Ruxolitinib in Aicardi-Goutières syndrome

Metabolic Brain Disease - Aicardi-Goutières Syndrome (AGS) is a monogenic leukodystrophy with pediatric onset, clinically characterized by a variable degree of neurologic impairment. It...     

Mediators of asthma: nitric oxide

Endogenous nitric oxide is an ubiquitous gaseous molecule that regulates many aspects of human airway biology including the modulation of airway and vascular smooth muscle tone. It is generated from the three different enzymes nitric oxide synthases (NOS) -1, -2 and -3 which are all expressed in pulmonary cells. NOS-1 is localised primarily to neuronal structures, where NO is a mediator of the inhibitory Non-Adrenergic Non-Cholinergic System and NOS-3 is present in endothelial cells. While these enzymes are constitutively expressed, NOS-2 is an inducible enzyme independent of calcium and highly induced in inflammatory diseases such as allergic asthma, where NO may act beneficial or deleterious depending on the site of and amount of generation. The use of NO-donor compounds or classical unselective NOS inhibitors did not lead to significant therapeutical effects in asthmatic patients. Insights on the precise role of NO in asthma can only be achieved by targeting NO generation selectively. More potent and selective NOS-2 inhibitors have to clarify a role of NOS-modification based therapy in clinical routine. NO can also be detected in the exhaled air. Increased levels of exhaled NO in asthmatic patients may be useful for a non-invasive determination of airway inflammation.     

A new variant of Bernard-Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV

We describe a new variant of Bernard-Soulier syndrome characterized by almost normal amounts of GPIb and severely reduced GPIX and GPV. Despite surface expression, GPIbα failed to support ristocetin-induced platelet agglutination and to bind two conformation-dependent monoclonal antibodies, suggesting a qualitative defect. Sequence analysis of the gene coding for GPIX revealed a T-to-C substitution at base 1811, leading to a Leu40Pro conversion, whereas no defects were found in the coding region of the GPIbα gene. Allele-specific restriction enzyme analysis showed that the propositus and one of his sisters, both with severe bleeding diathesis, were homozygous for the GPIX mutation; the members of the family with mild bleeding diathesis and/or giant platelets in the peripheral blood were heterozygous, whereas the healthy ones were homozygous for the normal allele.
Infusion of 1-desamino-8- d -arginine vasopressin normalized bleeding time in the two severely affected patients, although it did not modify ristocetin-induced platelet agglutination or membrane expression of GPIbα, GPIX, GPIIb–IIIa and GMP-140. Moreover, in one patient, normalization of bleeding time and rise of von Willebrand factor plasma concentration did not seem to be directly related.     

Effect of sensory denervation with capsaicin on liver fibrosis induced by common bile duct ligation in rat

Hepatic fibrosis represents an important stage in the progression of chronic liver disease to cirrhosis. In the present paper we have investigated whether capsaicin-sensitive neuropeptide-containing sensory neurons may participate in the development of liver fibrosis. The expression of hepatic fibrosis induced by common bile duct obstruction has been studied both in capsaicin- and vehicle-treated rats. Common bile duct-induced liver fibrosis was less marked in capsaicin-treated rats than in vehicle-treated rats. Diffuse alterations of liver parenchyma structure with marked collagen deposition and nodular regeneration occurred 8 weeks after common bile duct ligation in vehicle-treated animals, while none of the capsaicin-treated rats exhibited the formation of complete connective septa altering the parenchyma architecture. Both vehicle- and capsaicin-treated rats showed an increasing number of desmin-positive cells in the perivenular zone, but the density of these cells was lower in treated animals than in untreated rats. The hydroxyproline content of the liver increased after common bile duct ligation in a time-dependent manner. Eight weeks after bile duct obstruction vehicle-treated rats showed a 7-fold increase of liver collagen content in comparison to normal animals. This enhancement was about 3.5-fold in capsaicin-treated rats. These findings raise the possibility that the peripheral release of neuropeptides stored in sensory nerves might participate in the development of liver fibrosis following common bile duct obstruction.     

The TRPA1 channel in migraine mechanism and treatment

Migraine remains an elusive and poorly understood disease. The uncertainty is reflected by the currently unsatisfactory acute and prophylactic treatments for this disease. Genetic and pharmacological information points to the involvement of some transient receptor potential (TRP) channels in pain mechanisms. In particular, the TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) channels seem to play a major role in different models of pain diseases. Recent findings have underscored the possibility that TRP channels expressed in the nerve terminals of peptidergic nociceptors contribute to the migraine mechanism. Among this channel subset, TRPA1, a sensor of oxidative, nitrative and electrophilic stress, is activated by an unprecedented series of irritant and pain-provoking exogenous and endogenous agents, which release the pro-migraine peptide, calcitonin gene-related peptide, through this neuronal pathway. Some of the recently identified TRPA1 activators have long been known as migraine triggers. Furthermore, specific analgesic and antimigraine medicines have been shown to inhibit or desensitize TRPA1 channels. Thus, TRPA1 is emerging as a major contributing pathway in migraine and as a novel target for the development of drugs for pain and migraine treatment.

Linked Articles

This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10     

Glucose transporter type 1 deficiency: Ketogenic diet in three patients with atypical phenotype

Glucose transporter type I deficiency syndrome (GLUT-1 DS) is an inborn error of glucose transport characterized by seizures, developmental delay, spasticity, acquired microcephaly and ataxia. Diagnosis is based on the finding of low cerebrospinal fluid glucose, in the absence of hypoglycemia, and identification of GLUT-1 gene mutation on chromosome 1. The classic phenotype is a severe form of early onset epileptic encephalopathy, but patient with different clinical presentation have been reported expanding the clinical spectrum. In particular, many patients show a prominent movement disorder other than epilepsy. It is known that this disease represents a treatable condition and ketogenic diet (KD) is the elective treatment in GLUT-1 DS patients. We report on KD in three unrelated Italian GLUT-1 DS female patients, diagnosed in early adulthood, all presenting with an atypical phenotype. Preliminary results seem to demonstrate efficacy of KD on paroxysmal movement disorder while positive effect on cognitive impairment result less evident.     

Tachykinins via Tachykinin NK(2) receptor activation mediate ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs

1. Acute exposure to ozone is known to cause airway hyperresponsiveness, which, at least in part, seems to result from an increase in the permeability of the airway mucosa. Recently, we demonstrated that depletion of sensory neuropeptides inhibits the ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs. The aim of this study was to determine whether tachykinins mediate ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs. 2. Anaesthetized guinea-pigs were exposed to either 3 p.p.m. ozone or filtered air for 30 min. Immediately after exposure, a tracheal segment was isolated in vivo and administered with horseradish peroxidase (HRP). The permeability was assessed by monitoring the appearance of HRP in the blood. 3. A low dose of NKA increased the permeability of the tracheal mucosa, whereas a low dose of SP was without effect. Low and high doses of the selective NK(3) receptor agonist, senktide, were also without effect. The effect of a low dose of NKA was abolished by the NK(2) receptor antagonist, SR-48,968. A high dose of SP increased the permeability in a manner reversible by the NK(1) receptor antagonist, CP-96,345. 4. Pretreatment with SR-48,968 completely inhibited the ozone-induced increase in the permeability, whereas CP-96,345 had no effect. 5. It is thus concluded that endogenous tachykinins mediate the ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs mainly via NK(2) receptor activation.