crosstalk between different cell death pathways may provide insight into new future ischemic stroke therapies.

/pdf/crosstalk-between-autophagy-and-ferroptosis-and-its-putative-2ew6ooi2rq.pdf

Crosstalk Between Autophagy and Ferroptosis and Its Putative Role in Ischemic Stroke

[High-sensitivity C-reactive protein].

Autophagy regulates intracerebral hemorrhage induced neural damage via apoptosis and NF-κB pathway.

The hippocampal CA1 region is sensitive to hypoxic and ischemic injury but can be protected by ischemic preconditioning (IPC). However, the mechanism through which IPC protects hippocampal CA1 neurons is still under investigation. Additionally, the role of autophagy in determining the fate of hippocampal neurons is unclear. Here, we examined whether IPC induced autophagy to alleviate hippocampal CA1 neuronal death in vitro and in vivo with oxygen glucose deprivation (OGD) and bilateral carotid artery occlusion (BCCAO) models. Survival of hippocampal neurons increased from 51.5% ± 6.3% in the non-IPC group (55 min of OGD) to 77.3% ± 7.9% in the IPC group (15 min of OGD, followed by 55 min of OGD 24 h later). The number of hippocampal CA1 layer neurons increased from 182 ± 26 cells/mm2 in the non-IPC group (20 min of BCCAO) to 278 ± 55 cells/mm2 in the IPC group (1 min × 3 BCCAO, followed by 20 min of BCCAO 24 h later). Akt phosphorylation and microtubule-associated protein light chain 3 (LC3)-II/LC3-I expression were increased in the preconditioning group. Moreover, the protective effects of IPC were abolished only by inhibiting the activity of autophagy, but not by blocking the activation of Akt in vitro. Using in vivo experiments, we found that LC3 expression was upregulated, accompanied by an increase in neuronal survival in hippocampal CA1 neurons in the preconditioning group. The neuroprotective effects of IPC on hippocampal CA1 neurons were completely inhibited by treatment with 3-MA. In contrast, hippocampal CA3 neurons did not show changes in autophagic activity or beneficial effects of IPC. These data suggested that IPC may attenuate ischemic injury in hippocampal CA1 neurons through induction of Akt-independent autophagy.

/pdf/ischemic-preconditioning-mediates-neuroprotection-against-17mzo79l7n.pdf

Ischemic Preconditioning Mediates Neuroprotection against Ischemia in Mouse Hippocampal CA1 Neurons by Inducing Autophagy.

Parkinson's disease (PD) is associated with enteric nervous system dysfunction and gut microbiota dysbiosis. Short-chain fatty acids (SCFAs), derived from gut microbiota, are supposed to anticipate PD pathogenesis via the pathway of spinal cord and vagal nerve or the circulatory system. However, the serum concentration of SCFAs in PD patients is poorly known. This study aims to investigate the exact level of SCFAs in PD patients and its correlation with Parkinson's symptoms.50 PD patients and 50 healthy controls were recruited, and their demographic and clinical characteristics were collected. The serum concentration of SCFAs was detected using a gas chromatography-mass spectrometer. SCFAs were compared between PD and control groups. The correlation between serum SCFAs and Parkinson's symptoms and the potential effects of medications on the serum SCFAs was analyzed.Serum propionic acid, butyric acid and caproic acid were lower, while heptanoic acid was higher in PD patients than in control subjects. However, only the serum level of propionic acid was correlated with Unified Parkinson's Disease Rating Scale (UPDRs) part III score (R = -0.365, P = 0.009), Mini-mental State Examination (MMSE) score (R = -0.416, P = 0.003), and Hamilton Depression Scale (HAMD) score (R = 0.306, P = 0.03). There was no correlation between other serum SCFAs and motor complications. The use of trihexyphenidyl or tizanidine increased the serum concentration of propionic acid.Serum SCFAs are altered in PD patients, and the decrease of serum propionic acid level is correlated with motor symptoms, cognitive ability and non-depressed state. Thus, the gut microbial-derived SCFAs potentially affect Parkinson's symptoms through the blood circulation. Propionic acid supplementation might ameliorate motor and non-motor symptoms of PD patients, although clinical trials are needed to test this hypothesis. 

/pdf/serum-short-chain-fatty-acids-and-its-correlation-with-motor-6mncaofe.pdf

Serum short-chain fatty acids and its correlation with motor and non-motor symptoms in Parkinson’s disease patients

Background: High-sensitivity C-reactive protein (hs-CRP) is an inflammatory marker that is associated with the outcomes of ischemic stroke. However, the role of hs-CRP levels in the functional outc...

The role of high-sensitivity C-reactive protein levels in functional outcomes in patients with large-artery atherosclerosis and small-artery occlusion.

Background: Neurological deterioration (ND) shortly after stroke is common in Chinese patients. We aimed to determine the effects of ND during hospitalization on stroke prognosis.
 Methods: We retrospectively reviewed files from the stroke registry of the Department of Neurology of Tianjin Huanhu Hospital between October 1, 2008, and December 31, 2015. The inclusion criteria were: age ≥18 years, diagnosis of acute ischemic stroke, and first-ever ischemic stroke occurring within 7 days prior to admission. ND was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) score by ≥4 points during hospitalization. Early neurological deterioration (END) was defined as an increase in the NIHSS score by ≥4 points between the baseline and 48-hour evaluations. Late neurological deterioration (LND) was defined as an increase in the NIHSS score by ≥4 points between the 48-hour and discharge evaluations. Multivariate regression was used to evaluate the relationship between early and late ND and short- and long-term outcomes. Primary and secondary outcomes based on the modified Rankin scale (mRS) were evaluated at 3 months and 1 year. Favorable and poor outcomes were defined as mRS scores of 0–2 and ≥3, respectively.
 Results: A total of 9,650 patients were included. ND occurred in 293 patients (3.0%) during hospitalization. Among them, 192 (65.5%) were in the END group, and 101 (34.5%) were in the LND group. After adjusting for age, gender, and NIHSS scores, END was a significant independent predictor of poor outcome at both 3 months (primary outcome OR 8.069, secondary outcome OR 8.194) and 1 year (primary outcome OR 7.895, secondary outcome OR 5.679). The same pattern was seen in the LND group (3 months primary outcome OR 7.608, secondary outcome OR 6.349, 1-year primary outcome OR 10.793, secondary outcome OR 5.245).
 Conclusions: ND during hospitalization, regardless of whether it occurs in the early or late period after stroke, is an independent predictor of poor prognosis.

/pdf/association-between-neurological-deterioration-and-outcomes-5dqd2c5eo0.pdf

Association between neurological deterioration and outcomes in patients with stroke

Background: High-sensitivity C-reactive protein (hs-CRP) is not only a marker of inflammation but also a prognostic factor for ischemic stroke. The objective of our study was to investigative the association between hs-CRP levels and outcomes of patients with small-artery occlusion (SAO). Methods: We selected 718 participants diagnosed with SAO (according to Trial of Org 10172 in Acute Stroke Treatment classification) using the stroke registry of the Department of Neurorehabilitation of Tianjin HuanHu Hospital. Hs-CRP values at admission were classified into 3 categories: 2.77 mg/L) were at increased risk of poor outcome (adjusted odds ratio, 1.917; 95% CI, 1.050–3.500; P = 0.034), and more than twice the risk of poor outcome among patients in the younger subgroup (adjusted odds ratio, 2.092; 95% CI, 1.079–4.058; P = 0.029). These associations persisted after adjustment for confounding risk factors. However, hs-CRP levels were not significantly associated with outcome among patients in the elder subgroup. Conclusions: Elevated hs-CRP in patients with SAO is an independent predictor of poor prognosis; however, this association is only present in younger patients (< 75 years).

/pdf/association-between-hs-crp-levels-and-the-outcomes-of-2bxw5ytfv7.pdf

Yajing Wang

Papers

Ischemic Preconditioning Mediates Neuroprotection against Ischemia in Mouse Hippocampal CA1 Neurons by Inducing Autophagy.

Serum short-chain fatty acids and its correlation with motor and non-motor symptoms in Parkinson’s disease patients

The role of high-sensitivity C-reactive protein levels in functional outcomes in patients with large-artery atherosclerosis and small-artery occlusion.

Association between neurological deterioration and outcomes in patients with stroke

Association between hs-CRP Levels and the Outcomes of Patients with Small-Artery Occlusion.