Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate.

Anna Migdalska‐Richards,Qin Li,Erwan Bezard,Wai Kin D Ko,Anthony H V Schapira

doi:10.1002/syn.21967

Abstract

Mutations in the glucocerebrosidase 1 (GBA1) gene are related to both Parkinson disease (PD) and Gaucher disease (GD). In both cases, the condition is associated with deficiency of glucocerebrosidase (GCase), the enzyme encoded by GBA1. Ambroxol is a small molecule chaperone that has been shown in mice to cross the blood‐brain barrier, increase GCase activity and reduce alpha‐synuclein protein levels. In this study, we analyze the effect of ambroxol treatment on GCase activity in healthy nonhuman primates. We show that daily administration of ambroxol results in increased brain GCase activity. Our work further indicates that ambroxol should be investigated as a novel therapy for both PD and neuronopathic GD in humans.

Highlights

Glucocerebrosidase (GCase) is an enzyme that catalyses the breakdown of glycolipid glucocerebroside to ceramide and glucose, which is encoded by the glucocerebrosidase 1 (GBA1) gene (Beutler, 1992)
This study provides the first preliminary data of the effect of ambroxol treatment on GCase activity in different brain regions in wild-type nonhuman primates
We observed about a 20% increase in GCase activity in the midbrain, cortex, and striatum of a cynomolgus monkey treated with 100 mg of ambroxol for 28 consecutive days

Summary

| INTRODUCTION

Glucocerebrosidase (GCase) is an enzyme that catalyses the breakdown of glycolipid glucocerebroside to ceramide and glucose, which is encoded by the glucocerebrosidase 1 (GBA1) gene (Beutler, 1992). Current estimates predict that 5–10% of PD patients carry a GBA1 mutation (PD-GBA1), this figure is much greater in PD patients of Ashkenazi origin (Bultron et al, 2010; Migdalska-Richards and Schapira, 2016; Sidransky et al, 2009). The increasing evidence highlighting the significance of GCase deficiency in both PD-GBA1 and idiopathic PD patients suggests that treatments that increase GCase might be advantageous to PD patients both with and without GBA1 mutations To this end, we have recently investigated a small molecular chaperone, ambroxol hydrochloride (ambroxol), in wild-type mice, in transgenic Gba mice carrying a heterozygous L444P mutation, and in transgenic mice overexpressing human alpha-synuclein (SNCA). We extend this work by analyzing the effect of ambroxol treatment on GCase activity in healthy nonhuman primates

| MATERIAL AND METHODS

| RESULTS

Findings

| DISCUSSION