afdb42fb792e353ee3f00334c0c4ea12 pmc_30181440.pdf 534212ef1c18082b39388cfe7918807738ef7d81 pmc_30181440.pdf 1372d36aa94532d6876ba79d9bce1002da1e9631c527a7035f68e0083979e9a3 pmc_30181440.pdf Title: Neuroprotective Effects of the Multitarget Agent AVCRI104P3 in Brain of Middle-Aged Mice Subject: Molecular factors involved in neuroprotection are key in the design of novel multitarget drugs in aging and neurodegeneration. AVCRI104P3 is a huprine derivative that exhibits potent inhibitory effects on human AChE, BuChE, and BACE-1 activities, as well as on AChE-induced and self-induced A aggregation. More recently, cognitive protection and anxiolytic-like effects have also been reported in mice treated with this compound. Now, we have assessed the ability of AVCRI104P3 (0.43 mg/kg, 21 days) to modulate the levels of some proteins involved in the anti-apoptotic/apoptotic processes (pAkt1, Bcl2, pGSK3, p25/p35), inflammation (GFAP and Iba1) and neurogenesis in C57BL/6 mice. The effects of AVCRI104P3 on AChE-R/AChE-S isoforms have been also determined. We have observed that chronic treatment of C57BL/6 male mice with AVCRI104P3 results in neuroprotective effects, increasing significantly the levels of pAkt1 and pGSK3 in the hippocampus and Bcl2 in both hippocampus and cortex, but slightly decreasing synaptophysin levels. Astrogliosis and neurogenic markers GFAP and DCX remained unchanged after AVCRI104P3 treatment, whereas microgliosis was found to be significantly decreased pointing out the involvement of this compound in inflammatory processes. These results suggest that the neuroprotective mechanisms that are behind the cognitive and anxiolytic effects of AVCRI104P3 could be partly related to the potentiation of some anti-apoptotic and anti-inflammatory proteins and support the potential of AVCRI104P3 for the treatment of brain dysfunction associated with aging and/or dementia. Keywords: acetylcholinesterase inhibitors; huprine derivatives; AVCRI104P3; apoptosis; neuroprotection; neuroinflammation Author: Julia Relat, Julio Come, Belen Perez, Pelayo Camps, Diego Muñoz-Torrero, Albert Badia, Lydia Gimenez-Llort and M. 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