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Current Molecular Pharmacology


ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

Lactoferrin Suppresses Decreased Locomotor Activities by Improving Dopamine and Serotonin Release in the Amygdala of Ovariectomized Rats

Author(s): Nobuo Izumo*, Ishibashi Yukiko, Nobuharu Kagaya, Megumi Furukawa, Rina Iwasaki, Akihide Sumino, Kohsuke Hayamizu, Makoto Nakano, Tatsuo Hoshino, Haruna Kurono, Yasuo Watanabe and Takayuki Manabe*

Volume 14, Issue 2, 2021

Published on: 29 April, 2020

Page: [245 - 252] Pages: 8

DOI: 10.2174/1570163817666200430002937



Background: Decreases in female hormones not only affect bone metabolism and decrease bone mass, but also affect the central nervous system, causing brain disorders such as depression and dementia. Administration of estradiol by hormone replacement therapy can improve dementia, while reduced estradiol in ovariectomized (OVX) model rats can reduce both bone density and locomotor activity. The antidepressant fluvoxamine, which is widely used in clinical practice, can improve this effect on locomotor reduction. Similarly, lactoferrin (LF) can reportedly improve inhibitory locomotion due to stress.

Objective: In this study, we examined the effect of LF on neurite outgrowth in vitro and in vivo using PC12 cells and rats, respectively.

Methods: We performed an in vivo study in which 8-week-old female OVX rats were administered LF five days a week for 6 weeks from the day after surgery. After administration was completed, spontaneous locomotor activity in the dark period, immobility time in a forced swim test, and release amount of dopamine and serotonin in the brain were measured.

Results: LF was found to have a neurite outgrowth function in PC12 cells. Moreover, LF was found to improve OVX-induced decreases in locomotor activity and increases in immobility time in the forced swim test. Furthermore, the administration of LF elicited significant recovery of decreased dopamine and serotonin release in the brains of OVX group rats.

Conclusion: These results strongly suggest that LF improved OVX-induced decreases in momentum during the dark period and, moreover, that release of dopamine and serotonin in the brain was involved in this effect.

Keywords: Amygdala, 5-HT. dopamine, Estradiol. Lactoferrin, OVX, PC12.

Graphical Abstract
Sniekers, Y.H.; Weinans, H.; Bierma-Zeinstra, S.M.; van Leeuwen, J.P.; van Osch, G.J. Animal models for osteoarthritis: the effect of ovariectomy and estrogen treatment - a systematic approach. Osteoarthritis Cartilage, 2008, 16(5), 533-541.
[] [PMID: 18280756]
ter Horst, G.J. Estrogen in the limbic system. Vitam. Horm., 2010, 82, 319-338.
[] [PMID: 20472146]
Pratap, U.P.; Patil, A.; Sharma, H.R.; Hima, L.; Chockalingam, R.; Hariharan, M.M.; Shitoot, S.; Priyanka, H.P.; ThyagaRajan, S. Estrogen-induced neuroprotective and anti-inflammatory effects are dependent on the brain areas of middle-aged female rats. Brain Res. Bull., 2016, 124, 238-253.
[] [PMID: 27242078]
Brown, C.M.; Mulcahey, T.A.; Filipek, N.C.; Wise, P.M. Production of proinflammatory cytokines and chemokines during neuroinflammation: novel roles for estrogen receptors alpha and beta. Endocrinology, 2010, 151(10), 4916-4925.
[] [PMID: 20685874]
Samavat, H.; Kurzer, M.S. Estrogen metabolism and breast cancer. Cancer Lett., 2015, 356(2 Pt A), 231-243.
[] [PMID: 24784887]
Brown, SB; Hankinson, SE Endogenous estrogens and the risk of breast, endometrial, and ovarian cancers. Steroids., 2015, 99(Pt A), 8-10.
Izumo, N.; Ishibashi, Y.; Ohba, M.; Morikawa, T.; Manabe, T. Decreased voluntary activity and amygdala levels of serotonin and dopamine in ovariectomized rats. Behav. Brain Res., 2012, 227(1), 1-6.
[] [PMID: 22056749]
Ishibashi, Y.; Izumo, N.; Iwata, K.; Morikawa, T.; Kameyama, T. Fluvoxamine reverses estrogen-dependent decline in voluntary activities and decreased amygdala levels of serotonin in ovariectomized rats. Journal of Brain Science, 2016, 46, 5-19.
Kamemori, N.; Takeuchi, T.; Hayashida, K.; Harada, E. Suppressive effects of milk-derived lactoferrin on psychological stress in adult rats. Brain Res., 2004, 1029(1), 34-40.
[] [PMID: 15533313]
Wang, B.; Timilsena, Y.P.; Blanch, E.; Adhikari, B. Lactoferrin: Structure, function, denaturation and digestion. Crit. Rev. Food Sci. Nutr., 2019, 59(4), 580-596.
[] [PMID: 28933602]
Hayashida, K.; Kaneko, T.; Takeuchi, T.; Shimizu, H.; Ando, K.; Harada, E. Oral administration of lactoferrin inhibits inflammation and nociception in rat adjuvant-induced arthritis. J. Vet. Med. Sci., 2004, 66(2), 149-154.
[] [PMID: 15031542]
Terada, K.; Izumo, N.; Suzuki, B.; Karube, Y.; Morikawa, T.; Ishibashi, Y.; Kameyama, T.; Chiba, K.; Sasaki, N.; Iwata, K.; Matsuzaki, H.; Manabe, T. Fluvoxamine moderates reduced voluntary activity following chronic dexamethasone infusion in mice via recovery of BDNF signal cascades. Neurochem. Int., 2014, 69, 9-13.
[] [PMID: 24582626]
Izumo, N.; Ono, Y.; Inatomi, C.; Toho, M.; Katoh, S. Potentiation of nerve growth factor-induced neurite outgrowth by a novel SERM, MU314, in PC12 cells. Pharmacometrics, 2017, 92(1/2), 45-52.
Ochoa, T.J.; Sizonenko, S.V. Lactoferrin and prematurity: a promising milk protein? Biochem. Cell Biol., 2017, 95(1), 22-30.
[] [PMID: 28085488]
Ono, T.; Murakoshi, M.; Suzuki, N.; Iida, N.; Ohdera, M.; Iigo, M.; Yoshida, T.; Sugiyama, K.; Nishino, H. Potent anti-obesity effect of enteric-coated lactoferrin: decrease in visceral fat accumulation in Japanese men and women with abdominal obesity after 8-week administration of enteric-coated lactoferrin tablets. Br. J. Nutr., 2010, 104(11), 1688-1695.
[] [PMID: 20691130]
Fukuyama, R.; Shimokawa, A.; Kodama, Y.; Fujita, M.; Ohishi, Y.; Ando, Y.; Koida, M.; Nakamuta, H. Anti-osteoporosis effect of 5-bromo-2-(4-chlorobenzoyl)-(Z)-3-(2-cyano-3-hydroxybut-2-enonyl)aminobenzo[b]furan: a novel selective estrogen receptor modulator. J. Pharmacol. Sci., 2011, 116(2), 214-220.
[] [PMID: 21606624]
Beral, V.; Bull, D.; Reeves, G. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet, 2005, 365(9470), 1543-1551.
[] [PMID: 15866308]
Nishimura, T.; Ishima, T.; Iyo, M.; Hashimoto, K. Potentiation of nerve growth factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP3 receptors and cellular signaling pathways. PLoS One, 2008, 3(7)e2558
[] [PMID: 18596927]
Liu, M.; Fan, F.; Shi, P.; Tu, M.; Yu, C.; Yu, C.; Du, M. Lactoferrin promotes MC3T3-E1 osteoblast cells proliferation via MAPK signaling pathways. Int. J. Biol. Macromol., 2018, 107(Pt A), 137-143.
[] [PMID: 28863893]

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