ABSTRACT
Title
Estrogens-independent effect of melatonin on adult hippocampal neurogenesis in mice
Authors
R. Crupi
Doctorate School in Experimental Medicine
Dep. of Clinical and Experimental Medicine and Pharmacology, School of Medicine,
University of Messina, Torre Biologica- Policlinico Universitario Messina, Italy.
Doctorate School in Experimental Medicine
Dep. of Clinical and Experimental Medicine and Pharmacology, School of Medicine,
University of Messina, Torre Biologica- Policlinico Universitario Messina, Italy.
Abstract
Melatonin, chemically known as N-acetyl-5-methoxytryptamine, is an endogenous substance produced by the pineal gland and by various other organs such as the retina, the extraorbital lacrimal gland, the gut and bone marrow cells or the enterochromaffin cells of the gastrointestinal tract [1]. The high lipophilicity of melatonin permits its rapid transfer into other organs and fluids. Its presence has been reported in the cerebrospinal fluid (CSF), saliva, amniotic fluid, male seminal fluid and ovarian follicular fluid [2]. The primary goal of our investigation was studiedwhether endogenous melatonin treatment affects proliferation, survival and differentiation of neuronal progenitors cells (NPCs) in the dentate gyrus (DG) of the hippocampus in naïve female mice as well as in ovariectomized (OVX) mice. As a secondary goal it was to investigated whether estradiol levels influence the birth of SGZ cells. To verify this, SGZ proliferation, survival and differentiation were evaluated in naïve female mice as well as in ovariectomized (OVX) mice. To correlate neuronal development with neuronal plasticity, dendritic spine density has been analyzed in the same brain region in both experimental groups. Finally, to confirm the antidepressant like-effect of melatonin administration, the tail suspension test (TST) has been performed.
Chronic exogenous melatonin administration (21 days) increases the bromodeoxyuridine (BrdU) (OVX sham 72.5 ± 3.22 versus OVX mel 122.25 ± 12.05; P<0.05) and doublecortin (DCX) (OVX sham 88.6 ± 3.18 versus OVX mel 176.6 ± 9.96; P<0.05) immunoreactive cells in the hippocampus of ovariectomized mice. Our results show that, in OVX mice, depletion of estrogens specifically improves the spine maturation in granule cells of DG.The quantitative analysis of DG spine density suggests that melatonin treatment causes an increase in the number of these spines. To assess the behavioral consequences of the melatonin administration, mice were subjected to TST that, as reported by Steru et al [3], is selectively sensitive to clinically effective antidepressants treatment. We observed that estrogen deprivation did not affect the immobility time. 21-days melatonin treatment reduced the immobility time in both N-OVX and OVX mice. Our data also demonstrate that SGZ proliferation in mice is not dependent on endogenous levels of estradiol, as assessed across the estrous cycle or in OVX mice. Taken together these findings demonstrate that melatonin may be useful in improving brain functions acting on birth, survival and differentiation of new neurons in the hippocampus; stimulating maturation of spines and exerting an antidepressant-like action under estrogen-deprived conditions.
Chronic exogenous melatonin administration (21 days) increases the bromodeoxyuridine (BrdU) (OVX sham 72.5 ± 3.22 versus OVX mel 122.25 ± 12.05; P<0.05) and doublecortin (DCX) (OVX sham 88.6 ± 3.18 versus OVX mel 176.6 ± 9.96; P<0.05) immunoreactive cells in the hippocampus of ovariectomized mice. Our results show that, in OVX mice, depletion of estrogens specifically improves the spine maturation in granule cells of DG.The quantitative analysis of DG spine density suggests that melatonin treatment causes an increase in the number of these spines. To assess the behavioral consequences of the melatonin administration, mice were subjected to TST that, as reported by Steru et al [3], is selectively sensitive to clinically effective antidepressants treatment. We observed that estrogen deprivation did not affect the immobility time. 21-days melatonin treatment reduced the immobility time in both N-OVX and OVX mice. Our data also demonstrate that SGZ proliferation in mice is not dependent on endogenous levels of estradiol, as assessed across the estrous cycle or in OVX mice. Taken together these findings demonstrate that melatonin may be useful in improving brain functions acting on birth, survival and differentiation of new neurons in the hippocampus; stimulating maturation of spines and exerting an antidepressant-like action under estrogen-deprived conditions.
- Hardeland R et al. (1993) Neuroscience and biobehavioral reviews; 17:347-57
- Reiter RJ (1991) Molecular and cellular endocrinology; 79:C153-8
- Steru L et al. (1985) Psychopharmacology; 85:367-70