Managing amyotrophic lateral sclerosis: Slowing disease progression and improving patient quality of life

Brooks, Benjamin Rix

doi:10.1002/ana.21544

Cited by 41 publications

(15 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The increase in neurotoxin QUIN is of significance as it would result in increase excitotoxicity and oxidative stress, exacerbating motor neuron degeneration in ALS. As the glutamate modulator, riluzole, is the only drug currently approved for ALS treatment and studies support ALS as a multifactorial disease, combination therapies that target other pathogenic mechanisms may be more effective in slowing disease progression and prolonging survival (Brooks 2009). Compounds targeting the KP offer a novel and potentially effective treatment for ALS.…”

Section: Discussionmentioning

confidence: 99%

The Kynurenine Pathway and Inflammation in Amyotrophic Lateral Sclerosis

et al. 2009

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease of unknown pathogenesis. The kynurenine pathway (KP), activated during neuroinflammation, is emerging as a possible contributory factor in ALS. The KP is the major route for tryptophan (TRP) catabolism. The intermediates generated can be either neurotoxic, such as quinolinic acid (QUIN), or neuroprotective, such as picolinic acid (PIC), an important endogenous chelator. The first and inducible enzyme of the pathway is indoleamine 2,3-dioxygenase (IDO). The present study aimed to characterize the expression of the KP in cerebrospinal fluid (CSF), serum and central nervous system (CNS) tissue of ALS patients. Using high performance liquid chromatography, we analysed the levels of TRP and kynurenine (KYN), and, with gas chromatography/mass spectrometry, the levels of PIC and QUIN, in the CSF and serum of ALS patients and control subjects. Immunohistochemistry was employed to determine the expression of QUIN, IDO and human leukocyte antigen-DR (HLA-DR) in sections of brain and spinal cord from ALS patients. There were significantly increased levels of CSF and serum TRP (P < 0.0001), KYN (P < 0.0001) and QUIN (P < 0.05) and decreased levels of serum PIC (P < 0.05) in ALS samples. There was a significant increase in activated microglia expressing HLA-DR (P < 0.0001) and increased neuronal and microglial expression of IDO and QUIN in ALS motor cortex and spinal cord. We show the presence of neuroinflammation in ALS and provide the first strong evidence for the involvement of the KP in ALS. These data point to an inflammation-driven excitotoxic-chelation defective mechanism in ALS, which may be amenable to inhibitors of the KP.

show abstract

Section: Discussionmentioning

confidence: 99%

The Kynurenine Pathway and Inflammation in Amyotrophic Lateral Sclerosis

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Transport of taurine, a beta-amino acid and has neuroprotective effect, which is mediated by TAUT in TR-BBB cells [22]. Riluzole (2-amino-6-trifluoromethoxy benzothiazole) is a neuroprotective drug approved for amyotrophic lateral sclerosis [45] and activates GLT-1 and GLAST to enhance glutamate uptake [46, 47], but there have been poor mechanistic experiments to transport riluzole across the BBB to the brain. L -Citrulline transport is not affected by these two drugs via different transport systems in TR-BBB cells.…”

Section: Discussionmentioning

confidence: 99%

Characteristics of L-citrulline transport through blood-brain barrier in the brain capillary endothelial cell line (TR-BBB cells)

Lee

Kang

2017

J Biomed Sci

View full text Add to dashboard Cite

Background L-Citrulline is a neutral amino acid and a major precursor of L-arginine in the nitric oxide (NO) cycle. Recently it has been reported that L-citrulline prevents neuronal cell death and protects cerebrovascular injury, therefore, L-citrulline may have a neuroprotective effect to improve cerebrovascular dysfunction. Therefore, we aimed to clarify the brain transport mechanism of L-citrulline through blood-brain barrier (BBB) using the conditionally immortalized rat brain capillary endothelial cell line (TR-BBB cells), as an in vitro model of the BBB.MethodsThe uptake study of [14C] L-citrulline, quantitative real-time polymerase chain reaction (PCR) analysis, and rLAT1, system b0,+, and CAT1 small interfering RNA study were performed in TR-BBB cells.ResultsThe uptake of [14C] L-citrulline was a time-dependent, but ion-independent manner in TR-BBB cells. The transport process involved two saturable components with a Michaelis–Menten constant of 30.9 ± 1.0 μM (Km1) and 1.69 ± 0.43 mM (Km2). The uptake of [14C] L-citrulline in TR-BBB cells was significantly inhibited by neutral and cationic amino acids, but not by anionic amino acids. In addition, [14C]L-citrulline uptake in the cells was markedly inhibited by 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), which is the inhibitor of the large neutral amino acid transporter 1 (LAT1), B0, B0,+ and harmaline, the inhibitor of system b0,+. Gabapentin and L-dopa as the substrates of LAT1 competitively inhibited the uptake of [14C] L-citrulline. IC50 values for L-dopa, gabapentin, L-phenylalanine and L-arginine were 501 μM, 223 μM, 68.9 μM and 33.4 mM, respectively. The expression of mRNA for LAT1 was predominantly increased 187-fold in comparison with that of system b0,+ in TR-BBB cells. In the studies of LAT1, system b0,+ and CAT1 knockdown via siRNA transfection into TR-BBB cells, the transcript level of LAT1 and [14C] L-citrulline uptake by LAT1 siRNA were significantly reduced compared with those by control siRNA in TR-BBB cells.ConclusionsOur results suggest that transport of L-citrulline is mainly mediated by LAT1 in TR-BBB cells. Delivery strategy for LAT1-mediated transport and supply of L-citrulline to the brain may serve as therapeutic approaches to improve its neuroprotective effect in patients with cerebrovascular disease.

show abstract

“…8 Such a delay precludes early initiation of neuroprotective treatments. 9 Second, the phenotypic heterogeneity of the disease is an important confounding factor in clinical trials because it results in a limited inclusion of patients (which requires the fulfillment of the revised El Escorial criteria 10 ) and in a highly variable treatment response. Several neuroimaging modalities have been used with varying success either to aid the clinical process of establishing a diagnosis of sporadic ALS or to monitor disease progression.…”

mentioning

confidence: 99%

The Present and the Future of Neuroimaging in Amyotrophic Lateral Sclerosis

Agosta¹,

Chiò²,

Cosottini³

et al. 2010

AJNR Am J Neuroradiol

116

View full text Add to dashboard Cite

SUMMARY:In patients with ALS, conventional MR imaging is frequently noninformative, and its use has been restricted to excluding other conditions that can mimic ALS. Conversely, the extensive application of modern MR imagingϪbased techniques to the study of ALS has undoubtedly improved our understanding of disease pathophysiology and is likely to have a role in the identification of potential biomarkers of disease progression. This review summarizes how new MR imaging technology is changing dramatically our understanding of the factors associated with ALS evolution and highlights the reasons why it should be used more extensively in studies of disease progression, including clinical trials.ABBREVIATIONS: ALS ϭ amyotrophic lateral sclerosis; ALSFRS ϭ ALS Functional Rating Scale; Cho ϭ choline; Cr ϭ creatine; CST ϭ corticospinal tract; DTI ϭ diffusion tensor imaging; FA ϭ fractional anisotropy; FLAIR ϭ fluid-attenuated inversion recovery; fMRI ϭ functional MR imaging; FTD ϭ frontotemporal dementia; FUS/TLS ϭ fused in sarcoma/translocated in liposarcoma gene; GM ϭ gray matter; 1 H-MR spectroscopy ϭ proton MR spectroscopy; L ϭ left; LMN ϭ lower motor neuron; MD ϭ mean diffusivity; mIns ϭ myo-inositol; MT ϭ magnetization transfer; MTR ϭ MT ratio; NAA ϭ N-acetylaspartate; ns ϭ not significant; PD ϭ proton density; R ϭ right; SOD1 ϭ superoxide dismutase 1; SPM ϭ statistical parametric mapping; TDP-43 ϭ TAR DNA-binding protein gene; UMN ϭ upper motor neuron; VBM ϭ voxel-based morphometry; WM ϭ white matter A LS, also known as motor neuron disease, is a neurodegenerative disorder characterized by a progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, brain stem, and spinal cord. The phenotypic expression of ALS is highly heterogeneous and determined by 4 elements: 1) body region of onset, 2) relative mix of UMN and LMN involvement, 3) rate of progression, and 4) cognitive impairment.1 In approximately 5%-10% of patients, the disease is inherited; 20% of these individuals have a mutation of the SOD1 gene; approximately 2%-5%, of the TARDBP (TDP-43) gene; and 2%-4%, of the FUS/TLS gene. 2Most patients with ALS, however, have no obvious family history and have sporadic ALS.2 To date, the only specific marker of sporadic ALS is the presence of inclusions staining positively for ubiquitin and TDP-43 in degenerating motor neurons. 3Despite technical advances in medicine in the last century, the diagnosis of sporadic ALS relies on the interpretation of clinical symptoms and signs (ie, signs suggestive of combined UMN and LMN degeneration, together with disease progression compatible with a neurodegenerative disorder). Paraclinical and laboratory tests are used only to exclude "ALS-mimic" syndromes. 4,5 In ALS, the absence of a disease marker for UMN and LMN involvement has 2 main negative consequences. First, the delay from onset of the disease to diagnosis of ALS can vary between 13 and 18 months 6,7

show abstract

Managing amyotrophic lateral sclerosis: Slowing disease progression and improving patient quality of life

Cited by 41 publications

References 81 publications

The Kynurenine Pathway and Inflammation in Amyotrophic Lateral Sclerosis

The Kynurenine Pathway and Inflammation in Amyotrophic Lateral Sclerosis

Characteristics of L-citrulline transport through blood-brain barrier in the brain capillary endothelial cell line (TR-BBB cells)

The Present and the Future of Neuroimaging in Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

About