The blood-brain barrier (BBB) dysfunction represents an early feature of Alzheimer's disease (AD) that precedes the hallmarks amyloid beta (amyloid β) plaque deposition and neuronal neurofibrillary tangle (NFT) formation. A damaged BBB correlates directly with neuroinflammation involving microglial activation reactive astrogliosis, which is associated increased expression and/or release high-mobility group box protein 1 (HMGB1) thrombin. However, link between presence these molecules,...

The objective of this study was to investigate the safety and efficacy recombinant human insulinlike growth factor-I (rhIGF-I) in treatment sporadic ALS. A double-blind, placebo-controlled, randomized 266 patients conducted at eight centers North America. Placebo or rhIGF-I(0.05 mg/kg/day 0.10 mg/kg/day) administered for 9 months. primary outcome measure disease symptom progression, assessed by rate change (per patient slope) Appel ALS rating scale total score. Sickness Impact Profile (SIP),...

Abstract Minocycline, a clinically used tetracycline for over 40 years, crosses the blood–brain barrier and prevents caspase up‐regulation. It reduces apoptosis in mouse models of Huntington's disease familial amyotrophic lateral sclerosis (ALS) is clinical trial sporadic ALS. Because also occurs after brain spinal cord (SCI) injury, its prevention may be useful improving recovery. We analyzed minocycline's neuroprotective effects 28 days following contusion SCI found significant functional...

Following a controlled, severe contusion lesion to the lower thoracic spinal cord in adult rats, we found that apoptosis occurred cells located both gray and white matter. This suggested nonneuronal cells, including astrocytes, oligodendroglia microglia, as well neurons, might participate programmed cell death (PCD) following injury (SCI). Determination of which populations participate, kinetics extent their involvement reveal new paradigms for approaches therapy. Consequently, assessed...

Previous studies have demonstrated that electrically induced seizures in rat result an increased brain intracellular sodium which can be decreased by treatment with diphenylhydantoin (DPH). The correlation of cation transport membrane-oriented sodium-potassium-adenosine triphosphatase (Na-K-ATPase) prompted investigation the effect DPH upon ATPase enzyme activity.Rat cerebral cortical synaptosomes isolated Ficoll gradients were employed as source for Na-K-ATPase. With 50 mM Na, 10 K, 7.5 Mg,...

Abstract In synaptosomes isolated from rat brain cortex, sodium- and potassium-activated adenosine triphosphatase is present in high concentration (70 µmoles of Pi per mg protein 30 min). The maximal sodium-potassium-ATPase activity occurred with sodium potassium concentrations similar to those necessary achieve synthesis, oxygen uptake, accumulation (50 mm 10 potassium). Furthermore, varying the or yielded parallel alterations activity, transport. Ouabain (10-4 m) inhibited by 98%; 40%;...

Abstract Activation of microglia, the resident macrophages in CNS, plays a significant role neuronal death or degeneration broad spectrum CNS disorders. Recent studies indicate that nanomolar concentrations serine protease, thrombin, can activate microglia culture. However, contrast to other neural cells responsive participation novel protease‐activated receptors (PARs), such as prototypic thrombin receptor PAR1, thrombin‐induced microglial activation was cast doubt. In this report, by...

Molecular mechanisms of activity-dependent synapse reduction were studied in an vitro mammalian neuromuscular preparation. Synapse this model is and substantially reduced by the broad-spectrum protease inhibitor, leupeptin, suggesting role proteolytic action process. Our present experiments show that a potent specific thrombin hirudin, at nanomolar concentration completely blocked reduction. Furthermore, naturally occurring serine nexin I (PNI), which closely colocalizes with acetylcholine...

Increasing evidence indicates several roles for thrombin-like serine proteases and their cognate inhibitors (serpins) in normal development and/or pathology of the nervous system. In addition to its prominent role thrombosis hemostasis, thrombin inhibits neurite outgrowth neuroblastoma primary neuronal cells vitro, prevents stellation glial cells, induces cell death cultures. Thrombin is known act via a surface protease-activated receptor (PAR-1), recent suggests that rodent neurons express...

Abstract Endplate 16S acetylcholinesterase (16S‐AChE) from rat anterior gracilis muscle was assessed, 6 hr to 10 days after denervation, by velocity sedimentation analysis on linear sucrose gradients. The innervating obturator nerve transected either close (1‐2 mm, short stump) or far (35‐40 long the muscle. In both instances, activity of 16S‐AChE gradually decreased and reached approximately same level (10%‐20% control) denervation. However, enzymatic decay started considerably earlier in...

Neuroinflammation occurs in Alzheimer's disease (AD). While AD genetic studies implicate inflammation-relevant genes and fibrillar amyloid-β protein promotes inflammation, our understanding of neuroinflammation nevertheless remains incomplete. In

We have previously reported that thrombin, the ultimate serine protease in coagulation cascades, is a proinflammatory agent causes proliferation and activation of brain microglial cells. However, participation its principal receptor, protease-activated receptor 1 (PAR1) appears to be limited promoting not induction inflammatory mediators. In present study, we now report thrombin action mediators from microglia mediated through another PAR4. Here show PAR4 agonist peptide (PAR4AP, GYPGKF),...

In order to understand the mechanism for insoluble neurotoxic protein polymerization in Alzheimer's disease (AD) brain neurons, we examined and gene expression transglutaminase (TGase 2; tissue (tTG)) hippocampus isocortex. We found co-localization of tTG activity with tau-positive neurofibrillary tangles, whereas mRNA sequence analysis indicated an absolute increase synthesized. Although apoptosis AD is now established mode neuronal cell death, no definite underlying mechanism(s) known....

<h3>Objective:</h3> To identify the genetic variant that causes autosomal dominantly inherited motor neuron disease in a 4-generation Israeli-Arab family using linkage and whole exome sequencing. <h3>Methods:</h3> Genetic analysis was performed this Illumina single nucleotide polymorphism chips. Whole sequencing then undertaken on DNA samples from 2 affected members an 2000 HiSeq platform pursuit of potentially pathogenic variants comigrate with pedigree. Variants meeting these criteria were...

Protease nexin I (PNI) is a member of the family serine protease inhibitors (serpins) that have been shown to promote neurite outgrowth in vitro from different neuronal cell types. These include neuroblastoma cells, hippocampal neurons, and sympathetic neurons. Free PNI protein markedly decreased various anatomical brain regions, including hippocampus, patients with Alzheimer disease. Here, we report rescued spinal motoneurons during period naturally occurring (programmed) death chicken...

Tau hyperphosphorylation, leading to self-aggregation, is widely held underlie the neurofibrillary degeneration found in Alzheimer's disease (AD) and other tauopathies. However, it unclear exactly what environmental factors may trigger this pathogenetic tau hyperphosphorylation. From several perspectives, coagulation serine protease, thrombin, has been implicated AD activates different protein kinase pathways but not previously shown how contribute pathogenesis. Here we report that nanomolar...

Abstract Astrocytes appear star‐shaped in the brain, increasingly so after injury. When astroglia are cultures serum‐containing medium, they exhibit a flat, fibroblast‐like morphology. In serum‐free astrocytes become stellate, with many long processes. The serine protease α‐thrombin mimics effects of serum at subnanomolar concentractions, whereas thrombin‐inhibiting serpin, nexin I (PNI), reverses thrombin effect. our current experiements, murine neonatal spinal cord became stellate 4 hr...