Simultaneous modulation of 5-HT6 and SERT by MM394: a dual-target ligand providing neuroprotection against amyloid-β toxicity, memory preservation, and alleviation of BPSD symptoms.

In addition to cognitive decline, 90 % of dementia patients experience behavioral and psychological symptoms of dementia, for which no safe and effective pharmacotherapy currently exists. Our study aimed to determine the therapeutic potential of the new dual 5-HT6/SERT-acting ligand MM394 in the context of pro-cognitive and neuroprotective properties, as well as its effects on behavioral symptoms and mood disorders in patients diagnosed with Alzheimer's disease. We performed in vitro experiments to examine the neuroprotective and antioxidant properties of MM394, as well as in vivo studies on male rats to evaluate its pharmacokinetics and potential in behavioral modulation of memory and mood. Following this, we attempted to determine the molecular mechanism of action of the dual 5-HT6/SERT targeting compound in ex vivo experiments using rats' hippocampus and prefrontal cortex. The results of our study in the HT-22 cell line support the potential of MM394 to target excitotoxicity and oxidative stress, which play a key role in neurodegeneration. Furthermore, the compound exhibits antidepressant-like activity in the forced swim test and counteracts the memory impairments caused by MK-801 in the novel object recognition assessment in rats. Ex vivo findings demonstrate that MM394 modulates mTOR and ERK1/2 phosphorylation in the studied brain areas and increases the level of BDNF in the hippocampus when co-administered with MK-801 in the novel object recognition test. As a result of these findings, MM394 may be useful as a therapeutic for BPSD, which should be further explored.