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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30 neurological disorders with long ACRONYMS…and their checklists

Many neurological disorders and syndromes have very long and windy names. To bypass these tongue-twisting appellations, neurologists have become adept at coming up with great and catchy acronyms. Many neurological acronyms are very short, for example multiple sclerosis (MS), and Parkinosn’s disease (PD). Some are slightly longer, with three or four letters, for example frontotemporal dementia (FTD) and Lambert […]

via 30 neurological disorders with long ACRONYMS…and their checklists — Neurochecklists Updates

Is low vitamin D a cause of multiple sclerosis?

Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk Rhead B, Bäärnhielm M, Gianfrancesco M, et al. Neurol Genet 2016; 2:e97. Abstract OBJECTIVE: We sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject […]

via Is low vitamin D a cause of multiple sclerosis? — Neurochecklists Updates

What is the relationship of pregnancy to myasthenia gravis?

Increased risk for clinical onset of myasthenia gravis during the postpartum period Boldingh MI, Maniaol AH, Brunborg C, Weedon-Fekjær H, Verschuuren JJ, Tallaksen CM. Neurology 2016; 87:2139-2145. Abstract OBJECTIVE: To study the risk of clinical onset of myasthenia gravis (MG) in pregnancy and during the first 6 months postpartum because an association between pregnancy or […]

via What is the relationship of pregnancy to myasthenia gravis? — Neurochecklists Updates

Resolving the treatment conundrums of CIDP

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is as complicated to articulate, as it is to manage. CIDP is the result of an inflammatory attack against myelin, the fatty layer that encases large nerves. The damage to the myelin sheath considerably slows down the speed at which nerves transmit electrical impulses. This leads to limb weakness, sensory impairment, and a host of other symptoms.

By Dr. Jana - http://docjana.com/#/saltatory ; https://www.patreon.com/posts/4374048, CC BY 4.0, Link
By Dr. Jana – http://docjana.com/#/saltatory ; https://www.patreon.com/posts/4374048, CC BY 4.0, Link

The diagnosis of CIDP is made on the basis of a clinical examination, nerve conduction studies (NCS), spinal fluid analysis, and countless blood tests. If this convoluted diagnostic process is hair-tearing, the treatment is even more perplexing.

By Gentaur - Gentaur, Public Domain, https://commons.wikimedia.org/w/index.php?curid=7222221
By Gentaur – Gentaur, Public Domain, https://commons.wikimedia.org/w/index.php?curid=7222221

There are 2 major CIDP treatment conundrums. The first is whether to start the treatment with steroids, or with intravenous immunoglobulins (IVIg). The second conundrum is what to do when the patient fails to respond to both of these first line CIDP treatments. Two recent papers have now come to the rescue, and they hope to settle, once and for all, these two major neurological puzzles.

1. Choosing steroids or IVIg as 1st line treatment

PRED SOV 5. Leo Reynolds on Flikr. https://www.flickr.com/photos/lwr/3300474346
PRED SOV 5. Leo Reynolds on Flikr. https://www.flickr.com/photos/lwr/3300474346

The first line treatment for CIDP is usually a toss-up between steroids and intravenous  immunoglobulins (IVIg). This is because neurologists had no way of telling who will do well on steroids, and who will respond to IVIg. Until now, that is. A recent report in the Journal of Neurology, Neurosurgery and Psychiatry (JNNP) set out to understand what patient characteristics predict response to IVIg. The authors studied >200 people with CIDP treated with IVIg, and reported that 1/4 did not respond. These IVIg non-responders had the following features:

  • The presence of pain
  • Association with other autoimmune diseases
  • A difference in the severity of weakness between the arms and the legs
  • The absence of anti-myelin associated glycoprotein (anti-MAG)

The authors conclude that people with CIDP who have the features above should start their treatment with steroids rather than IVIg. This surely beats tossing a coin.

2. Choosing rituximab as 1st line treatment

By Oguenther at de.wikipedia - Own work mit Jmol auf Basis RCSB PDB: 2OSL., Public Domain, Link
By Oguenther at de.wikipediaOwn work mit Jmol auf Basis RCSB PDB: 2OSL., Public Domain, Link

Choosing the 2nd line treatment of CIDP is comparatively easy; swap between IVIG and steroids, or go for plasma exchange (PE). Rituximab, a monoclonal antibody, is now also recognised as an effective treatment for CIDP. Conventional practice is to use this expensive treatment only when both IVIg and steroids fail. A recent paper however suggests that people with CIDP who also have IgG4 antibodies do not respond to either IVIg or steroids. On the bright side however, they do well when treated with Rituximab. The paper in the journal Neurology is titled Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins. The authors studied only 4 patients, but the number was enough for them to suggest that patients with CIDP, who also have IgG4 antibodies, should be treated with Rituximab. Makes sense to me, if the alternative is predictable failure.

Flash light. Steve Johnson on Flikr. https://www.flickr.com/photos/artbystevejohnson/5202597852
Flash light. Steve Johnson on Flikr. https://www.flickr.com/photos/artbystevejohnson/5202597852

Now that some light has been shone on the treatment of CIDP, the next stage is to see how things work at the coal face. Do you have any feedback on CIDP treatment? Please leave a comment.

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40 rare metabolic neurological disorders and their checklists

Metabolic neurological disorders are rare and complex. Their diagnosis requires deep knowledge and long experience. These characteristics make metabolic neurological disorders most amenable to checklists. Below are 40 metabolic neurological disorders which are all covered in Neurochecklists 4H syndrome Adrenoleukodystrophy Adult polyglucosan body disease Alexander disease Autophagic vacuolar myopathy Biotin responsive basal ganglia disease Canavan disease Carnitine palmitoyl […]

via 40 rare metabolic neurological disorders and their checklists — Neurochecklists Updates