Resolvin(g) Parkinson’s

A major focus on Parkinson’s research is inflammation. Inflammation is a vital part of our immune system’s response to infection or injury. It is means by which the body signals to the cells of immune system that something might be wrong and help is required. It is a complex, multi-stage process, involving many different mechanisms which help to amplify and resolve the response. Recently, some researchers reported some interesting data regarding the ‘resolving’ aspect of the inflammatory response in Parkinson’s. It involved a protein called Resolvin. In today’s post, we will look at what Resolvin is, what the new research reported, and how this information could be useful in the development of future therapies for Parkinson’s.

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Spot the unhealthy cell – exhibiting signs of stress (yellow). Source: Gettyimages

When cells in your body are stressed or sick, they begin to release tiny messenger proteins which inform the rest of your body that something is wrong.

When enough of these messenger proteins are released that the immune system becomes activated, it can cause inflammation.

What is inflammation?

Inflammation is a critical part of the immune system’s response to trouble. It is the body’s way of communicating to the immune system that something is wrong and activating it so that it can help deal with the situation.

By releasing the messenger proteins (called cytokines), injured/sick cells kick off a process that results in multiple types of immune cells entering the troubled area of the body and undertaking very specific tasks.

The inflammatory process. Source: Trainingcor

The strength of the immune response depends on the volume of the signal arising from those released messenger proteins. And there are processes that can amplify the immune response.

But an important component of the immune response that is often overlooked is resolution.

Once an infection/injury has been dealt with, the immune response must be resolved. And there are tiny messenger proteins that our body producing naturally which involved in dampening down the immune response. They are typically released when a situation has been resolved.

One group of resolving messenger proteins are called Resolvins.

What are Resolvins?

This is Prof Charles Serhan:

Prof Charles Serhan. Source: Serhanlab

He is a Professor of Anaesthesia at Harvard Medical School (Click here to check out his lab).

Back in the early 2000s, Prof Serhan and colleagues published this report:

Title: Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals.
Authors: Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, Moussignac RL.
Journal: J Exp Med. 2002 Oct 21;196(8):1025-37.
PMID: 12391014                 (This report is OPEN ACCESS if you would like to read it)

In this study, the investigators treated mice with aspirin and docosahexaenoic acid (DHA) and found that this resulted in the production a novel family of proteins that were very effective at reducing inflammation. Remarkably, these proteins inhibited microglial cell cytokines at very low doses (IC(50) approximately 50 pM).

The researchers called these molecules “Resolvins” (short for resolution phase interaction products).

Further research found that there Resolvins were generated during the resolution phase of the inflammatory process, and that they play protective roles by dampening down inflammation, promoting a pro-resolution state.

They are naturally produced by your body from omega-3 fatty acids (we have discussed omega-3 fatty acids in a previous SoPD post – click here to read that post).

Of the fatty acids, resolvins are primarily produced from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Resolvins belong to a class of polyunsaturated fatty acid (PUFA) metabolites termed specialized proresolving mediators.

There are three types of resolvins:

• Resolvin E that comes from EPA
• Resolvin D which is derived from DHA
• Aspirin-triggered Resolvin D (AT-RvD)

Of particular interest to us today is Resolvin D1 which is derived from DHA:

Why is Resolvin D1 interesting?

Because very recently, this report was published:

Title: Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease.
Authors: Krashia P, Cordella A, Nobili A, La Barbera L, Federici M, Leuti A, Campanelli F, Natale G, Marino G, Calabrese V, Vedele F, Ghiglieri V, Picconi B, Di Lazzaro G, Schirinzi T, Sancesario G, Casadei N, Riess O, Bernardini S, Pisani A, Calabresi P, Viscomi MT, Serhan CN, Chiurchiù V, D’Amelio M, Mercuri NB.
Journal: Nat Commun. 2019 Sep 2;10(1):3945. doi: 10.1038/s41467-019-11928-w.
PMID: 31477726                (This report is OPEN ACCESS if you would like to read it)

In this study, the Italian researchers used rats which have been genetically engineered to produce high levels of human α-synuclein. The researchers reported that these rats develop early alterations in dopamine neuron activity – dopamine neurons are a population of cells in the brain that are badly affected by Parkinson’s (Click here to read more about this).

The alterations in dopamine neuron activity in these rats included changes in dopamine transmission and motor behaviour. They also reported a marked increase in inflammatory markers (such as interferon – see the previous SoPD post for an explanation of these) in the cerebrospinal fluid of the rats.

As the human alpha synuclein-producing rats got older, they started to lose dopamine neurons (in a similar fashion to what we see in Parkinson’s), but critically, all of the dopamine signalling, inflammation and motor problems occurred long before any dopamine neuron degeneration.

Given the increase in inflammatory markers, the researchers next investigated whether there were any alterations in the mechanisms involved in inflammation – in particular, they were curious about the processes involved with the resolution of inflammation. What was happening to these mechanisms in the dysfunctioning brain of the human alpha synuclein-producing rats?

And here they investigated two major resolvins, Resolvin D1 and Resolvin D2.

They found that that while there was little difference in Resolvin D2 levels over time, the levels of resolvin D1 were significantly higher in the cerebropinal fluid (CSF; the protective liquid that your brain sits in) of the human alpha synuclein-producing rats as they aged compared to normal rats. Curiously, the levels of Resolvin D1 dropped significantly in the blood (plasma) of the human alpha synuclein-producing rats as they got older (see image below).

Source: Nature

The researchers next wondered what would happen if they treated the rats with Resolvin D1. So they began treating the human alpha synuclein-producing rats with Resolvin D1 twice a week for 8 consecutive weeks (from 2 months of age).

Amazingly, they found that not only did the resolvin D1 treatment significantly reduce interferon levels (see image below)…

Source: Nature

…but it reduced microglia activation and inflamation in the brain, AND also improved dopamine neuron function.

Finally, the researchers were curious to see how these results reflected on the human condition, and so they analysed postmortem samples for people who passed away with and without Parkinson’s. They found that while resolvin D2 levels in blood and cerebrospinal fluid samples from people with Parkinson’s were the same as control samples, the Resolvin D1 levels were significantly lower, in both the blood and plasma samples.

Source: Nature

The researchers concluded that their “study provides further proof of the critical involvement of inflammation in PD but also sets the basis for using Resolvin D1 as a clinical biomarker of inflammation, also highlighting the translational potential of endogenous pro-resolving mediators”.

And this is not the first time Resolvin D1 has demonstrated beneficial effects in models of Parkinson’s. Resolvin D1 has been reported to have beneficial effects in a cell culture model of PD:

Title: Resolvin D1 Attenuates Mpp+-Induced Parkinson Disease via Inhibiting Inflammation in PC12 Cells.
Authors: Xu J, Gao X, Yang C, Chen L, Chen Z.
Journal: Med Sci Monit. 2017 Jun 2;23:2684-2691.
PMID: 28572562                  (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers pre-treated cells in culture with different doses of Resolvin D1 before then exposing them to a neurotoxin (MPTP) 2 hours later. They found that Resolvin D1 treatment reduced cell death and inflammatory protein (TNF-α/IL-6) in a dose dependent manner.

And this anti-inflammatory effect in a model of Parkinson’s may not be specific to Resolvin D1: Resolvin D2 has also been demonstrated for anti-inflammatory properties in rodents:

Title: Resolvin D2 recovers neural injury by suppressing inflammatory mediators expression in lipopolysaccharide-induced Parkinson’s disease rat model.
Authors: Tian Y, Zhang Y, Zhang R, Qiao S, Fan J.
Journal: Biochem Biophys Res Commun. 2015 May 8;460(3):799-805.
PMID: 25824039

Are there any clinical trials for Resolvins?

In Parkinson’s? Not that I am aware of.

There was a biotech company back in the 2000s called Resolvyx Pharmaceuticals

Source: FlagshipPioneering

It was foundered in 2005, but ceased operations in 2011. It was clinically developing a product called RX-10001, which was a synthetic version of Resolvin E1. RX-10001 was being targetted as an oral treatment of asthma and other inflammatory conditions (such as rheumatoid arthritis and inflammatory bowel disease). It had some interesting preclinical results (Click here for an example) and it started clinical testing (Click here for more details about the Phase I trial).

But that is where the trail ends.

If this new Resolvin D1 result can be independently replicated, it would be interesting to explore how this inflammation resolving agent could be translated into clinical use.

So what does it all mean?

Inflammation is a major component of many medical conditions, including Parkinson’s. At present, the majority of the therapeutic agents that attemtp to reduce inflammatory responses, do so by blocking messenger proteins/cyctokines or the receptors of those proteins.

Now Italian researchers have highlighted the potential use of molecules involved in the resolution of inflammation. These agents could not only be investigated as possible therapies, but also potential biomarkers.

Fascinating research that we will be keeping an eye on.

 

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The banner for today’s post was sourced from Caymanchem