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Background: The development of cholinergic deficit is considered an early sign of a number of pathological conditions, including Alzheimer’s disease. Cholinergic dysfunction underlies cognitive decline associated with both normal aging and Alzheimer’s disease. Objective: Here, we studied a possible mechanism of functional impairment of cholinergic neurons using an olfactory bulbectomy model. Methods: Male mice were subjected to olfactory bulbectomy or sham surgery. Three weeks after that they were trained in Morris water maze and then euthanized one month after surgery. The cholinergic indices as well as the indices of oxidative stress were studied using immunohistochemistry, western blot and ELISA. Gene expression was studied using RT-qPCR. Results: The experimental treatment was followed by impaired learning of a standard spatial task in a water maze. This was associated with a decrease in the number of cells containing choline acetyltransferase (ChAT), in relation to total number of neurons in the medial septum and lower ChAT enzymatic activity in the hippocampus. However, the levels of mRNAs of ChAT, vesicular ACh transporter and acetylcholine esterase remained unchanged in bulbectomized mice compared to sham-operated animals. These alterations were preceded by the accumulation of protein-bound carbonyls, indicating oxidative damage of proteins, whereas oxidative damage of nucleic acids was not detected. Conclusion: We assume that in olfactory bulbectomy model, oxidative damage of proteins may cause cholinergic dysfunction rather than irreversible neuronal damage. These data indicate that cholinergic neurons of the basal forebrain are very sensitive to oxidative stress, which may be responsible for the appearance of early cognitive decline in Alzheimer’s disease.

Recently, we have shown the differences in the early response of corticosterone and inflammatory cytokines in the hippocampus and frontal cortex (FC) of rats with middle cerebral artery occlusion (MCAO), according to the methods of Longa et al. (LM) and Koizumi et al. (KM) which were used as alternatives in preclinical studies to induce stroke in rodents. In the present study, corticosterone and proinflammatory cytokines were assessed 3 months after MCAO. The most relevant changes detected during the first days after MCAO became even more obvious after 3 months. In particular, the MCAO-KM (but not the MCAO-LM) group showed significant accumulation of corticosterone and IL1β in both the ipsilateral and contralateral hippocampus and FC. An accumulation of TNFα was detected in the ipsilateral hippocampus and FC in the MCAO-KM group. Thus, unlike the MCAO-LM, the MCAO-KM may predispose the hippocampus and FC of rats to long-lasting bilateral corticosterone-dependent distant neuroinflammatory damage. Unexpectedly, only the MCAO-LM rats demonstrated some memory deficit in a one-trial step-through passive avoidance test. The differences between the two MCAO models, particularly associated with the long-lasting increase in glucocorticoid and proinflammatory cytokine accumulation in the limbic structures in the MCAO-KM, should be considered in the planning of preclinical experiments, and the interpretation and translation of received results.

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