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.

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C-reactive protein (CRP) is an inflammatory biomarker of inflammation and may reflect progression of vascular disease. Conflicting evidence suggests CRP may be a prognostic biomarker of ischemic stroke outcome. Most studies that have examined the relationship between CRP and ischemic stroke outcome have used mortality or subsequent vascular event as the primary outcome measure. Given that nearly half of stroke patients experience moderate to severe functional impairments, using a biomarker like CRP to predict functional recovery rather than mortality may have clinical utility for guiding acute stroke treatments. The primary aim of this study was to systematically and critically review the relationship between CRP and long-term functional outcome in ischemic stroke patients to evaluate the current state of the literature. PubMed and MEDLINE databases were searched for original studies which assessed the relationship between acute CRP levels measured within 24 hours of symptom onset and long-term functional outcome. The search yielded articles published between 1989 and 2012. Included studies used neuroimaging to confirm ischemic stroke diagnosis, high-sensitivity CRP assay, and a functional outcome scale to assess prognosis beyond 30 days after stroke. Study quality was assessed using the REMARK recommendations. Five studies met all inclusion criteria. Results indicate a significant association between elevated baseline high sensitivity CRP and unfavorable long-term functional outcome. Our results emphasize the need for additional research to characterize the relationship between acute inflammatory markers and long-term functional outcome using well-defined diagnostic criteria. Additional studies are warranted to prospectively examine the relationship between high sensitivity CRP measures and long-term outcome.

Drug discovery for CNS disorders has been restricted by the inability for therapeutic agents to cross the blood-brain barrier (BBB). Moreover, current drugs aim to correct neuron cell signaling, thereby neglecting pathophysiological changes affecting other cell types of the neurovascular unit (NVU). Components of the NVU (pericytes, microglia, astrocytes, and neurons, and basal lamina) act as an intricate network to maintain the neuronal homeostatic microenvironment. Consequently, disruptions to this intricate cell network lead to neuron malfunction and symptoms characteristic of CNS diseases. A lack of understanding in NVU signaling cascades may explain why current treatments for CNS diseases are not curative. Current therapies treat symptoms by maintaining neuron function. Refocusing drug discovery to sustain NVU function may provide a better method of treatment by promoting neuron survival. In this review, we will examine current therapeutics for common CNS diseases, describe the importance of the NVU in cerebral homeostasis and discuss new possible drug targets and technologies that aim to improve treatment and drug delivery to the diseased brain.

ObjectivesLoneliness is a biopsychosocial determinant of health and contributes to physical and psychological chronic illnesses, functional decline, and mortality in older adults. This paper presents the results of the first randomized trial of LISTEN, which is a new cognitive behavioral intervention for loneliness, on loneliness, neuroimmunological stress response, psychosocial functioning, quality of life, and measures of physical health.MethodsThe effectiveness of LISTEN was evaluated in a sample population comprising 27 lonely, chronically ill, older adults living in Appalachia. Participants were randomized into LISTEN or educational attention control groups. Outcome measures included salivary cortisol and DHEA, interleukin-6, interleukin-2, depressive symptoms, loneliness, perceived social support, functional ability, quality of life, fasting glucose, blood pressure, and body mass index.ResultsAt 12 weeks after the last intervention session, participants of the LISTEN group reported reduced loneliness (p = 0.03), enhanced overall social support (p = 0.05), and decreased systolic blood pressure (p = 0.02). The attention control group reported decreased functional ability (p = 0.10) and reduced quality of life (p = 0.13).ConclusionsLISTEN can effectively diminish loneliness and decrease the systolic blood pressure in community-dwelling, chronically ill, older adults. Results indicate that this population, if left with untreated loneliness, may experience functional impairment over a period as short as 4 months. Further studies on LISTEN are needed with larger samples, in varied populations, and over longer periods of time to assess the long-term effects of diminishing loneliness in multiple chronic conditions.

Background and Purpose-This study utilized middle cerebral artery occlusion (MCAO) with tissue plasminogen activator (tPA) to assess inhibition of the NOX2 isoform of NADPH oxidase on brain injury and functional recovery in aged rats.Methods-Effects of NOX2 on the degree of brain injury and functional recovery following MCAO and tPA reperfusion was assessed in young adult and aged rats. Rats received apocynin (NOX2 inhibitor; 5 mg/kg) or saline 30 min prior to MCAO. At 24 h following MCAO, blood-brain barrier permeability (BBB), stroke infarct volume, edema formation, and oxidative damage were measured.Results-Apocynin treatment in aged rats increased mortality rate and failed to improve functional outcome, total infarct volume, edema formation, and BBB permeability. Aged rats displayed increased BBB permeability to sucrose in the contralateral hemisphere following MCAO and diminished antioxidant capacity in the brain as compared to young adult rats.Conclusions-We conclude that inhibition of NOX2 in the aged rat exacerbates stroke injury and diminishes functional outcome. These results suggest age is an important factor in stroke damage and more rigorous examination of apocynin as a therapeutic agent for treatment of stroke must be done.