One abstract discussing 3-71 at AAIC already available:
(Note, not from the company, independent)
An M1/sigma-1 receptor agonist prevents cognitive deficits, reduces amyloid plaques and neuroinflammation in a transgenic rat model of Alzheimer’s amyloid pathology.
Abstract ID: 69100
Abstract:
Chiara Orciani, MSc; Sonia Do Carmo, PhD; Morgan K Foret, PhD; Hélène Hall, PharmD, PhD; Quentin Bonomo, BSc; Agustina Lavagna, MSc; Chunwei Huang, MD and Claudio A Cuello, MD, McGill University, Montreal, QC, Canada
Background: Acetylcholinesterase inhibitors represent four out of six drugs for treating Alzheimer's disease (AD), with time-limited efficacy likely due to the progressive loss of cholinergic neurons. The selective allosteric M1 muscarinic and sigma-1 receptor agonist Anavex 3-71 (aka AF710B) [1] takes advantage of the fact that acetylcholine postsynaptic M1 muscarinic brain receptor levels remain unchanged in AD. Previously, Anavex 3-71 treatment attenuated AD hallmarks in McGill-R-Thy1-APP transgenic rats when administered at advanced stages of the AD-like pathology [2]. However, preventive strategies instead of late treatment should be more effective in AD. Therefore, we tested whether Anavex 3-71 administration during early amyloid pathology stages could prevent cognitive impairment, plaque deposition and neuroinflammation.
Method: Pre-plaque, seven-month-old McGill-R-Thy1-APP rats were subjected to daily oral administration of Anavex 3-71 (10 µg/kg) for seven months. After one month of drug interruption (wash-out), we performed Novel Object Recognition (NOR), Morris Water Maze (MWM) and Social Preference (SP) behavioural tests. Subsequently, brains were extracted, fixed and analyzed by histochemistry and immunohistochemistry.
Result: McGill-APP rats had deficits in discriminating the novel object in the NOR and locating the hidden platform in the MWM compared to wild-type littermates. Anavex 3-71 restored the abilities of McGill-APP rats in the NOR task to wild-type levels and partially rescued the deficits in the MWM. In the SP task, Anavex 3-71-treated McGill-APP rats exhibited diminished deficits in SP interaction time with a “stranger rat”. Treatment significantly reduced the number of mature Thioflavin-S positive plaques in the subiculum compared to vehicle-treated McGill-APP rats and diminished the number of diffuse plaques in the cortex and hippocampus. Furthermore, Anavex 3-71 treatment significantly reduced microglia and astrocyte recruitment towards CA1 hippocampal Aß-burdened neurons compared to untreated McGill-APP rats.
Conclusion: The long-lasting effect of Anavex 3-71 in preventing cognitive decline of McGill-R-Thy1-APP rats, even after a wash-out period would suggest some preventative, disease-modifying, properties of the compound over the AD-like amyloid pathology. This is supported by the attenuation of extracellular Aß deposition and reduced glial cell recruitment towards hippocampal neurons. [1] Fisher et al., 2016; Neurodegenerative Diseases. DOI:10.1159/000440864 [2] Hall et al., 2018; Alzheimer's & Dementia. DOI:10.1016/j.jalz.2017.11.009
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