BackgroundCurrently there are no disease-modifying treatments for Parkinson’s disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson's disease is being a carrier in the gene for β-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures.MethodsThis is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer’s disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician’s Global Impression of Change (CGIC). Secondary measures will include the Parkinson’s disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson’s disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes.DiscussionIf found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD.Trial registrationClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered.

Calpains are cytosolic, neutral proteases that normally exist in an inactive or quiescent state. They require higher than normal levels of calcium for activation which, once accomplished, lead to irreversible proteolysis of numerous cytoskeletal, membrane-associated and regulatory proteins. Because of these characteristics, calpain is gaining attention as a potentially important pathogenic variable in ischemic neuronal death. This manuscript explores this hypothesis by briefly reviewing current support for the role played by calpain in ischemic neurodegeneration, and then discussing a series of recently published studies which: 1. offer further evidence for the hypothesis, and 2. provide direct support for the idea that selective inhibition of calpain can greatly limit the neuronal damage that would normally occur following both global as well as focal brain ischemia. Thus, the data reviewed in this manuscript support the ideas that unregulated activation and proteolysis of intraneuronal calpain plays a significant role in the brain damage that occurs following an ischemic event and that delivering selective and membrane permeant calpain inhibitors to ischemic tissue may provide a powerfully effective therapeutic means of limiting neuronal damage.

One of the most challenging fundamental problems in establishing prebiotically plausible routes for phosphorylation reactions using phosphate is that they are thermodynamically unfavorable in aqueous conditions. Diamidophosphate (DAP), a potentially prebiotically relevant compound, was shown to phosphorylate nucleosides in aqueous medium, albeit at a very slow rate (days/weeks). Here, we demonstrate that performing these reactions within an aerosol environment, a suitable model for the early Earth ocean-air interface, yields higher reaction rates when compared to bulk solution, thus overcoming these rate limitations. As a proof-of-concept, we demonstrate the effective conversion (~6.5–10%) of uridine to uridine-2′,3′-cyclophosphate in less than 1 h. These results suggest that aerosol environments are a possible scenario in which prebiotic phosphorylation could have occurred despite unfavorable rates in bulk solution.

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