Donecopride, a Swiss army knife with potential against Alzheimer's disease

 A research group in France found out that donecopride, a drug that has multiple mechanisms of action, attenuates Alzheimer’s Disease effects on mice, enhancing the memory of them and protecting them from neurotoxic effects, being this study published in the British Pharmacological Society journal.

It has been more than 20 years since a new drug became available in the market for Alzheimer’s Disease (AD), they mainly being memantine and the acetylcholinesterase inhibitors (AchEIs), that help alleviate the symptoms by indirectly increasing the amount of acetylcholine, extremely reduced in AD. Rochais et al, the authors of this article, consider that due to the multiple mechanisms of the pathology it is also needed to have a multi-mechanism approach to its treatment.

One of the most commonly used theories to explain AD is the amyloid-β (Aβ) one: in the brain APPs (amyloid precursor proteins) are produced naturally, however enzymes may turn these molecules in Aβ, being them majorly Aβ40, that has a much lower relative neurotoxic activity, and Aβ42, the most known neurotoxic form, and its increased deposition in brain creates tangles that are not soluble, being those tangles responsible for neuron death. It’s also studied that the ratio between Aβ42:Aβ40 is related to the outcome of AD, being that higher levels of Aβ42 contribute for more tangles, hence higher toxicity.

 

 

 Figure 1 - amyloid plaque as seen in hippocampus after HE stain.

Source: Wikimedia Commons

 

Those researchers, based on the premise that donepezil, an AchEI drug, was successfully tested with idalopirdine, a molecule that works suppressing the specific serotonin receptor 5-HT₆, then came up with donecopride: a molecule that acts like donepezil for AD, and has an effect on a slightly different serotonin receptor, 5-HT₄, that’s associated with the release of APPα (amyloid precursor protein alpha), that actually reduces Aβ42 production and also releases acetylcholine.

This drug was tested previously on NMRI type of mice and the rats showed cognitive enhancement and could reverse memory impairment induced by scopolamine. Based on those results, they tested it on transgenic mice, that produced more amyloid proteins, and on mice injected with Aβ into the ventricular region of their brains.

The mice were treated either with a non-pharmacological solution or a solution with the drugs, twice a week, for 3 months in the transgenic 5XFAD mice, and 18 days for the induced ones, then they were tested in tested both in vitro and in vivo.

After the treatment, the scientists then found that the mice treated with donecopride had no differences on the amount of Aβ40 but instead Aβ42 was lowered significatively, noticed in the transgenic mice by the significative reduction of plaques in the cortex (anatomical part associated with long-term memory) and lower number of astrocyte cells death. Long-term memory in transgenic mice (NOR test), short-term memory (Y-maze test) and long-term memory in AD-induced mice (tested via Morris Water Maze) were tested and they had significant enhancement in comparison to no treatment at all.

In vitro models also showed that cell cultures treated with donecopride had higher survival rates than the soluble Aβ not treated with it, with neurite networks being preserved as well, also noticing lower levels of hyperphosphorylated Tau protein, linked to AD and its worsening, and even formation of new synapses (the way which two neurons may communicate).

With the data of this study, the researchers conclude that donepocride has neuroprotective and neurotrophic, also reducing the two main aspects seen in AD at cellular level. As the authors say, it is a “swiss knife” drug due to multiple mechanisms of action, meaning donepocride and its derivatives may reduce the socioeconomic impact AD causes.

 

Erick Yudi Maruyama Rodrigues

 

Sources:

Rochais C, Lecoutey C, Hamidouche K, et al. Donecopride, a Swiss army knife with potential against Alzheimer's disease. Br J Pharmacol. 2020;177(9):1988-2005. doi:10.1111/bph.14964. Available in: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161555/

Gu L, Guo Z. Alzheimer's Aβ42 and Aβ40 peptides form interlaced amyloid fibrils. J Neurochem. 2013;126(3):305-311. doi:10.1111/jnc.12202. Available in: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716832/