Progress and Prospects in Parkinson's Research/Therapy/Neuroprotection/Neuroprotective agents

"Very many compounds are being explored for their potential neuroprotective properties. Finding one that was truly effective in preventing or slowing down Parkinson's would represent a major breakthrough. The sub-pages in this Neuroprotection section report on research on the following substances:"

More candidate neuroprotective agents
"This page can also be used for references to new neuroprotective agents that could be expanded on in subpages to be developed later."

Rescue of PD-infected yeast cells by four compounds found by screening 100,000 compounds
Su et al carried out a series of experiments using genetically modified yeast.

They modelled many of the features of alpha synuclein pathology observed in PD cases. They identified the YPK9 gene, which is the yeast homolog of PARK9/ATP13A2, as a suppressor of α-synuclein toxicity, were able to reproduce abnormalities in mitochondria observed in PD affected nigral neurons and established that:-

"mitochondrial dysfunction elicited by α-syn is not due to specific mislocalization to mitochondria through a cryptic signalling sequence. Rather, it is the perturbation of other cellular pathways impinged on by α-synuclein that leads to mitochondrial dysfunction and the generation of reactive free radicals."

They then carried out a high-throughput chemical screen to identify single agents that might be capable of rescuing the robust toxicity of this strain using a library of 115,000 small compounds. To score positive in the screen, the compounds needed to be able to (1) enter cells, (2) avoid clearance by core metabolic pathways, (3) alleviate α-syn toxicity without causing toxicity on their own at the screening concentration and (4) protect against at least two different features of α-synuclein toxicity within the HiTox cells.

Four compounds were identified that met these criteria.

The compounds were then used to treat PD-infected nematode worms and were found to rescue their affected nigral neurons.

"It is remarkable that brief treatment of adult worms with these compounds was neuroprotective well after the onset of α-synuclein expression, revealing that it is possible to arrest cell death even after the onset of toxicity."

The treatment was then tried out on mammalian cells using PD-infected neurons harvested from the embryos of rats and three of the compounds rescued these cells. Successful reversal of PD induced toxicity was achieved using cells that had been infected with rotenone.

Further results from this lab should be looked for and reported here or on a subpage as it emerges.

Anle138b - oligomer inhibitor
Wagner et al report an important breakthrough in the search for disease-modifying therapy for Parkinson’s and other neurological disorders. Parkinson’s disease is characterised by the formation of aggregates of the protein α-synuclein in the brain. Such oligomeric aggregations are presumed to be the key neurotoxic agents. In an article published on-line on 19 April 2013, in the journal Acta Neuropathologica, the research team describe work on Anle138b, an oligomer modulator, showing that in three different mouse models of PD, it strongly inhibits oligomer accumulation, neuronal degeneration and disease progression. Furthermore it has no detectable toxicity at therapeutic doses and an excellent bioavailability and blood-brain-barrier penetration.

This work needs to be monitored and reported on in a subpage as further results emerge.