What are the drugs promising neuroprotection in PD?

This is a follow up to my previous blog post titled The emerging research boosting Parkinson’s disease treatment. That post reviewed breakthroughs in the treatment of Parkinson’s disease (PD). But what are the advances in preventing the dreaded disease? What is the state of neuroprotection in PD? What are the hopes for attaining this elusive holy grail of neurology, the lodestone of neuroscientists?

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Previous claims to neuroprotection have unfortunately fallen flat on their faces. For example, those with long memories will remember the unfulfilled hopes of selegiline. It is therefore not surprising that neurologists entertain all reports of neuroprotection with a heavy dose of scepticism. But this has not deterred the flow of drugs which aim to achieve the seemingly improbable. After scanning the neuroprotection horizon, I came up with this list of 7 potential neuroprotective drugs for PD.

LB-3627

Lab Mouse chekin out the camera. Rick Eh? on Flikr. https://www.flickr.com/photos/rick-in-rio/2593063816
Lab Mouse chekin out the camera. Rick Eh? on Flikr. https://www.flickr.com/photos/rick-in-rio/2593063816

LB-3627 is a drug which is reported to protect dopamine-producing cells in experimental animals. The wary neurologist will surely ignore the hype in the headlines such as New drug that protects dopamine cells raises treatment hope for Parkinson’s, or Pioneering Neuroprotective Results Achieved in Parkinson’s Disease Preclinical Studies. The neurologists will prefer to forensically interrogate the study directly, and it is published in Journal of Neuroscience as Selective VIP Receptor Agonists Facilitate Immune Transformation for Dopaminergic Neuroprotection in MPTP-Intoxicated Mice. The researchers theorise that the damage to dopamine producing cells in the brain is a result of some sort of inflammation, and this damage can be prevented if vasoactive intestinal peptide (VIP) receptors on the cells are ‘tuned’ correctly. LB-3627, by acting as a VIP-like substance, seems to do this tuning quite well. By doing this, it protects up to 80% of the cells in PD mice. The dubious, but curious, neurologists will await the results of human trials.

Phenylbutyrate

By Marvin 101 - Own work, CC BY-SA 3.0, Link
By Marvin 101Own work, CC BY-SA 3.0, Link

α-synuclein is the abnormal protein which accumulates in brain cells, thereby causing the damage which results in PD. α-synuclein is removed from the brain by another protein named DJ-1. Researchers have shown that the gene which regulates the production of DJ-1 is abnormal in a hereditary form of PD called PARK-7. This is where phenylbutyrate steps into the picture; studies have shown that phenylbutyrate ‘up-regulates‘ the DJ-1 gene, thereby enhancing its activity, which is to efficiently flush α-synuclein out of the brain. As phenylbutyrate seems to do this trick in mice, human trials are now under way. All is explained in the paper published in the Journal of Biological Chemistry titled Phenylbutyrate upregulates DJ-1 and protects neurons in cell culture and in animal models of Parkinson’s disease.

Rapamycin

mTOR-FKBP12-RAPAMYCIN. Enzymlogic on Flikr. https://www.flickr.com/photos/101755654@N08/9735128265
mTOR-FKBP12-RAPAMYCIN. Enzymlogic on Flikr. https://www.flickr.com/photos/101755654@N08/9735128265

What we need is a drug which stops PD from taking its first step. And this is what Rapamycin seems to have done in mice. I first read this in an article in PsyPost brilliantly titled Rapamycin prevents Parkinson’s in mouse model of incurable neurodegenerative disease. I followed the link to the research paper published in Journal of Neuroscience, irritatingly titled Mitochondrial Quality Control via the PGC1α-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin. I tried to decipher what the abstract was saying but read like a foreign language to me. I therefore recommend the PsyPost article for the sake of sanity. Again, we have to wait and see what rapamycin does in humans.

Safinamide

Microglia. Servier Medical Art on Flikr. https://www.flickr.com/photos/serviermedicalart/9731764084
Microglia. Servier Medical Art on Flikr. https://www.flickr.com/photos/serviermedicalart/9731764084

PD researchers are also exploring the neuroprotective potential of safinamide. This is a monoamine oxidase inhibitor (MAOI) which reduces the breakdown of levodopa, the key drug treatment of PD. Safinamide is already licensed as an add-on drug in the treatment of PD. Its neuroprotective effect has been linked to its ability to suppress the activation of microglia, the brain cells which mediate inflammatory cellular damage. Only time will tell.

Miscellaneous

The last three potentially  neuroprotective PD drugs are:

Simvastatin

Ambroxol

Exenatide

 

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Portents of great things to come, I’m sure. Want to explore more on PD? Have a look at these older posts, and do leave a comment

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