Latent Sex Differences in CaMKII-nNOS Signaling That Underlie Antidepressant-Like Effects of Yueju-Ganmaidazao Decoction in the Hippocampus

Previous studies have demonstrated that Yueju-Ganmaidazao (YG) decoction induces rapid antidepressant-like effects, and the antidepressant response is mostly dependent on the suppression of nitric oxide-cyclic guanosine monophosphate signaling in male mice. This study aimed to investigate the sex difference mediated by calcium/calmodulin-dependent protein kinase II (CaMKII)-neuronal nitric oxide synthase (nNOS) signaling involved in the antidepressant-like effect of YG in mice. We found that the immobility times in the tail suspension test (TST) were found to be decreased after the single injection of YG in male and female mice with the same dosage. Additionally, chronic administration for 4 days of subthreshold dosage of YG and escitalopram (ES) also significantly decreased the immobility time in mice of both sexes. Chronic subthreshold dosage of YG and ES in LPS-treated mice and in chronic unpredictable stress (CUS) mice both decreased the immobility time, which was increased by stress. Meanwhile, in CUS-treated mice, sucrose preference test, forced swimming test, and open field test were applied to further confirm the antidepressant-like effects of YG and ES. Moreover, CUS significantly decreased the expression of nNOS and CaMKII, and both YG and ES could enhance the expression in the hippocampus of female mice, which was opposite to that in male mice, while endothelial nitric oxide synthase expression was not affected by stress or drug treatment neither in male mice nor in female mice. Finally, subthreshold dosage of YG combined with 7-nitroindazole (nNOS inhibitor) induced the antidepressant-like effects both in female and in male mice, while the single use of YG or 7-NI did not display any effect. However, pretreatment with KN-93 (CaMKII inhibitor) only blocked the antidepressant-like effect of high-dosage YG in female mice. Meanwhile, in CUS mice, chronic stress caused NR1 overexpression and inhibited cAMP response element binding protein action, which were both reversed by YG and ES in male and female mice, implying that YG and ES produced the same antidepressant-like effect in mice of both sexes. The study revealed that chronic treatment with a subthreshold dose of YG also produced antidepressant-like effects in female mice, and these effects depended on the regulation of the CaMKII-nNOS signaling pathway.

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ET-1 overexpression and endothelial nitric oxide synthase knock-out induce different pathological responses in the heart of male and female mice

Life Sciences ◽

10.1016/j.lfs.2013.12.065 ◽

2013 ◽

Vol 93 (25-26) ◽

pp. e13

Author(s):

Nicolas Vignon-Zellweger ◽

Katharina Relle ◽

Jan Rahnenfuhrer ◽

Karima Schwab ◽

Berthold Hocher ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Male And Female ◽

Knock Out ◽

Female Mice ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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Mechanisms of sex differences in exercise capacity

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00394.2018 ◽

2019 ◽

Vol 316 (6) ◽

pp. R832-R838 ◽

Cited By ~ 8

Author(s):

Marko Oydanich ◽

Denis Babici ◽

Jie Zhang ◽

Nicole Rynecki ◽

Dorothy E. Vatner ◽

...

Keyword(s):

Nitric Oxide ◽

Sex Differences ◽

Nitric Oxide Synthase ◽

Myosin Heavy Chain ◽

Exercise Capacity ◽

Heavy Chain ◽

Type I ◽

Male Mice ◽

Female Mice ◽

Oxide Synthase

Sex differences are an important component of National Institutes of Health rigor. The goal of this investigation was to test the hypothesis that female mice have greater exercise capacity than male mice, and that it is due to estrogen, nitric oxide, and myosin heavy chain expression. Female C57BL6/J wild-type mice exhibited greater ( P < 0.05) maximal exercise capacity for running distance (489 ± 15 m) than age-matched male counterparts (318 ± 15 m), as well as 20% greater work to exhaustion. When matched for weight or muscle mass, females still maintained greater exercise capacity than males. Increased type I and decreased type II myosin heavy chain fibers in the soleus muscle from females are consistent with fatigue resistance and better endurance in females compared with males. After ovariectomy, female mice no longer demonstrated enhanced exercise, and treatment of male mice with estrogen resulted in exercise capacity similar to that of intact females (485 ± 37 m). Nitric oxide synthase, a downstream target of estrogen, exhibited higher activity in female mice compared with male mice, P < 0.05, whereas ovariectomized females exhibited nitric oxide synthase levels similar to males. Nitric oxide synthase activity also increased in males treated with chronic estrogen to levels of intact females. Nitric oxide synthase blockade with Nω-nitro-l-arginine methyl ester eliminated the sex differences in exercise capacity. Thus estrogen, nitric oxide, and myosin heavy chain expression are important mechanisms mediating the enhanced exercise performance in females.

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Endothelin-1 overexpression and endothelial nitric oxide synthase knock-out induce different pathological responses in the heart of male and female mice

Life Sciences ◽

10.1016/j.lfs.2013.12.003 ◽

2014 ◽

Vol 118 (2) ◽

pp. 219-225 ◽

Cited By ~ 7

Author(s):

Nicolas Vignon-Zellweger ◽

Katharina Relle ◽

Jan Rahnenführer ◽

Karima Schwab ◽

Berthold Hocher ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Male And Female ◽

Knock Out ◽

Female Mice ◽

Endothelin 1 ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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Estrous cycle influences the expression of neuronal nitric oxide synthase in the hypothalamus and limbic system of female mice

BMC Neuroscience ◽

10.1186/1471-2202-10-78 ◽

2009 ◽

Vol 10 (1) ◽

pp. 78 ◽

Cited By ~ 21

Author(s):

Monica Sica ◽

Mariangela Martini ◽

Carla Viglietti-Panzica ◽

GianCarlo Panzica

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Estrous Cycle ◽

Limbic System ◽

Neuronal Nitric Oxide Synthase ◽

Female Mice ◽

Oxide Synthase

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Chronic Administration of the Nitric Oxide Synthase Inhibitor, L-NAME, Increases Circulating Endothelin Levels in Guinea Pigs

Endothelium ◽

10.3109/10623329509024659 ◽

1995 ◽

Vol 3 (1) ◽

pp. 57-62 ◽

Cited By ~ 6

Author(s):

Mark J. S. Miller ◽

Upender K. Munshi ◽

Xiao-Jing Zhang ◽

Halina Sadowska-Krowicka ◽

Paula Savage ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Guinea Pigs ◽

Chronic Administration ◽

Nitric Oxide Synthase Inhibitor ◽

Synthase Inhibitor ◽

Oxide Synthase

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Sex-specific vascular responses of the rat aorta: effects of moderate term (intermediate stage) streptozotocin-induced diabetes

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2015-0272 ◽

2016 ◽

Vol 94 (4) ◽

pp. 408-415 ◽

Cited By ~ 3

Author(s):

Xiaoyuan Han ◽

Sonali Shaligram ◽

Rui Zhang ◽

Leigh Anderson ◽

Roshanak Rahimian

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Mrna Expression ◽

Intermediate Stage ◽

Diabetic Rats ◽

Female Rats ◽

Diabetic Rat ◽

Male And Female ◽

Male And Female Rats ◽

Oxide Synthase

Hyperglycemia affects male and female vascular beds differently. We have previously shown that 1 week after the induction of diabetes with streptozotocin (STZ), male and female rats exhibit differences in aortic endothelial function. To examine this phenomenon further, aortic responses were studied in male and female rats 8 weeks after the induction of diabetes (intermediate stage). Endothelium-dependent vasodilation (EDV) to acetylcholine (ACh) was measured in phenylephrine (PE) pre-contracted rat aortic rings. Concentration response curves to PE were generated before and after L-NAME, a nitric oxide synthase (NOS) inhibitor. Furthermore, mRNA expression of endothelial nitric oxide synthase (eNOS) and NADPH oxidase subunit (Nox1) were determined. At 8 weeks, diabetes impaired EDV to a greater extent in female than male aortae. Furthermore, the responsiveness to PE was significantly enhanced only in female diabetic rats, and basal NO, as indicated by the potentiation of the response to PE after L-NAME, was reduced in female diabetic rat aortae to the same levels as in males. In addition, eNOS mRNA expression was decreased, while the Nox1 expression was significantly enhanced in diabetic female rats. These results suggest that aortic function in female diabetic rats after 8 weeks exhibits a more prominent impairment and that NO may be involved.

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Elimination of Aggressive Behavior in Male Mice Lacking Endothelial Nitric Oxide Synthase

Journal of Neuroscience ◽

10.1523/jneurosci.19-19-j0004.1999 ◽

1999 ◽

Vol 19 (19) ◽

pp. RC30-RC30 ◽

Cited By ~ 78

Author(s):

Gregory E. Demas ◽

Lance J. Kriegsfeld ◽

Seth Blackshaw ◽

Paul Huang ◽

Stephen C. Gammie ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Aggressive Behavior ◽

Endothelial Nitric Oxide Synthase ◽

Male Mice ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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Student Research Award 1994: Nitric Oxide in the Rat Vestibular System

Otolaryngology ◽

10.1177/019459989411100407 ◽

1994 ◽

Vol 111 (4) ◽

pp. 430-438 ◽

Cited By ~ 23

Author(s):

Andrew Harper ◽

William R. Blythe ◽

Carlton J. Zdanski ◽

Jiri Prazma ◽

Harold C. Pillsbury

Keyword(s):

Nitric Oxide ◽

Nervous System ◽

Amino Acid ◽

Nitric Oxide Synthase ◽

Vestibular System ◽

Soluble Guanylate Cyclase ◽

Excitatory Amino Acid ◽

Nerve Fibers ◽

Guanosine Monophosphate ◽

Oxide Synthase

Nitric oxide is known to function as a neurotransmitter in the central nervous system. It is also known to be involved in the control nervous system excitatory amino acid neurotransmission cascade. Activation of excitatory amino acid receptors causes an influx of calcium, which activates nitric oxide synthase. The resulting increase in intracellular nitric oxide activates soluble guanylate cyclase, leading to a rise in cyclic guanosine monophosphate. The excitatory amino acids giutamate and aspartate are found in the vestibular system and have been postulated to function as vestibular system neurotransmitters. Although nitric oxide has ben investigated as a neurotransmitter in other tissues, no published studies have examined the role of nitric oxide in the vestibular system. Neuronal NADPH-dlaphorase has been characterized as a nitric oxide synthase. This enzyme catalyzes the conversion of L-arginine to l-citrulline, producing nitric oxide during the reaction. We used a histochemical stain characterized by Hope et al. (Proc Natl Acad Sci 1991;88:2811) as specific for neuronal nitric oxide synthase to localize the enzyme in the rat vestibular system. An Immunocytochemical stain was used to examine rat Inner ear tissue for the presence of the enzyme's end product, l-citrulline, thereby demonstrating nitric oxide synthase activity. Staining of vestibular ganglion sections showed nitric oxide synthase presence and activity in ganglion cells and nerve fibers. These results Indicate the presence of active nitric oxide synthase in these tissues and suggest modulation of vestibular neurotransmission by nitric oxide.

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Testosterone production in mice lacking inducible nitric oxide synthase expression is sensitive to restraint stress

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00412.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. E615-E620 ◽

Cited By ~ 10

Author(s):

Ben A. Weissman ◽

Chantal M. Sottas ◽

Ping Zhou ◽

Costantino Iadecola ◽

Matthew P. Hardy

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Restraint Stress ◽

Immobilization Stress ◽

Male Mice ◽

Wild Type ◽

Basal Plasma ◽

Oxide Synthase ◽

Inducible Nitric Oxide

Immobilization stress (IMO) induces a rapid increase in glucocorticoid secretion [in rodents, corticosterone CORT)] and this is associated with decreased circulating testosterone (T) levels. Nitric oxide (NO), a reactive free radical and neurotransmitter, has been reported to be produced at higher rates in tissues such as brain during stress. The biosynthesis of T is also known to be dramatically suppressed by NO. Specifically, the inducible isoform of nitric oxide synthase (iNOS) was directly implicated in this suppression. To assess the respective roles of CORT and NO in stress-mediated inhibition of T production, adult wild-type (WT) and inducible nitric oxide synthase knockout (iNOS−/−) male mice were evaluated. Animals of each genotype were assigned to either basal control or 3-h IMO groups. Basal plasma and testicular T levels were equivalent in both genotypes, whereas testicular weights of mutant mice were significantly higher compared with WT animals. Exposure to 3-h IMO increased plasma CORT and decreased T concentrations in mice of both genotypes. Testicular T levels were also affected by stress in WT and mutant males, being sharply reduced in both genotypes. However, the concentrations of nitrite and nitrate, the stable metabolites of NO measured in testicular extracts, did not differ between control and stressed WT and iNOS−/− mice. These results support the hypothesis that CORT, but not NO, is a plausible candidate to mediate rapid stress-induced suppression of Leydig cell steroidogenesis.

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