This study investigated the effects of streptozotocin-induced diabetes on the functional integrity of the blood-brain barrier in the rat at 7, 28, 56, and 90 days, using vascular space markers ranging in size from 342 to 65,000 Da. We also examined the effect of insulin treatment of diabetes on the formation and progression of cerebral microvascular damage and determined whether observed functional changes occurred globally throughout the brain or within specific brain regions. Results demonstrate that streptozotocin-induced diabetes produced a progressive increase in blood-brain barrier permeability to small molecules from 28 to 90 days and these changes in blood-brain barrier permeability were region specific, with the midbrain most susceptible to diabetes-induced microvascular damage. In addition, results showed that insulin treatment of diabetes attenuated blood-brain barrier disruption, especially during the first few weeks; however, as diabetes progressed, it was evident that microvascular damage occurred even when hyperglycemia was controlled. Overall, results of this study suggest that diabetes-induced perturbations to cerebral microvessels may disrupt homeostasis and contribute to long-term cognitive and functional deficits of the central nervous system.

Astrogliosis, a cellular response characterized by astrocytic hypertrophy and accumulation of GFAP, is a hallmark of all types of central nervous system (CNS) injuries. Potential signaling mechanisms driving the conversion of astrocytes into “reactive” phenotypes differ with respect to the injury models employed and can be complicated by factors such as disruption of the blood-brain barrier (BBB). As denervation tools, neurotoxicants have the advantage of selective targeting of brain regions and cell types, often with sparing of the BBB. Previously, we found that neuroinflammation and activation of the JAK2-STAT3 pathway in astrocytes precedes up regulation of GFAP in the MPTP mouse model of dopaminergic neurotoxicity. Here we show that multiple mechanistically distinct mouse models of neurotoxicity (MPTP, AMP, METH, MDA, MDMA, KA, TMT) engender the same neuroinflammatory and STAT3 activation responses in specific regions of the brain targeted by each neurotoxicant. The STAT3 effects seen for TMT in the mouse could be generalized to the rat, demonstrating cross-species validity for STAT3 activation. Pharmacological antagonists of the neurotoxic effects blocked neuroinflammatory responses, pSTAT3tyr705 and GFAP induction, indicating that damage to neuronal targets instigated astrogliosis. Selective deletion of STAT3 from astrocytes in STAT3 conditional knockout mice markedly attenuated MPTP-induced astrogliosis. Monitoring STAT3 translocation in GFAP-positive cells indicated that effects of MPTP, METH and KA on pSTAT3tyr705 were localized to astrocytes. These findings strongly implicate the STAT3 pathway in astrocytes as a broadly triggered signaling pathway for astrogliosis. We also observed, however, that the acute neuroinflammatory response to the known inflammogen, LPS, can activate STAT3 in CNS tissue without inducing classical signs of astrogliosis. Thus, acute phase neuroinflammatory responses and neurotoxicity-induced astrogliosis both signal through STAT3 but appear to do so through different modules, perhaps localized to different cell types.

Objective Immune dysregulation influences outcome following acute ischemic stroke (AIS). Admission white blood cell (WBC) counts are routinely obtained, making the neutrophil–lymphocyte ratio (NLR) a readily available biomarker of the immune response to stroke. This study sought to identify the relationship between NLR and 90 day AIS outcome. Methods A retrospective analysis was performed on patients who underwent endovascular therapy for AIS at West Virginia University Hospitals, Morgantown, West Virginia. Admission WBC differentials were analyzed as the NLR. Stroke severity was measured by the National Institutes of Health Stroke Scale (NIHSS) score and outcome by the modified Rankin Scale (mRS) score at 90 days. Univariate relationships between NLR, age, NIHSS, and mRS were established by correlation coefficients; the t test was used to compare NLR with recanalization and stroke location (anterior vs posterior). Logistic regression models were developed to identify the ability of NLR to predict mRS when controlling for age, recanalization, and treatment with IV tissue plasminogen activator (tPA). Results 116 patients were reviewed from 2008 to 2011. Mean age of the sample was 67 years, and 54% were women. Mean baseline NIHSS score was 17 and 90 day mRS score was 4. There was a significant relationship between NLR and mRS (p=0.02) that remained when controlling for age, treatment with IV tPA, and recanalization. NLR ≥5.9 predicted poor outcome and death at 90 days. Conclusions This study shows that the NLR, a readily available biomarker, may be a clinically useful tool for risk stratification when evaluating AIS patients as candidates for endovascular therapies.

No abstract