Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. The pathology is mimicked to a striking degree in transgenic mice carrying familial ALS-linked SOD1 gene mutations. Olesoxime (TRO19622), a novel neuroprotective and reparative compound identified in a high-throughput screen based on motoneuron (MN) survival, delays disease onset and improves survival in mutant SOD1(G93A) mice, a model for ALS. The present study further analyses the cellular basis for the protection provided by olesoxime at the neuromuscular junctions (NMJ) and the spinal cord. Studies were carried out at two disease stages, 60 days, presymptomatic and 104 days, symptomatic. Cohorts of wild type and SOD1(G93A) mice were randomized to receive olesoxime-charged food pellets or normal diet from day 21 onward. Analysis showed that olesoxime initially reduced denervation from 60 to 30% compared to SOD1(G93A) mice fed with control food pellets while at the symptomatic stage only a few NMJs were still preserved. Immunostaining of cryostat sections of the lumbar spinal cord with VAChT to visualize MNs, GFAP for astrocytes and Iba1 for microglial cells showed that olesoxime strongly reduced astrogliosis and microglial activation and prevented MN loss. These studies suggest that olesoxime exerts its protective effect on multiple cell types implicated in the disease process in SOD1(G93A) mice, slowing down muscle denervation, astrogliosis, microglial activation and MN death. A Phase 3 clinical study in ALS patients will determine whether olesoxime could be beneficial for the treatment of ALS.

Elevated levels of IFNγ and LIGHT in the spinal cord of patients with sporadic amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a paralytic and fatal neurodegenerative disorder caused by the gradual loss of both upper and lower motoneurons. There is compelling evidence from ALS experimental models that neuroinflammation actively contributes to motoneuron damage. We recently proposed that interferon gamma (IFNγ), a potent proinflammatory cytokine, induces motoneuron death by eliciting the activation of the lymphotoxin beta receptor (LT-ßR) through its ligand LIGHT. Here, we explore the pertinence of this non-cell-autonomous mechanism in human ALS. METHODS: The levels and expression pattern of IFNγ, LIGHT, and LT-ßR were investigated by Western blot and immunohistochemical analysis in spinal cord of patients with sporadic ALS. RESULTS: We observed significant increased levels of IFNγ in human ALS spinal cords compared to control cases. We found that large ventral horn neurons as well as glial cells were immunoreactive for IFNγ in sporadic ALS spinal cord. We further observed that LIGHT and LT-ßR were expressed mainly by motoneurons in both ALS and control cases, and while LT-ßR levels remained constant between ALS and control cases, LIGHT levels were increased in human ALS spinal cords. CONCLUSION: These findings in sporadic ALS cases, which are consistent with the observation made in ALS experimental models, propose that the IFNγ-triggered LIGHT/LT-ßR-mediated death pathway may contribute to human ALS pathogenesis.

IFNγ triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that primarily affects motoneurons in the brain and spinal cord. Dominant mutations in superoxide dismutase-1 (SOD1) cause a familial form of ALS. Mutant SOD1-damaged glial cells contribute to ALS pathogenesis by releasing neurotoxic factors, but the mechanistic basis of the motoneuron-specific elimination is poorly understood. Here, we describe a motoneuron-selective death pathway triggered by activation of lymphotoxin-ß receptor (LT-ßR) by LIGHT, and operating by a novel signaling scheme. We show that astrocytes expressing mutant SOD1 mediate the selective death of motoneurons through the proinflammatory cytokine interferon-γ (IFNγ), which activates the LIGHT-LT-ßR death pathway. The expression of LIGHT and LT-ßR by motoneurons in vivo correlates with the preferential expression of IFNγ by motoneurons and astrocytes at disease onset and symptomatic stage in ALS mice. Importantly, the genetic ablation of Light in an ALS mouse model retards progression, but not onset, of the disease and increases lifespan. We propose that IFNγ contributes to a cross-talk between motoneurons and astrocytes causing the selective loss of some motoneurons following activation of the LIGHT-induced death pathway.

[Pirbuterol and salbutamol aerosol for exercise-induced bronchoconstriction]. / Pirbuterol- und Salbutamol-Aerosol gegen die anstrengungs-induzierte Bronchokonstriktion.

Exercise-induced bronchoconstriction was produced in 12 asthmatic patients after a 6 minutes run on a 10% steep treadmill ergometer. FEV1 decreased by 12-73% (average 27%) of the control value measured before the run. The rather severe exercise-induced bronchoconstriction remained constant for 10-20 minutes after the run. 21 minutes after the run two puffs of a bronchodilator (salbutamol 0.2 mg or pirbuterol 0.4 mg) were inhaled in an open randomized cross-over fashion at intervals of 1 to 3 days. Following both bronchodilators FEV1 returned to the control value within 5 minutes. There was no significant difference between the bronchodilating effect of salbutamol versus pirbuterol. Furthermore, no significant differences were observed in pulse rates after inhalation of the two selective beta-2-stimulators. In our trial both pirbuterol and salbutamol seemed to be well tolerated; side effects were not observed for either drug.