Reduction of neutrophil activity decreases early microvascular injury after subarachnoid haemorrhage

<p>Abstract</p> <p>Background</p> <p>Subarachnoid haemorrhage (SAH) elicits rapid pathological changes in the structure and function of parenchymal vessels (≤ 100 μm). The role of neutrophils in these changes has not been determined. This study investigates the role of neutrophils in early microvascular changes after SAH</p> <p>Method</p> <p>Rats were either untreated, treated with vinblastine or anti-polymorphonuclear (PMN) serum, which depletes neutrophils, or treated with pyrrolidine dithiocarbamate (PDTC), which limits neutrophil activity. SAH was induced by endovascular perforation. Neutrophil infiltration and the integrity of vascular endothelium and basement membrane were assessed immunohistochemically. Vascular collagenase activity was assessed by <it>in situ </it>zymography.</p> <p>Results</p> <p>Vinblastine and anti-PMN serum reduced post-SAH accumulation of neutrophils in cerebral vessels and in brain parenchyma. PDTC increased the neutrophil accumulation in cerebral vessels and decreased accumulation in brain parenchyma. In addition, each of the three agents decreased vascular collagenase activity and post-SAH loss of vascular endothelial and basement membrane immunostaining.</p> <p>Conclusions</p> <p>Our results implicate neutrophils in early microvascular injury after SAH and indicate that treatments which reduce neutrophil activity can be beneficial in limiting microvascular injury and increasing survival after SAH.</p

Genetic Ablation of PLA2G6 in Mice Leads to Cerebellar Atrophy Characterized by Purkinje Cell Loss and Glial Cell Activation

Infantile neuroaxonal dystrophy (INAD) is a progressive, autosomal recessive neurodegenerative disease characterized by axonal dystrophy, abnormal iron deposition and cerebellar atrophy. This disease was recently mapped to PLA2G6, which encodes group VI Ca2+-independent phospholipase A2 (iPLA2 or iPLA2β). Here we show that genetic ablation of PLA2G6 in mice (iPLA2β-/-) leads to the development of cerebellar atrophy by the age of 13 months. Atrophied cerebella exhibited significant loss of Purkinje cells, as well as reactive astrogliosis, the activation of microglial cells, and the pronounced up-regulation of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, glial cell activation and the elevation in TNF-α and IL-1β expression occurred before apparent cerebellar atrophy. Our findings indicate that the absence of PLA2G6 causes neuroinflammation and Purkinje cell loss and ultimately leads to cerebellar atrophy. Our study suggests that iPLA2β-/- mice are a valuable model for cerebellar atrophy in INAD and that early anti-inflammatory therapy may help slow the progression of cerebellar atrophy in this deadly neurodegenerative disease

Effect of Silane Coupling Agents on the Rheology, Dynamic and Mechanical Properties of Ethylene Propylene Diene Rubber/Calcium Carbonate Composites

The effects of three trimethoxysilanes with different functional groups on the rheology, dynamic and mechanical properties of ethylene propylene diene rubber (EPDM)/calcium carbonate (CaCO3) composites were investigated respectively. The results showed that the addition of silane increased the value of MH and MH–ML of the compounds. Geniosil XL 33 silane decreased the shear modulus of the EPDM/CaCO3 compounds, and the bound rubber content increased slightly with the addition of vinyl trimethoxy silane (VTMS) and methylacryloxy-methyltrimethoxysilane (Geniosil XL 33) silane in the compounds. The vulcanizates with the addition of the VTMS and Geniosil XL 33 silane showed a significant increase in tensile strength and abrasion resistance; however, ethyltrimethoxysilane (ETMS) silane weakened the tensile strength and abrasion resistance of the vulcanizates. At low strain, the cross-linking and reaggregation of fillers resulted in a high storage modulus of vulcanizates with silane. When the strain exceeded 10%, the storage modulus of the vulcanizates with the Geniosil XL 33 and VTMS silane was higher. The loss modulus and tan δ of the vulcanized rubber with the Geniosil XL 33 and VTMS silanes were lower compared to the ETMS and 0 silane

Shape Memory Behavior of Carbon Black-reinforced Trans-1,4-polyisoprene and Low-density Polyethylene Composites

Shape memory composites of trans-1,4-polyisoprene (TPI) and low-density polyethylene (LDPE) with easily achievable transition temperatures were prepared by a simple physical blending method. Carbon black (CB) was introduced to improve the mechanical properties of the TPI/LDPE composites. The mechanical, cure, thermal and shape memory properties of the TPI/LDPE/CB composites were investigated in this study. In these composites, the crosslinked network generated in both the TPI and LDPE portions acted as a fixed domain, while the crystalline regions of the TPI and LDPE portions acted as a reversible domain in shape memory behavior. We found the mechanical properties of composites were promoted significantly with an increase of CB content, accompanied with the deterioration of shape memory properties of composites. When CB dosage was 5 parts per hundred of rubber composites (phr), best shape memory property of composites was obtained with a shape fixity ratio of 95.1% and a shape recovery ratio of 95.0%

Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease.

Parkinson's disease (PD) is one of the most common movement disorders, and currently there is no effective treatment that can slow disease progression. Preserving and enhancing DA neuron survival is increasingly regarded as the most promising therapeutic strategy for treating PD. IRX4204 is a second generation retinoid X receptor (RXR) agonist that has no cross reactivity with retinoic acid receptors, farnesoid X receptor, liver X receptors or peroxisome proliferator-activated receptor PPARγ. We found that IRX4204 promotes the survival and maintenance of nigral dopaminergic (DA) neurons in a dose-dependent manner in primary mesencephalic cultures. Brain bioavailability studies demonstrate that IRX4204 can cross the blood brain barrier and reach the brain at nM concentration. Oral administration of IRX4204 can activate nuclear receptor Nurr1 downstream signaling in the substantia nigra (SN) andattenuate neurochemical and motor deficits in a rat model of PD. Our study suggests that IRX4204 represents a novel, potent and selective pharmacological means to activate cellular RXR-Nurr1 signaling and promote SN DA neuron survival in PD prevention and/or treatment

Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease.

Parkinson's disease (PD) is one of the most common movement disorders, and currently there is no effective treatment that can slow disease progression. Preserving and enhancing DA neuron survival is increasingly regarded as the most promising therapeutic strategy for treating PD. IRX4204 is a second generation retinoid X receptor (RXR) agonist that has no cross reactivity with retinoic acid receptors, farnesoid X receptor, liver X receptors or peroxisome proliferator-activated receptor PPARγ. We found that IRX4204 promotes the survival and maintenance of nigral dopaminergic (DA) neurons in a dose-dependent manner in primary mesencephalic cultures. Brain bioavailability studies demonstrate that IRX4204 can cross the blood brain barrier and reach the brain at nM concentration. Oral administration of IRX4204 can activate nuclear receptor Nurr1 downstream signaling in the substantia nigra (SN) andattenuate neurochemical and motor deficits in a rat model of PD. Our study suggests that IRX4204 represents a novel, potent and selective pharmacological means to activate cellular RXR-Nurr1 signaling and promote SN DA neuron survival in PD prevention and/or treatment