Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Neuroprotective and Disease Modifying Effects of the Triazinetrione ACD856, a Positive Allosteric Modulator of Trk-Receptors for the Treatment of Cognitive Dysfunction in Alzheimer’s Disease

Version 1 : Received: 7 June 2023 / Approved: 8 June 2023 / Online: 8 June 2023 (09:55:01 CEST)

A peer-reviewed article of this Preprint also exists.

Parrado Fernandez, C.; Juric, S.; Backlund, M.; Dahlström, M.; Madjid, N.; Lidell, V.; Rasti, A.; Sandin, J.; Nordvall, G.; Forsell, P. Neuroprotective and Disease-Modifying Effects of the Triazinetrione ACD856, a Positive Allosteric Modulator of Trk-Receptors for the Treatment of Cognitive Dysfunction in Alzheimer’s Disease. Int. J. Mol. Sci. 2023, 24, 11159. Parrado Fernandez, C.; Juric, S.; Backlund, M.; Dahlström, M.; Madjid, N.; Lidell, V.; Rasti, A.; Sandin, J.; Nordvall, G.; Forsell, P. Neuroprotective and Disease-Modifying Effects of the Triazinetrione ACD856, a Positive Allosteric Modulator of Trk-Receptors for the Treatment of Cognitive Dysfunction in Alzheimer’s Disease. Int. J. Mol. Sci. 2023, 24, 11159.

Abstract

The introduction of anti-amyloid monoclonal antibodies against Alzheimer’s disease (AD) is of high importance. However, even though treated patients show very little amyloid pathology, there is only a modest effect on the rate of cognitive decline. Although this effect possibly can increase over time, there is still a need for alternative treatments that will improve the cognitive function in patients with AD. Therefore, the purpose of this study was to characterize the triazinetrione ACD856, a novel pan-Trk positive allosteric modulator, in multiple models to address its neuroprotective and potential disease modifying effects. The pharmacological effect of ACD856 was tested in recombinant cell lines, primary cortical neurons or animals. We demonstrate that ACD856 enhanced NGF-induced neurite outgrowth, increased the levels of the pre-synaptic protein SNAP25 in PC12 cells and increased the degree of phosphorylated TrkB in SH-SY5Y cells. In primary cortical neurons, ACD856 led to increased levels of phospho-ERK1/2, showed neuroprotective effect against amyloid-beta or energy-deprivation induced neurotoxicity, and increased the levels of brain derived neurotrophic factor (BDNF). Consequently, administration of ACD856 resulted in a significant increase of BDNF in the brains of 21-months old mice. Furthermore, repeated administration of ACD856 resulted in a sustained anti-depressant effect which lasted up to seven days, suggesting effects that go beyond merely symptomatic effects. In conclusion, the results confirm ACD856 as a cognitive enhancer, but more importantly, they provide substantial in vitro and in vivo evidence of neuroprotective and long-term effects that contribute to neurotrophic support and increased neuroplasticity. Presumably, the described effects of ACD856 may improve cognition, increase resilience, and promote neurorestorative processes, thereby leading to a healthier brain in patients with AD.

Keywords

Brain-derived neurotrophic factor; nerve growth factor; Alzheimer’s disease; allosteric modulator; cognitive function; anti-depressant

Subject

Medicine and Pharmacology, Neuroscience and Neurology

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