Cotinine ameliorates memory and learning impairment in senescent mice

This study aimed to assess the effects of cotinine on age-induced memory and learning impairment and related downstream pathways in mice. Thirty aged (18-month old) and 10 young mice (8-week old) were randomly divided into 4 groups (n = 10 each) and subjected to cotinine at 5 mg/kg dose and/or methyllycaconitine (MLA) at 1 mg/kg, i.p. dose (α₇ nAChRs antagonist) for 4 weeks. Morris water maze (MWM) and novel object recognition (NOR) tasks were used to assess spatial and recognition learning and memories of the mice, respectively. Levels of oxidative stress, apoptosis, neuroinflammation, and structural synaptic plasticity, and also neurotrophic factors and α₇ nAChRs were assessed in the hippocampus using either ELISA or Western blotting. Aging was associated with learning and memory disabilities and dysregulation of the assessed pathways in the hippocampus of mice. Chronic cotinine treatment improved learning and memory in aged animals, indicated by decreased latency time, and increased time spent in the target quadrant and discrimination index (DI) in the MWM and NOR tasks. Also, chronic cotinine injection increased total antioxidant capacity (TAC), SOD and GSH-px activity, PSD-95, GAP-43, SYN, brain-derived neurotrophic factor, and neural growth factor levels and decreased malondialdehyde, TNF-α, and IL-1β in the hippocampus of aged mice. Conversely, MLA treatment reversed most of the mentioned effects via the blockade of α₇ nAChRs. Cotinine improves age-induced memory and learning impairment via its modulatory effects on α₇ nAChRs and subsequent activation/deactivation of the mentioned pathways in the hippocampus of aged mice.