Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate

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.

Keywords: Parkinson disease; ambroxol; glucocerebrosidase; nonhuman primate.

Figure 1

Glucocerebrosidase (GCase) and β‐hexosaminidase (HEXB) activity after daily treatment with different levels of ambroxol. (a–d) GCase activity did not increase with 22.5 mg ambroxol treatment in any region, but increased by about 20% in the midbrain, cortex and striatum and 5% in the cerebellum with 100 mg treatment. (e‐h) HEXB activity was increased by about 20% in the midbrain, cortex, and striatum, but not in the cerebellum, when treated with 100 mg ambroxol