The inflammatory response is an unavoidable process and contributes to the destruction of cerebral tissue during the acute ischemic stroke (AIS) phase and has not been addressed fully to date. Insightful understanding of correlation of inflammatory mediators and stroke outcome may provide new biomarkers or therapeutic approaches for ischemic stroke. Here, we prospectively recruited 180 first-ever AIS patients within 72 hrs after stroke onset. We used the National Institutes of Health Stroke Scale (NIHSS) to quantify stroke severity and modified Rankin scale (mRS) to assess the 3-month outcome for AIS patients. Initially, we screened 35 cytokines, chemokines, and growth factors in sera from 75 AIS patients and control subjects. Cytokines that were of interest were further investigated in the 180 AIS patients and 14 heathy controls. We found that IL-1RA, IL-1β, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, IL-15, EGF, G-CSF, Flt-3L, GM-CSF and Fractalkine levels were significantly decreased in severe stroke patients. In particular, IL-1β, IL-4, IL-5, IL-7, IL-9, IL-10, IL-15, G-CSF and GM-CSF were significantly reduced in AIS patients with poor outcome, compared to those with good prognosis. IL-6 was notably higher in the poor outcome group. Only IL-9 level decreased in the large infarct volume group. After adjusting for confounders, we found that IL-5 was an independent protective factor for prognosis in AIS patients with an adjusted OR of 0.042 (P = 0.007), whereas IL-6 was an independent risk predictor for AIS patients with an adjusted OR of 1.293 (P = 0.003). Our study suggests the levels of serum cytokines are related to stroke severity, short-term prognosis and cerebral infarct volume in AIS patients.

Rationale: The systemic inflammatory milieu plays an important role in the age-related decline in functional integrity, but its contribution to age-related disease (eg, stroke) remains largely unknown. Objective: To determine the role of systemic inflammatory milieu in ischemic stroke. Methods and Results: Here, we report that systemic administration of serum exosomes from young rats into aged ischemic rats improved short- and long-term functional outcomes after ischemic stroke and reduced synaptic loss. By contrast, similar injections of serum exosomes from aged rats into aged ischemic rats worsened sensorimotor deficits through exacerbation of synaptic dysfunction due to excessive microglial phagoptosis (primary phagocytosis). Our proteomic analysis further revealed that the expression of CD46, a C3b/C4b-inactivating factor, was higher in serum exosomes from young rats, compared with serum exosomes from aged rats. Whereas the prevalence of proinflammatory mediators (C1q [complement component 1q], C3a, and C3b) in serum exosomes increased with age. Microglial expression of C3a/b and C3aR (C3a receptor) increased after serum exosomes from aged rats treatment, compared with serum exosomes from young rats and vehicle groups. Administration of a selective C3aR inhibitor or microglial depletion attenuated synaptic dysfunction associated with serum exosomes from aged rats treatment and improved poststroke functional recovery. Conclusions: Our data suggest that the levels of proinflammatory mediators in serum exosomes increase with age and are associated with worsened stroke outcomes through excessive C3aR-dependent microglial phagoptosis. Modulation of this process may serve as a promising therapy for stroke and other age-related brain disorders.

Branched-chain amino acid transaminase 1 (BCAT1) is upregulated selectively in human isocitrate dehydrogenase (IDH) wildtype (WT) but not mutant glioblastoma multiforme (GBM) and promotes IDHWT GBM growth. Through a metabolic synthetic lethal screen, we report here that α-ketoglutarate (AKG) kills IDHWT GBM cells when BCAT1 protein is lost, which is reversed by reexpression of BCAT1 or supplementation with branched-chain α-ketoacids (BCKA), downstream metabolic products of BCAT1. In patient-derived IDHWT GBM tumors in vitro and in vivo, cotreatment of BCAT1 inhibitor gabapentin and AKG resulted in synthetic lethality. However, AKG failed to evoke a synthetic lethal effect with loss of BCAT2, BCKDHA, or GPT2 in IDHWT GBM cells. Mechanistically, loss of BCAT1 increased the NAD+/NADH ratio but impaired oxidative phosphorylation, mTORC1 activity, and nucleotide biosynthesis. These metabolic alterations were synergistically augmented by AKG treatment, thereby causing mitochondrial dysfunction and depletion of cellular building blocks, including ATP, nucleotides, and proteins. Partial restoration of ATP, nucleotides, proteins, and mTORC1 activity by BCKA supplementation prevented IDHWT GBM cell death conferred by the combination of BCAT1 loss and AKG. These findings define a targetable metabolic vulnerability in the most common subset of GBM that is currently incurable. Significance: Metabolic synthetic lethal screening in IDHWT glioblastoma defines a vulnerability to ΑΚG following BCAT1 loss, uncovering a therapeutic strategy to improve glioblastoma treatment. See related commentary by Meurs and Nagrath, p. 2354

The global incidence of age-associated neurological diseases is expected to rise with increasingly greying societies. In the aged brain, there is a dramatic decrease in the number of stem cells, which is a main cause for the decrease in brain function. Intrinsic factors, such as cell metabolism, have been studied but its role in neurogenesis is still unknown. Therefore, this study sought to establish whether AMP-activated protein kinase (AMPK) signaling does indeed regulate hippocampal neurogenesis in the aged brain. We found that i) AMPKα2 was the predominant catalytic subunit in the subgranular and subventricular zones; ii) AMPK activation was at a significantly higher level in the aged vs. young hippocampus; iii) short term (7 days) treatment with selective AMPK signaling inhibitor Compound C (10 mg/kg/day, i.p.) significantly increased the numbers of newborn (BrdU+), Type 2 (MCM2+), and Type 3 (DCX+) neural stem cells, but not Type 1 (GFAP+/Sox2+) cells, in the aged hippocampus. Taken together, our results demonstrate that AMPK signaling plays a critical role in the age-related decline of hippocampal neurogenesis.