Cannabis use and its association with psychopathological symptoms in a Swiss adult population: a cross-sectional analysis.

Background: As the most commonly used illicit substance, cannabis is gaining global acceptance through increasing legalization efforts. This shift intensifies the need for research to guide policymakers and healthcare providers in harm reduction and treatment strategies. Nonetheless, the relationship between psychopathological symptoms and cannabis use remains inadequately understood. Methods: A sample of regular cannabis consumers completed self-reported assessments for depression (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), Attention-Deficit/Hyperactivity Disorder (ADHD; Adult ADHD Self-Report Scale V1.1), and psychosis (Early Recognition Inventory based on IRAOS) as well as previous black-market cannabis use patterns. Cannabis Use Disorder Identification Test Revised (CUDIT-R) was used to identify cannabis use disorder (CUD). To understand psychopathological symptom load related to cannabis consumption as well as cannabis use motives, multiple regression models were performed to identify psychopathological variables predicting cannabis use frequency and quantity. Linear regression and correlation analyses were conducted, adjusting for relevant covariates (age, gender, education, alcohol, other substance use). Results: Three-hundred-sixty regular cannabis users interested in a study on regulated cannabis access in Basel, Switzerland were examined. In bivariate analysis, cannabis use frequency correlated with depressive (r(358) = 0.16, p = 0.003) and anxiety symptom load (r(358) = 0.11, p = 0.034). Cannabis quantity correlated with depressive (r(358) = 0.15, p = 0.005), ADHD (r(358) = 0.14, p = 0.008), and psychosis symptom load (r(358) = 0.16, p = 0.002). However, in the adjusted regression models only depressive and ADHD symptom loads were significantly associated with cannabis use frequency (p = 0.006 and p = 0.034, respectively) and quantity (p = 0.037 and p = 0.019, respectively). No significant correlations between cannabis consumption and anxiety or psychosis remained after adjustment. Conclusion: ADHD and depressive symptoms correlate with increased cannabis use in a cohort of regular users, suggesting potential self-medication in nonclinical populations. With the rising availability of cannabis worldwide, these results highlight the necessity for longitudinal studies to disentangle the complex dynamics between cannabis consumption and mental health symptoms.

Quality of Life and Patient Satisfaction After the Provision of an Orthopedic Knee Scooter­a Multicenter Randomized Controlled Trial.

BACKGROUND: Partial or total avoidance of weight-bearing by a lower limb is regularly needed after trauma and surgery. There are approximately 200 such cases per 100 000 persons per year. Underarm crutches have mainly been used in Germany until now to keep these patients mobile. For those who lack the strength or coordination needed to use crutches, a wheelchair may become necessary, or they might find themselves forced to continue weight-bearing on the affected limb, with possible impending adverse consequences and complications. METHODS: The supplementary use of a new type of orthopedic scooter by patients who must avoid weight-bearing by a lower limb, wholly or in part, was studied in a multicenter randomized controlled trial involving 88 subjects. The endpoints were improvement in quality of life (EQ5D, SF36) and improved abilities in everyday life (retrospective registration: DRKS00032980). RESULTS: Patients who used orthopedic knee scooters (KS) reported a better overall state of health more frequently than those who used underarm crutches (UC) (SF-36 score: 67 [KS group], 95% CI [61; 73]; 59 [UC group], [53; 64]). They also reported less anxiety and depressed mood, greater mobility, and more independence than the patients who used crutches. In addition, they more frequently reported being able to transport themselves 4 x 500 meters in less than 20 minutes (n = 30 [KS], 63.8% [48.5; 77.3]; n = 6 [UC], 14.6% [5.6, 29.2]). CONCLUSION: The supplementary use of an orthopedic knee scooter can improve these patients' mobility and independence and prolong the distance over which they can transport themselves. For many patients, this form of treatment may well shorten the time of their total or partial inability to work and thus lower the socioeconomic costs of lower limb injuries and surgery.

Glyoxal in hyperglycaemic ischemic stroke - a cohort study.

BACKGROUND: Hyperglycaemia is frequent in acute ischemic stroke and denotes a bad prognosis, even in the absence of pre-existing diabetes. However, in clinical trials treatment of elevated glucose levels with insulin did not improve stroke outcome, suggesting that collateral effects rather than hyperglycaemia itself aggravate ischemic brain damage. As reactive glucose metabolites, glyoxal and methylglyoxal are candidates for mediating the deleterious effects of hyperglycaemia in acute stroke. METHODS: In 135 patients with acute stroke, we used liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) to measure glyoxal, methylglyoxal and several of their glycated amino acid derivatives in serum. Results were verified in a second cohort of 61 stroke patients. The association of serum concentrations with standard stroke outcome scales (NIHSS, mRS) was tested. RESULTS: Glucose, glyoxal, methylglyoxal, and the glyoxal-derived glycated amino acid Nδ-(5-hydro-4-imidazolon-2-yl)ornithine (G-H1) were positively correlated with a bad stroke outcome at 3 months as measured by mRS90, at least in one of the two cohorts. However, the glycated amino acids Nε-carboxyethyllysine (CEL) and in one cohort pyrraline showed an inverse correlation with stroke outcome probably reflecting lower food intake in severe stroke. Patients with a poor outcome had higher serum concentrations of glyoxal and methylglyoxal. CONCLUSIONS: The glucose-derived α-dicarbonyl glyoxal and glycated amino acids arising from a reaction with glyoxal are associated with a poor outcome in ischemic stroke. Thus, lowering α-dicarbonyls or counteracting their action could be a therapeutic strategy for hyperglycaemic stroke.

LCP1 triggers mTORC2/AKT activity and is pharmacologically targeted by enzastaurin in hypereosinophilia.

Hypereosinophilia (HE) is caused by a variety of disorders, ranging from parasite infections to autoimmune diseases and cancer. Only a small proportion of HE cases are clonal malignancies, and one of these, the group of eosinophilia-associated tyrosine kinase fusion-driven neoplasms, is sensitive to tyrosine kinase inhibitors, while most subtypes lack specific treatment. Eosinophil functions are highly dependent on actin polymerization, promoting priming, shape change, and infiltration of inflamed tissues. Therefore, we investigated the role of the actin-binding protein lymphocyte cytosolic protein 1 (LCP1) in malignant and nonmalignant eosinophil differentiation. We use the protein kinase C-ß (PKCß) selective inhibitor enzastaurin (Enza) to dephosphorylate and inactivate LCP1 in FIP1L1-platelet-derived growth factor receptor α (PDGFRA)-positive Eol-1 cells, and this was associated with reduced proliferation, metabolic activity, and colony formation as well as enhanced apoptosis and impaired migration. While Enza did not alter FIP1L1-PDGFRA-induced signal transducer and activator of transcription 3 (STAT3), STAT5, and ERK1/2 phosphorylation, it inhibited STAT1Tyr701 and AKTSer473 (but not AKTThr308 ) phosphorylation, and short hairpin RNA knockdown experiments confirmed that this process was mediated by LCP1 and associated mammalian target of rapamycin complex 2 (mTORC2) activity loss. Homeobox protein HoxB8 immortalized murine bone marrow cells showed impaired eosinophilic differentiation upon Enza treatment or LCP1 knockdown. Furthermore, Enza treatment of primary HE samples reduced eosinophil differentiation and survival. In conclusion, our data show that HE involves active LCP1, which interacts with mTOR and triggers mTORC2 activity, and that the PKCß inhibitor Enza as well as targeting of LCP1 may provide a novel treatment approach to hypereosinophilic disorders.

Antibodies against neural antigens in patients with acute stroke: joint results of three independent cohort studies.

BACKGROUND AND PURPOSE: Ischemic stroke (IS) and hemorrhagic stroke (HemS) typically lead to a breakdown of the blood-brain barrier with neural antigen presentation. This presentation could potentially generate destructive auto-immune responses. Pre-existing antineuronal and antiglial antibodies (AA), predominantly NMDA receptor antibodies, have been reported in patients with stroke. This article summarizes three independent prospective studies, the Lübeck cohort (LC), Barcelona cohort (BC), and Heidelberg cohort (HC), exploring the frequency and clinical relevance of AA in patients with acute stroke (AS). METHODS: In all cohorts together, 344 consecutive patients admitted with AS (322 × IS, 22 × HemS) were screened for AA in serum at admission. Clinical outcome parameters as well as a second AA screening were available at 30 days in the LC or at 90 days in the BC. A control group was included in the BC (20 subjects free from neurological disease) and the HC (78 neurological and ophthalmological patients without evidence for stroke). RESULTS: The rate of positivity for AA was similar in control subjects and AS patients (13%, 95% CI [7%, 22%] vs. 13%, 95% CI [10%, 17%]; p = 0.46) with no significant difference between cohorts (LC 25/171, BC 12/75, HC 9/98). No patient had developed new AA after 30 days, whereas 2 out of 60 patients had developed new AA after 90 days. AA positive patients did not exhibit significant differences to AA negative patients in stroke subtype (LC, BC), initial stroke severity (BC, LC, HC), infarct volume (BC), and functional status at admission (BC, LC, HC) and follow-up (BC, LC). CONCLUSIONS: AS does not induce AA to a relevant degree. Pre-existing AA can be found in the serum of stroke patients, but they do not have a significant association with clinical features and outcomes.

Infliximab therapy together with tyrosine kinase inhibition targets leukemic stem cells in chronic myeloid leukemia.

BACKGROUND: Expression of Bcr-Abl in hematopoietic stem cells is sufficient to cause chronic myeloid leukemia (CML) and tyrosine kinase inhibitors (TKI) induce molecular remission in the majority of CML patients. However, the disease driving stem cell population is not fully targeted by TKI therapy, and leukemic stem cells (LSC) capable of re-inducing the disease can persist. Single-cell RNA-sequencing technology recently identified an enriched inflammatory gene signature with TNFα and TGFß being activated in TKI persisting quiescent LSC. Here, we studied the effects of human TNFα antibody infliximab (IFX), which has been shown to induce anti-inflammatory effects in mice, combined with TKI treatment on LSC function. METHODS: We first performed GSEA-pathway analysis using our microarray data of murine LSK cells (lin-; Sca-1+; c-kit+) from the SCLtTA/Bcr-Abl CML transgenic mouse model. Bcr-Abl positive cell lines were generated by retroviral transduction. Clonogenic potential was assessed by CFU (colony forming unit). CML mice were treated with nilotinib or nilotinib plus infliximab, and serial transplantation experiments were performed. RESULTS: Likewise to human CML, TNFα signaling was specifically active in murine CML stem cells, and ectopic expression of Bcr-Abl in murine and human progenitor cell lines induced TNFα expression. In vitro exposure to human (IFX) or murine (MP6-XT22) TNFα antibody reduced clonogenic growth of CML cells. Interestingly, TNFα antibody treatment enhanced TKI-induced effects on immature cells in vitro. Additionally, in transplant and serial transplant experiments, using our transgenic CML mouse model, we could subsequently show that IFX therapy boosted TKI-induced effects and further reduced the proportion of malignant stem cells in vivo. CONCLUSION: TNFα signaling is induced in CML stem cells, and anti-inflammatory therapy enhances TKI-induced decline of LSC, confirming that successful targeting of persisting CML stem cells can be enhanced by addressing their malignant microenvironment simultaneously.

Stem cell persistence in CML is mediated by extrinsically activated JAK1-STAT3 signaling.

Tyrosine kinase inhibitor (TKI) therapy effectively blocks oncogenic Bcr-Abl signaling and induces molecular remission in the majority of CML patients. However, the disease-driving stem cell population is not fully targeted by TKI therapy in the majority of patients, and leukemic stem cells (LSCs) capable of re-inducing the disease can persist. In TKI-resistant CML, STAT3 inhibition was previously shown to reduce malignant cell survival. Here, we show therapy-resistant cell-extrinsic STAT3 activation in TKI-sensitive CML cells, using cell lines, HoxB8-immortalized murine BM cells, and primary human stem cells. Moreover, we identified JAK1 but not JAK2 as the STAT3-activating kinase by applying JAK1/2 selective inhibitors and genetic inactivation. Employing an IL-6-blocking peptide, we identified IL-6 as a mediator of STAT3 activation. Combined inhibition of Bcr-Abl and JAK1 further reduced CFUs from murine CML BM, human CML MNCs, as well as CD34+ CML cells, and similarly decreased LT-HSCs in a transgenic CML mouse model. In line with these observations, proliferation of human CML CD34+ cells was strongly reduced upon combined Bcr-Abl and JAK1 inhibition. Remarkably, the combinatory therapy significantly induced apoptosis even in quiescent LSCs. Our findings suggest JAK1 as a potential therapeutic target for curative CML therapies.

High Mobility HgTe Microstructures for Quantum Spin Hall Studies.

The topic of two-dimensional topological insulators has blossomed after the first observation of the quantum spin Hall (QSH) effect in HgTe quantum wells. However, studies have been hindered by the relative fragility of the edge states. Their stability has been a subject of both theoretical and experimental investigation in the past decade. Here, we present a new generation of high quality (Cd,Hg)Te/HgTe-structures based on a new chemical etching method. From magnetotransport measurements on macro- and microscopic Hall bars, we extract electron mobilities µ up to about 400 × 103 cm2/(V s), and the mean free path λmfp becomes comparable to the sample dimensions. The Hall bars show quantized spin Hall conductance, which is remarkably stable up to 15 K. The clean and robust edge states allow us to fabricate high quality side-contacted Josephson junctions, which are significant in the context of topological superconductivity. Our results open up new avenues for fundamental research on QSH effect as well as potential applications in spintronics and topological quantum computation.

Tumor Suppressor Analysis in CML.

Retroviral models have tremendously contributed to our understanding of CML development and have been indispensable for preclinical drug testing which facilitated the implementation of a targeted therapy. The retroviral insertion of Bcr-Abl into mice that are genetically depleted for a potential tumor suppressor is a tool to test for a specific gene function in Bcr-Abl disease. Here we describe how to generate a Bcr-Abl retrovirus that is subsequently used for infection of primary murine BM cells, which are genetically depleted for a potential tumor suppressor gene. We will suggest control experiments and outline further methods that are required to allow for assessment of disease development upon tumor suppressor knockout in CML.

Serum protein S100ß is a diagnostic biomarker for distinguishing posterior circulation stroke from vertigo of nonvascular causes.

BACKGROUND: In patients presenting with acute vertigo or dizziness, identifying the posterior fossa stroke as the underlying cause can be a major challenge. We therefore evaluated the serum biomarkers for the differential diagnosis of nonvascular vertigo and posterior circulation stroke. METHODS: Of a total of 80 patients, 31 patients had an ischemic stroke in the posterior circulation and 12 infratentorial hemorrhage. Findings in these patients were compared with those in 22 patients with vertigo of nonvascular origin and 15 matched control patients without neurological symptoms. Blood samples drawn <24 h after symptom onset were analyzed for S100 calcium-binding protein B (S100ß), matrix metalloproteinase 9 (MMP-9), soluble vascular cellular adhesion molecule-1 (sVCAM-1), and glial fibrillary acidic protein (GFAP). RESULTS/CONCLUSION: Serum levels of S100ß were significantly higher in stroke patients than in nonvascular vertigo patients. Serum concentrations of MMP-9 tended to be higher in stroke patients, whereas no significant differences among groups were found for sVCAM-1 and GFAP. Receiver-operating characteristic analysis revealed a sensitivity of 94.4% and a specificity of 31.8% for detecting stroke in patients presenting with vertigo for S100ß. S100ß may serve as a biomarker for distinguishing between vertigo of vascular causes and nonvascular, acute vertigo.

Fast-track intubation for accelerated interventional stroke treatment.

BACKGROUND: As intravenous thrombolysis frequently fails to recanalize occluded proximal intracerebral arteries, interventional recanalization therapy is increasingly being considered as treatment option in acute ischemic stroke patients. The optimal periprocedural patient management for these interventions is currently unknown. The aim of this study was to identify factors delaying door-to-treatment times, and to evaluate the effect of a fast-track intubation standard operating procedure (I-SOP) on door-to-angiography time. METHODS: First, we retrospectively reviewed records of 48 acute stroke patients who were treated by interventional recanalization of intracranial occlusions between 2006 and 2009 at our institution. Time to angiography was defined as time from hospital admission to the beginning of the angiographic procedure. Second, an I-SOP for fast-track intubation was implemented and effects on door-to-angiography time were prospectively analyzed in 23 consecutive patients. RESULTS: In the retrospective dataset (n = 48), the mean door-to-angiography time was 2.2 ± 0.1 h (mean ± SEM). A clinically relevant time loss attributable to the intubation procedure was suggested by a 51 ± 21 min shorter door-to-angiography time for patients already intubated prior to admission (P = 0.0189). Additional factors associated with a prolonged door-to-angiography time were: door-to-diagnosis time (P < 0.001), onset-to-door time (P = 0.0117), and male gender (mean difference +27 ± 15 min, P = 0.0822). In the prospective dataset (n = 23), I-SOP implementation reduced mean door-to-angiography time by 25 ± 10 min (P = 0.0164). CONCLUSIONS: In acute stroke patients, intubation prior to interventional recanalization therapy can delay treatment initiation. The implementation of an I-SOP accelerates interventional treatment initiation.

Blood pressure variability after intravenous thrombolysis in acute stroke does not predict intracerebral hemorrhage but poor outcome.

BACKGROUND: The relevance of blood pressure variability (BPV) in the development of intracerebral hemorrhage (ICH) after intravenous thrombolysis (IVT) in acute stroke still remains uncertain. METHODS: 427 consecutive patients treated with IVT in the years 2007-2009 were studied. Blood pressure (BP) values were analyzed from admission to follow-up imaging scan and described as mean, maximum, minimum, standard deviation (SD), difference between maximum and minimum, successive variation (SV) and maximum SV. ICH was categorized based on radiologic criteria and symptomatic ICH (sICH) was defined as ICH plus worsening of the National Institute of Health Stroke Scale by ≥4 points or leading to death. Three-month outcome was described by means of the modified Rankin Scale. RESULTS: We observed any ICH in 51 (11.9%) and sICH in 10 (2.3%) patients. Systolic and diastolic BP profiles, including mean, maximum, minimum, SD, difference between maximum and minimum, SV and maximum SV, did not differ between ICH-negative, ICH-positive and sICH patients. In univariate analysis, high systolic BPV was associated with sICH (p = 0.03). A logistic regression model to predict ICH only found early CT findings (OR = 2.74, 95% CI = 1.47-5.11, p < 0.01) as independently associated with ICH. Poor 3-month outcome was independently predicted by age (OR = 0.96, 95% CI = 0.94-0.97, p < 0.001), NIHSS on admission (OR = 0.84, 95% CI = 0.80-0.87, p < 0.001), ICH (OR = 0.29, 95% CI = 0.13-0.66, p < 0.01) and high systolic BPV (OR = 1.68, 95% CI = 1.05-2.69, p < 0.05). CONCLUSIONS: We demonstrate that high BPV in patients receiving IVT leads to poor outcome but does not increase the risk of ICH/sICH.

Regulation of GDF-15, a distant TGF-ß superfamily member, in a mouse model of cerebral ischemia.

GDF-15 is a novel distant member of the TGF-ß superfamily and is widely distributed in the brain and peripheral nervous system. We have previously reported that GDF-15 is a potent neurotrophic factor for lesioned dopaminergic neurons in the substantia nigra, and that GDF-15-deficient mice show progressive postnatal losses of motor and sensory neurons. We have now investigated the regulation of GDF-15 mRNA and immunoreactivity in the murine hippocampal formation and selected cortical areas following an ischemic lesion by occlusion of the middle cerebral artery (MCAO). MCAO prominently upregulates GDF-15 mRNA in the hippocampus and parietal cortex at 3 h and 24 h after lesion. GDF-15 immunoreactivity, which is hardly detectable in the unlesioned brain, is drastically upregulated in neurons identified by double-staining with NeuN. NeuN staining reveals that most, if not all, neurons in the granular layer of the dentate gyrus and pyramidal layers of the cornu ammonis become GDF-15-immunoreactive. Moderate induction of GDF-15 immunoreactivity has been observed in a small number of microglial cells identified by labeling with tomato lectin, whereas astroglial cells remain GDF-15-negative after MCAO. Comparative analysis of the size of the infarcted area after MCAO in GDF-15 wild-type and knockout mice has failed to reveal significant differences. Together, our data substantiate the notion that GDF-15 is prominently upregulated in the lesioned brain and might be involved in orchestrating post-lesional responses other than the trophic support of neurons.

Functional testing in a mouse stroke model induced by occlusion of the distal middle cerebral artery.

Reducing post-stroke disability is the major goal of stroke therapy. Consequently, functional testing is essential in experimental stroke studies to increase the predictive value of animal models. We used several sensory and motor tests to assess functional disability in a mouse model of permanent distal middle cerebral artery occlusion (pdMCAO) that induced mainly cortical infarcts. Gait dynamics were transiently disturbed after pdMCAO as measured by different analysis techniques. Stance and brake duration were shorter after pdMCAO. Consistent with sensory and motor deficits the latency to move was prolonged up to 14 days after pdMCAO and the performance in the corner test and handedness were affected on day 1 or 2 after pdMCAO. Heart rate was decreased and heart rate variability were increased after pdMCAO indicating sympathetic-parasympathetic imbalance. In summary, pdMCAO-induced cortical infarcts lead to clinically relevant sensory, motor and cardiac autonomic dysfunction in mice. The present study provides a basis to explore the potential of functional testing for neuroprotection and neuroregeneration after stroke.

NF-kappaB induces PGE2-synthesizing enzymes in neurons.

The transcription factor NF-kappaB is activated in neurons and promotes neuronal death in cerebral ischemia. Its target genes include cytosolic phospholipase A-2 (cPLA-2), cyclooxygenase-2 (COX-2), and microsomal prostaglandin E(2) synthase-1 (mPGES-1), three genes that are involved in the synthesis of prostaglandin E(2) (PGE(2)). In our study, oxygen glucose deprivation (OGD), an in vitro model of cerebral ischemia, activated NF-kappaB activity in primary cortical neurons. Furthermore, OGD and the NF-kappaB activator tumor necrosis factor stimulated the expression of cPLA-2, cyclooxygenase-2 (COX-2), and mPGES-1 and increased the release of PGE(2) from neurons. Expression of a constitutively active IkappaB kinase (IKK) or the NF-kappaB subunit p65 in neurons stimulated the transcription of cPLA-2, COX-2, and mPGES-1. Finally, inhibition of IKK in neurons blocked the induction of the three genes involved in PGE(2) synthesis in vivo. In summary, NF-kappaB controls the neuronal expression of three genes involved in PGE(2) synthesis in cerebral ischemia.

Neuronal NF-kappaB influences thermoregulation and survival in a sepsis model.

Gene regulation in sepsis is known to be controlled by the transcription factor NF-kappaB. However, the function of neuronal NF-kappaB in sepsis is not well defined. In a mouse model of sepsis induced by i.p. injection of lipopolysaccharides (LPS), we found an activation of NF-kappaB in the brain as shown by the induction of a transgenic NF-kappaB reporter. Inhibition of neuronal NF-kappaB by cell-specific expression of the NF-kappaB super-repressor IkappaBalpha-SR improved LPS-induced hypothermia and survival but had no effect on body weight or on the humoral response to LPS. In contrast, glial inhibition of NF-kappaB did not influence body temperature and survival. By immunohistochemistry, we detected the active NF-kappaB subunit RelA in neuronal nuclei of the organum vasculosum of the lamina terminalis. Our data reveal an important role of neuronal NF-kappaB in thermoregulation and survival. The upcoming group of NF-kappaB inhibitors may have a place in the treatment of the acute-phase response.

Bim and Noxa are candidates to mediate the deleterious effect of the NF-kappa B subunit RelA in cerebral ischemia.

The transcription factor nuclear factor kappaB (NF-kappaB) is well known for its antiapoptotic action. However, in some disorders, such as cerebral ischemia, a proapoptotic function of NF-kappaB has been demonstrated. To analyze which subunit of NF-kappaB is functional in cerebral ischemia, we induced focal cerebral ischemia in mice with a germline deletion of the p52 or c-Rel gene or with a conditional deletion of RelA in the brain. Only RelA deficiency reduced infarct size. Interestingly, expression of the proapoptotic BH3 (Bcl-2 homology domain 3)-only genes Bim and Noxa in cerebral ischemia depended on RelA and the upstream kinase IKK (IkappaB kinase). RelA stimulated Bim and Noxa gene transcription in primary cortical neurons and bound to the promoter of both genes. Thus, the deleterious function in cerebral ischemia is specific for the NF-kappaB subunit RelA and may be mediated through Bim and Noxa.

Oxygen therapy in permanent brain ischemia: potential and limitations.

BACKGROUND: Both normobaric (NBO) and hyperbaric (HBO) oxygen therapy are protective in transient cerebral ischemia. In contrast, in permanent ischemia models, which reflect the majority of clinical strokes, the effectiveness of NBO is unknown, and the effectiveness of HBO is controversial. The goals of the present study were to compare both oxygen therapies in 2 models of permanent ischemia, to study the effect of time window, and to evaluate the combination of both oxygen therapies. METHODS: Distal or proximal permanent occlusion of middle cerebral artery (MCAO) was induced by coagulation or filament, respectively. Mice received air, NBO, a single or repeated HBO (3 ata) treatments. Infarct sizes were quantified at 7 days (coagulation) and 24 h (filament), respectively. RESULTS: Following MCA coagulation, infarct volume was 12.9+/-1.6 mm3 in mice breathing air. When started 45 min or 120 min after MCAO, NBO (10.8+/-2.2) and significantly more potently HBO (7.8+/-0.9) reduced infarct size. Repeated HBO treatments had no additional effect (8.3+/-2.3). HBO also significantly decreased TUNEL cell staining at 24 h. Combination of 60 min NBO plus 60 min HBO resulted in smaller cortical infarcts (8.7+/-1.5) than 120 min NBO alone (11.1+/-3.2). In contrast, infarct volumes in filament-induced permanent MCAO did not differ among rodents receiving air (50+/-24 mm3), NBO (48+/-16), or HBO (46+/-21). After filament-induced transient MCAO, however, HBO reduced infarct volume significantly. CONCLUSIONS: NBO and more effectively HBO protect the brain against permanent cortical ischemia. In extensive focal ischemia, however, oxygen therapy is only effective in case of early recanalization.

Neuronal expression of peroxisome proliferator-activated receptor-gamma (PPARgamma) and 15d-prostaglandin J2--mediated protection of brain after experimental cerebral ischemia in rat.

Existing experimental evidence suggests that PPARgamma may play a beneficial role in neuroprotection from various brain pathologies. Here we found that focal cerebral ischemia induced by middle cerebral/common carotid arteries occlusion (MCA/CCAo) induced up-regulation of PPARgamma messenger RNA in the ischemic hemisphere as early as 6 h after the ischemic event. The increased PPARgamma mRNA expression was primarily associated with neurons in the ischemic penumbra, suggesting an important role for PPARgamma in neurons after ischemia. Intraventricular injection of 15d-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a proposed endogenous PPARgamma agonist, into the ischemic rat brains significantly increased the PPARgamma-DNA-binding activity and reduced infarction volume at 24 h after reperfusion. We propose that PPARgamma up-regulation in response to ischemia may contribute to PPARgamma activation in the presence of PPARgamma agonists. Activation of PPARgamma in neurons at an early stage after ischemia may represent a pro-survival mechanism against ischemic injury.

IKK mediates ischemia-induced neuronal death.

The IkappaB kinase complex IKK is a central component of the signaling cascade that controls NF-kappaB-dependent gene transcription. So far, its function in the brain is largely unknown. Here, we show that IKK is activated in a mouse model of stroke. To investigate the function of IKK in brain ischemia we generated mice that contain a targeted deletion of Ikbkb (which encodes IKK2) in mouse neurons and mice that express a dominant inhibitor of IKK in neurons. In both lines, inhibition of IKK activity markedly reduced infarct size. In contrast, constitutive activation of IKK2 enlarged the infarct size. A selective small-molecule inhibitor of IKK mimicked the effect of genetic IKK inhibition in neurons, reducing the infarct volume and cell death in a therapeutic time window of 4.5 h. These data indicate a key function of IKK in ischemic brain damage and suggest a potential role for IKK inhibitors in stroke therapy.