Intranasal delivery of exenatide as a disease modifying approach for Parkinson’s

Original article: Mitral cells and the glucagon-like peptide 1 receptor: The sweet smell of success?, European Journal of Neuroscience: 2018. 

The takeaway

The authors make the case for targeting cells in the olfactory bulb, the region of the brain that processes smell, with the antidiabetic drug exenatide to prevent the spread of alpha synuclein and potentially slow or stop the course of Parkinson’s.

Why is it important?

It explores the possibility that delivering exenatide through the nose, suggested to be one of the points at which toxins may trigger alpha synyclein misfolding, may be a way of directly targeting, and possibly protecting, these vulnerable cells.

Background

The link between disturbance in the sense of smell and Parkinson’s is well documented. The region of the brain that processes smell is called the olfactory bulb. The dual hit hypothesis that attempts to explain how Parkinson’s may start in the body holds that the olfactory bulb may be one of the starting points from which misfolded alpha synuclein may spread to affect the rest of the brain. How can understanding the finer anatomy and different cell types within the olfactory bulb bring us closer to a potential cure?

The details

The authors focus on mitral cells, a particular type of cell in close contact with the actual neurons that directly intercept substances inhaled through the nose and appear to be especially affected. They contain a large amount of alpha synuclein, which plays many roles, including an antibacterial function. Due to their location and lack of protective fatty layer which coats many other types of neurons, mitral cells need to generate up to 5,000 times the amount of energy required by other cells, which additionally means that toxic byproducts and oxidative stress can build up. These can interact with healthy alpha synuclein and trigger potential misfolding, which can then spread to the rest of the brain.

Intriguingly, mitral cells express GLP1 receptors on their surface, and in fact can be identified by the presence of these receptors. This makes them a natural target for the GLP1 agonist exenatide, an antidiabetic drug which has been shown in recent trials to have the potential to modify the course of Parkinson’s. The authors discuss the large range of beneficial effects exenatide is known to have on neurons: it protects mitochondria, the powerhouses of the cell, prevents neuronal death, reduces oxidative stress and neuroinflammation, and increases the production of BDNF, a trophic factor which promotes neuronal growth.

They propose that targeting mitral cells with direct, intranasally administered exenatide during the earliest, prodromal stage of Parkinson’s, could prevent alpha synuclein misfolding and cellular dysfunction in the olfactory bulb, and potentially stop its spread to other healthy parts of the brain.

Next steps

Supporting evidence for the feasibility of this approach comes mostly from animal studies.  Future studies will have to investigate methods of targeting these cells with intranasal exenatide administration which maximizes the amount of drug that can reach the target cells in humans.

Original article: Bagnoli, E. & FitzGerald, U. 2018. Mitral cells and the glucagon-like peptide 1 receptor: The sweet smell of success?

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