Glucosylceramide and Glucosylsphingosine Quantitation by Liquid Chromatography-Tandem Mass Spectrometry to Enable In Vivo Preclinical Studies of Neuronopathic Gaucher Disease.

Gaucher disease (GD) is caused by mutations in the GBA1 gene that encodes the lysosomal enzyme acid ß-glucosidase (GCase). Reduced GCase activity primarily leads to the accumulation of two substrates, glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Current treatment options have not been shown to ameliorate the neurological pathology observed in the most severe forms of GD, clearly representing an unmet medical need. To better understand the relationship between GlcCer and GlcSph accumulation and ultimately their connection with the progression of neurological pathology, we developed LC-MS/MS methods to quantify GlcCer and GlcSph in mouse brain tissue. A significant challenge in developing these methods was the chromatographic separation of GlcCer and GlcSph from the far more abundant isobaric galactosyl epimers naturally occurring in white matter. After validation of both methods, we evaluated the levels of both substrates in five different GD mouse models, and found significant elevation of brain GlcSph in all five, while GlcCer was elevated in only one of the five models. In addition, we measured GlcCer and GlcSph levels in the brains of wild-type mice after administration of the GCase inhibitor conduritol ß-epoxide (CBE), as well as the nonlysosomal ß-glucosidase (GBA2) inhibitor N-butyldeoxygalactonojirimycin (NB-DGJ). Inhibition of GCase by CBE resulted in elevation of both sphingolipids; however, inhibition of GBA2 by NB-DGJ resulted in elevation of GlcCer only. Taken together, these data support the idea that GlcSph is a more selective and sensitive biomarker than GlcCer for neuronopathic GD in preclinical models.

Inflammatory Biomarkers for Mood Disorders - A Brief Narrative Review.

BACKGROUND: The nervous system and the immune system interact consistently in the brain and peripheries. Inflammation in the brain not only alters the metabolism of neurotransmitters, but also causes network dysfunction, structural changes, and the development of mood symptomology in patients with mood disorders. In addition, the dysregulation of the neuroimmune axis in mood disorders drives multiple-system comorbidities. Furthermore, patients with low-grade inflammation are more likely to exhibit treatment resistance with both pharmacotherapy and non-pharmacotherapy. OBJECTIVE: The aim of this review was to examine the available data regarding not only evidence of inflammation in the pathophysiology of mood disorders and their comorbid conditions, but also potential inflammatory biomarkers of mood disorders. METHODS: Studies of the use of adjunct anti-inflammatory medications in mood disorders, and inflammatory biomarkers that may guide treatment outcomes in mood disorders, were summarized. RESULTS: Studies have demonstrated that certain adjunct anti-inflammatory medications might help to improve mood symptoms and reduce comorbidities, and the baseline levels of inflammatory biomarkers, such as peripheral C-reactive protein (CRP), could be used to stratify the treatment outcome. All results suggested that the identification of peripheral and brain inflammatory biomarkers for the diagnosis, outcome prediction, staging, and stratification of interventions of mood disorders has emerged as an important area of translational research in psychiatry. CONCLUSION: Inflammatory biomarkers could guide interventions and enhance treatment response in patients with mood disorders. The main challenge is that substantial complexities might hamper the attainment of this goal.