title: Combined beta-glucosylceramide and ambroxol hydrochloride in patients with Gaucher related Parkinson disease: From clinical observations to drug development.
abstract: Both patients with non-neuronopathic Gaucher disease (GD) and heterozygous GBA mutation carrier are at increased risk for Parkinson disease (PD). The risk for PD in these groups does not linearly increase with glucosylceramide (GC) accumulation or with acid β-glucocerebrosidase (GCase) activity. This observation, together with other clinical systemic observations raises the possibility that extra-cellular GC actually has beneficial, anti-inflammatory, properties. Based on this hypothesis, we suggest here that the administration of supplementary oral GC to GBA carriers at risk for PD may slow inflammatory-driven secondary neuronal death. Such a treatment may act synergistically in GBA carriers once given in combination with an agent that prevent the primary pathologic process that leads to cell death. Ambroxol hydrochloride, a pharmacological chaperone, which reduces endoplasmic reticulum (ER) stress induced by accumulation of mutant misfolded GCase could serve as such an agent. The efficacy of this combined therapy, derived from clinical observations, in vivo and in vitro studies, should be evaluated in clinical trials.
authors.affiliation: Department of Medicine, Hadassah Medical Center and the Hebrew University, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Ishay
authors.affiliation: Gaucher Clinic, Shaare Zedek Medical Center and the Hebrew University, Jerusalem, Israel.
authors.forename: Ari
authors.initials: A
authors.lastname: Zimran
authors.affiliation: Department of Clinical Hematology, The Royal Melbourne Hospital, Melbourne, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Szer
authors.affiliation: Gaucher Clinic, Shaare Zedek Medical Center and the Hebrew University, Jerusalem, Israel.
authors.forename: Tama
authors.initials: T
authors.lastname: Dinur
authors.affiliation: Department of Medicine, Hadassah Medical Center and the Hebrew University, Jerusalem, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Ilan
authors.affiliation: Department of Neurology, Hadassah Medical Center and the Hebrew University, Jerusalem, Israel. Electronic address: arkadir@hadassah.org.il.
authors.forename: David
authors.initials: D
authors.lastname: Arkadir
mesh_terms: D000551:Ambroxol / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D055808:Drug Discovery; D005100:Expectorants / Q000627:therapeutic use*; D005776:Gaucher Disease / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005962:Glucosylceramidase / Q000235:genetics; D005963:Glucosylceramides / Q000627:therapeutic use*; D006801:Humans; D009154:Mutation; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology* / Q000235:genetics / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D005100:Expectorants; D005963:Glucosylceramides; D000551:Ambroxol; D005962:Glucosylceramidase
keywords: Ambroxol hydrochloride; Beta glucosylceramide; Gaucher disease; Parkinson disease