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      Vanillin and 4-hydroxybenzyl alcohol attenuate cognitive impairment and the reduction of cell proliferation and neuroblast differentiation in the dentate gyrus in a mouse model of scopolamine-induced amnesia

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          Abstract

          4-Hydroxy-3-methoxybenzaldehyde (vanillin) and 4-hydroxybenzyl alcohol (4-HBA) are natural phenolic compounds, which present in many plants and have diverse biological properties. In this study, we examined effects of vanillin and 4-HBA on learning and memory function, cell proliferation, and neuroblast differentiation in the hippocampal dentate gyrus in a mouse model of scopolamine-induced amnesia. Scopolamine (SCO; 1 mg/kg/day, intraperitoneally), vanillin, and 4-HBA (40 mg/kg/day, orally) were administered for 28 days. Treatment with scopolamine alone impaired learning and memory function in the Morris water maze and passive avoidance tests, in addition, the treatment significantly reduced cell proliferation and neuroblast differentiation in the dentate gyrus, which were examined by immunohistochemistry for Ki-67 (a classic marker for cell proliferation) and doublecortin (a marker for neuroblasts). However, treatment with vanillin or 4-HBA significantly attenuated SCO-induced learning and memory impairment as well as the reduction of cell proliferation and neuroblast differentiation in the dentate gyrus. These results indicate that vanillin and 4-HBA may be helpful in improving cognitive function and in increasing endogenous neuronal proliferation in the brain.

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          Most cited references34

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          The cholinergic hypothesis of geriatric memory dysfunction.

          Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.
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            Doublecortin expression levels in adult brain reflect neurogenesis.

            Progress in the field of neurogenesis is currently limited by the lack of tools enabling fast and quantitative analysis of neurogenesis in the adult brain. Doublecortin (DCX) has recently been used as a marker for neurogenesis. However, it was not clear whether DCX could be used to assess modulations occurring in the rate of neurogenesis in the adult mammalian central nervous system following lesioning or stimulatory factors. Using two paradigms increasing neurogenesis levels (physical activity and epileptic seizures), we demonstrate that quantification of DCX-expressing cells allows for an accurate measurement of modulations in the rate of adult neurogenesis. Importantly, we excluded induction of DCX expression during physiological or reactive gliogenesis and excluded also DCX re-expression during regenerative axonal growth. Our data validate DCX as a reliable and specific marker that reflects levels of adult neurogenesis and its modulation. We demonstrate that DCX is a valuable alternative to techniques currently used to measure the levels of neurogenesis. Importantly, in contrast to conventional techniques, analysis of neurogenesis through the detection of DCX does not require in vivo labelling of proliferating cells, thereby opening new avenues for the study of human neurogenesis under normal and pathological conditions.
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              The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis.

              Adult animals continue to produce new neurons in the dentate gyrus of hippocampus. Until now, the principal method of studying neurogenesis has been to inject either tritiated thymidine or 5'-Bromo-2-deoxyuridine (BrdU) intraperitoneally followed by autoradiographic or immunohistochemical detection methods respectively. However, such exogenous markers may produce toxic effects. Our objective was to determine whether Ki-67, a nuclear protein expressed in all phases of the cell cycle except the resting phase, can be used as an alternative, endogenous marker. Using immunohistochemistry, we examined Ki-67 and BrdU expression pattern in rats. Ki-67 was expressed within the proliferative zone of the dentate gyrus and its expression pattern mimicked that of BrdU when examined soon after exogenous BrdU administration. Quantitative comparison of BrdU and Ki-67-positive cells showed 50% higher numbers of the latter when examined 24 h after the BrdU injection. This was expected, since BrdU can be incorporated into DNA only during the S-phase of the mitotic process, whereas Ki-67 is expressed for its whole duration. Experimental increases (by ischemia) or reductions (by radiation) in the number of mitotic cells produced parallel changes in BrdU and Ki-67 signals. Thus, Ki-67 is an effective mitotic marker and has most of the benefits of BrdU and none of the costs. This study provides evidence for Ki-67 to be used as a marker of proliferation in the initial phase of adult neurogenesis.
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                Author and article information

                Journal
                Anat Cell Biol
                Anat Cell Biol
                ACB
                Anatomy & Cell Biology
                Korean Association of Anatomists
                2093-3665
                2093-3673
                June 2017
                27 June 2017
                : 50
                : 2
                : 143-151
                Affiliations
                [1 ]Department of Surgery, Kangwon National University School of Medicine, Chuncheon, Korea.
                [2 ]Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, Korea.
                Author notes
                Corresponding author: Joon Ha Park. Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, 1 Hallimdaehak-gil, Chuncheon 24252, Korea. Tel: +82-33-248-3202, Fax: +82-33-248-3201, jh-park@ 123456hallym.ac.kr
                Article
                10.5115/acb.2017.50.2.143
                5509898
                28713618
                1c6c6997-8558-4972-83b3-e0a94225dd65
                Copyright © 2017. Anatomy & Cell Biology

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 May 2017
                : 16 May 2017
                : 18 May 2017
                Funding
                Funded by: National Research Foundation of Korea, CrossRef http://dx.doi.org/10.13039/501100003725;
                Award ID: NRF-2009-0093812
                Categories
                Original Article
                Cellular and Molecular Researches

                Cell biology
                learning and memory,hippocampus,scopolamine,phenolic compounds,neurogenesis
                Cell biology
                learning and memory, hippocampus, scopolamine, phenolic compounds, neurogenesis

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