Major progress has been made during the past three decades in understanding the inflammatory process and pathogenetic mechanisms in multiple sclerosis (MS). Consequently, effective anti-inflammatory and immunomodulatory treatments are now available for patients in the relapsing-remitting stage of the disease. This Review summarizes studies on the pathology of progressive MS and discusses new data on the mechanisms underlying its pathogenesis. In progressive MS, as in relapsing-remitting MS, active tissue injury is associated with inflammation, but the inflammatory response in the progressive phase occurs at least partly behind the blood-brain barrier, which makes it more difficult to treat. The other mechanisms that drive disease in patients with primary or secondary progressive MS are currently unresolved, although oxidative stress resulting in mitochondrial injury might participate in the induction of demyelination and neurodegeneration in both the relapsing-remitting and progressive stages of MS. Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age-dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process.

Progressive multiple sclerosis: pathology and pathogenesis

The translocator protein (18 kDa) (TSPO) is localized primarily in the outer mitochondrial membrane of steroid-synthesizing cells, including those in the central and peripheral nervous system. One of its main functions is the transport of the substrate cholesterol into mitochondria, a prerequisite for steroid synthesis. TSPO expression may constitute a biomarker of brain inflammation and reactive gliosis that could be monitored by using TSPO ligands as neuroimaging agents. Moreover, initial clinical trials have indicated that TSPO ligands might be valuable in the treatment of neurological and psychiatric disorders. This Review focuses on the biology and pathophysiology of TSPO and the potential of currently available TSPO ligands for the diagnosis and treatment of neurological and psychiatric disorders.

Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders

Amyotrophic lateral sclerosis (ALS) is a genetically diverse disease. At least 15 ALS-associated gene loci have so far been identified, and the causative gene is known in approximately 30% of familial ALS cases. Less is known about the factors underlying the sporadic form of the disease. The molecular mechanisms of motor neuron degeneration are best understood in the subtype of disease caused by mutations in superoxide dismutase 1, with a current consensus that motor neuron injury is caused by a complex interplay between multiple pathogenic processes. A key recent finding is that mutated TAR DNA-binding protein 43 is a major constituent of the ubiquitinated protein inclusions in ALS, providing a possible link between the genetic mutation and the cellular pathology. New insights have also indicated the importance of dysregulated glial cell-motor neuron crosstalk, and have highlighted the vulnerability of the distal axonal compartment early in the disease course. In addition, recent studies have suggested that disordered RNA processing is likely to represent a major contributing factor to motor neuron disease. Ongoing research on the cellular pathways highlighted in this Review is predicted to open the door to new therapeutic interventions to slow disease progression in ALS.

Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis

Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS.

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease affecting motor neurons with an incidence of about 1/100,000. Most ALS cases are sporadic, but 5-10% of the cases are familial ALS. Both sporadic and familial ALS (FALS) are associated with degeneration of cortical and spinal motor neurons. The etiology of ALS remains unknown. However, mutations of superoxide dismutase 1 have been known as the most common cause of FALS. In this study, we provide a comprehensive review of ALS. We cover all aspects of the disease including epidemiology, comorbidities, environmental risk factor, molecular mechanism, genetic factors, symptoms, diagnostic, treatment, and even the available supplement and management of ALS. This will provide the reader with an advantage of receiving a broad range of information about the disease.

A comprehensive review of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of cortical and spinal motor neurons, for which there is no effective treatment. Using a cell-based assay for compounds capable of preventing motor neuron cell death in vitro, a collection of approximately 40,000 low-molecular-weight compounds was screened to identify potential small-molecule therapeutics. We report the identification of cholest-4-en-3-one, oxime (TRO19622) as a potential drug candidate for the treatment of ALS. In vitro, TRO19622 promoted motor neuron survival in the absence of trophic support in a dose-dependent manner. In vivo, TRO19622 rescued motor neurons from axotomy-induced cell death in neonatal rats and promoted nerve regeneration following sciatic nerve crush in mice. In SOD1 G93A transgenic mice, a model of familial ALS, TRO19622 treatment improved motor performance, delayed the onset of the clinical disease, and extended survival. TRO19622 bound directly to two components of the mitochondrial permeability transition pore: the voltage-dependent anion channel and the translocator protein 18 kDa (or peripheral benzodiazepine receptor), suggesting a potential mechanism for its neuroprotective activity. TRO19622 may have therapeutic potential for ALS and other motor neuron and neurodegenerative diseases.

https://jpet.aspetjournals.org/content/jpet/early/2007/05/11/jpet.107.123000.full.pdf

Identification and Characterization of Cholest-4-en-3-one, Oxime (TRO19622), a Novel Drug Candidate for Amyotrophic Lateral Sclerosis

Dear Editor, Zonulin, or prehaptoglobin-2, mediates intestinal permeability in coeliac disease through the regulation of epithelial tight junctions.1 Tight junction breakdown at the blood–brain barrier (BBB) is a common pathological finding in neurological disease,2 and several in vitro and preclinical in vivo studies have suggested that zonulin plays a role inmodulation of BBBpermeability,3–6 yet using multiple methods, we here consistently find that zonulin plays a negligible role in human BBB permeability. Zonulin is a member of the MASP (mannose-binding lectin-associated serine protease) family of proteins, and elevated serum zonulin levels have been reported in a number of neurological conditions such as multiple sclerosis7 and Alzheimer’s disease.8 The significance of zonulin upregulation in these neurological diseases is not certain. Specifically, it is not clear whether zonulin is an epiphenomenon, or has an effect on the brain, whether directly or mediated through the gut–brain axis. To study the association between zonulin and BBB permeability in healthy individuals and patients with neurological disease, we employed two techniques to measure permeability across a range of molecular weights: QAlb, or the quotient of cerebrospinal fluid to serum albumin (60 000 Da) in Study A and dynamic contrastenhanced magnetic resonance imaging with gadobutrol tracer (600 Da) in Study B (Supplemental Methods). Participant characteristics are shown in Table 1. Out of a total of 217 cases (including people with neurological conditions and control individuals) across both studies, 58 (27%) individuals tested negative for serum zonulin using a novel enzyme-linked immunosorbent assay (ELISA) (Supplemental Methods). Serum zonulin concentration followed a non-Gaussian distributionwith a range of 0–11 μg/ml. Therewere no effects of sex, age or disease status (disease vs. control) on zonulin concentrations (analysis of covariance, F(3,216) = 1.06, p = .37). In order to assess zonulin using a complementary dual approach,

/pdf/zonulin-and-blood-brain-barrier-permeability-are-dissociated-d68e7uh1.pdf

Pascale Galéa

Papers

Identification and Characterization of Cholest-4-en-3-one, Oxime (TRO19622), a Novel Drug Candidate for Amyotrophic Lateral Sclerosis

Zonulin and blood–brain barrier permeability are dissociated in humans