Ambroxol clinical trials and Experimental Models of Parkinson Disease; Review Article

Abstract

A clear understanding of Parkinson’s disease (PD) pathogenesis would aid in the development of therapies that may be able to slow or prevent the progression of this neurodegenerative disorder. Ambroxol (AMB), an FDA-approved drug for the treatment of respiratory diseases is currently under investigation in PD patients. AMB acts as a chaperone to convert glucocerebrosidase (GCase) to its full-length form and facilitates trafficking of GCase through the endoplasmic reticulum (ER). AMB is reported to increase GCase activity in brainstem, midbrain and cortex of alpha synuclein (α-syn) transgenic mice, to improve lysosomal biochemistry and to rescue defective GCase in GBA1 mutation-linked PD, GBA1 is the gene encoding glucocerebrosidase. Moreover, AMB not only increased GCase activity in wild type (WT) mice but also reduced α-syn levels and restored GCase activity in mice overexpressing human α-syn. Additionally, AMB treatment has been shown to improve the translocation of mutant GCase to the lysosome, increasing GCase activity in the lysosomes of fibroblast and lymphoblasts carrying GBA1 mutations. Also, in control fibroblasts treated with AMB, the activity of GCase was increased. Furthermore, AMB increased GBA1 mRNA, protein levels and activity, as well as, several lysosomal proteins such as cathepsin D, lysosomal marker (LAMP1), the GCase transporter lysosomal integral membrane protein type-2 (LIMP2) and GCase endogenous activator saposin C. Also, nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis was increased upon treatment with AMB. That is associated with activation of macroautophagy. Experimental models can be categorized into two main flavors: toxic and genetic (and sometimes, both approaches are combined)