L-ornithine attenuates corticotropin-releasing factor-induced stress responses acting at GABAA receptors

Neuroscience. 2011 Jan 13;172:226-31.
L-ornithine attenuates corticotropin-releasing factor-induced stress responses acting at GABAA receptors in neonatal chicks.
Kurata K, Shigemi K, Tomonaga S, Aoki M, Morishita K, Denbow DM, Furuse M.

Laboratory of Regulation in Metabolism and Behavior, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka, Japan.

I.c.v. injection of L-ornithine has been shown to have sedative and hypnotic effects on neonatal chicks exposed to acute stressful conditions. To clarify the mechanism, we conducted three experiments under strengthened stressful conditions with corticotropin-releasing factor (CRF). In Experiment 1, the effect of i.c.v. injection of CRF, L-ornithine (0.5 μmol) or CRF with L-ornithine on the stressful response of chicks was investigated. Compared with the vehicle control, CRF increased distress vocalizations and the time spent in active wakefulness. L-ornithine increased the time spent in sleeping posture, even following stimulation with CRF. In Experiment 2, dose-dependent effects of L-ornithine were investigated using i.c.v. administration with vehicle, CRF alone or CRF plus L-ornithine (0.125, 0.25 or 0.5 μmol). L-ornithine decreased the CRF-stimulated distress vocalizations in a dose-dependent manner. In Experiment 3, the chicks were injected i.c.v. with either CRF, CRF plus L-ornithine (0.5 μmol), CRF plus the γ-aminobutyric acid (GABA)A receptor antagonist picrotoxin or L-ornithine with picrotoxin. The sedative and hypnotic effects induced by L-ornithine were blocked with co-administration of picrotoxin. These results suggest that L-ornithine could attenuate CRF-stimulated stress behaviors acting at GABAA receptors.

Since CRF Receptor Antagonist prevents alopecia in CRF Over-Expressing mice, perhaps L-ornithine will help. Taking L-ornithine orally does help with sleep.

If anyone tries this, the dose should be pretty high. 3 to 6 grams approximately.

This might be a better idea:

Pharmacol Biochem Behav. 2005 Dec;82(4):686-94. Epub 2005 Dec 27.
Antidepressant-like effect of icariin and its possible mechanism in mice.
Pan Y, Kong L, Xia X, Zhang W, Xia Z, Jiang F.

State Key Laboratory of Pharmaceutical Biotechnology, Immunobiological Laboratory, Institute of Functional Biomolecule, Nanjing University, PR China.

The behavioral, neurochemical and neuroendocrine effects of icariin isolated from Epimedium brevicornum were investigated in behavioral despair models of KunMing strain of male mice. Icariin was found to significantly shorten immobility time in the forced swimming test (FST) after orally administration for 21 consecutive days. Icarrin also produced a marked reduction in immobility time in the tail suspension test (TST) when administered for at least 7 consecutive days. The preferable antidepressant action by icariin was obtained at 17.5 and 35 mg/kg in the present study. Moreover, it was observed that the stress of FST exposure induced increases in brain monoamine oxidase (MAO) A and B activities, serum corticotropin-releasing factor (CRF) levels, as well as decreases in brain monoamine neurotransmitter levels. Treatment of icariin for 21 consecutive days mainly reversed the above effects in the mouse FST. These results suggested that icarrin possessed potent antidepressant-like properties that were mediated via neurochemical and neuroendocrine systems.

Biol Pharm Bull. 2006 Dec;29(12):2399-403.
Effects of icariin on hypothalamic-pituitary-adrenal axis action and cytokine levels in stressed Sprague-Dawley rats.
Pan Y, Zhang WY, Xia X, Kong LD.

State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.

Icariin is one of the major active flavonoids constituents of Epimedium brevicornum MAXIM (Berberidaceae). Icariin and E. brevicornum have a wide range of pharmacological activities. Abnormality in the hypothalamic-pituitary-adrenal (HPA) axis is considered to be a key neurobilogical factor in major depression, and cytokines have a close relationship with the activation of the HPA axis. In the present study, the aim was to determine whether icariin possesses an antidepressant-like activity, and to explore the effects of icariin on the HPA axis and cytokine levels in chronic mild stress (CMS) model of depression in Sprague-Dawley rats. Icariin significantly increased the sucrose intake of CMS-treated rats from week 3. It not only attenuated the CMS-induced increases in serum corticotropin-releasing factor (CRF) and cortisol levels, but also reversed the abnormal levels of serum interleukin-6 (IL-6) and tumor-necrosis-factor alpha (TNF-alpha) to the normal in the stressed rats. These results suggested that icariin possessed an antidepressant-like property that was at least in part mediated by neuroendocrine and immune systems.

Pharmacol Biochem Behav. 2007 May;87(1):130-40. Epub 2007 Apr 19.
Icariin from Epimedium brevicornum attenuates chronic mild stress-induced behavioral and neuroendocrinological alterations in male Wistar rats.
Pan Y, Kong LD, Li YC, Xia X, Kung HF, Jiang FX.

State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, School of Life Sciences, Nanjing University, Nanjing 210093, People's Republic of China.

Chronic mild stress (CMS) is suggested to produce abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamus-pituitary-thyroid (HPT) axis. Therefore, compound that attenuates the neuroendocrinological alterations may have potential as antidepressant. The behavioral and neuroendocrinological effects of icariin, a major constituent of flavonoids isolated from Epimedium brevicornum, were investigated in the CMS model of depression in male Wistar rats. CMS procedure caused an anhedonic state in rats resulted in increased corticotropin-releasing factor (CRF) concentrations in dissected brain regions and serum, decreased total triiodothyronine (tT3) in serum with no significant changes in serum adrenocorticotrophic hormone (ACTH) and thyroxine (tT4). Administration of icariin reversed CMS-induced sucrose intake reduction and CRF elevation. These results suggested that icariin possessed potent antidepressant-like activities which were at least in part mediated by improving the abnormalities in the HPA axis functions. However, we did not find a clear correlation between the HPT axis and icariin treatment in the CMS-treated rats.

Psychoneuroendocrinology. 2010 Feb;35(2):272-83. Epub 2009 Jul 23.
Icariin attenuates chronic mild stress-induced dysregulation of the LHPA stress circuit in rats.
Pan Y, Wang FM, Qiang LQ, Zhang DM, Kong LD.

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, People's Republic of China.

Chronic mild stress (CMS) is suggested to develop dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) stress circuit. Icariin, a major constituent of flavonoids isolated from Epimedium brevicornum, has been previously confirmed to rescue the HPA axis abnormalities in animal models of depression. However, antidepressant treatment of icariin on corticotropin-releasing factor (CRF) system within the LHPA stress circuit and its interaction with serotonergic receptor are still seldom studied in CMS model of animals. The present study further investigated the effects of CMS procedure and subsequent icariin treatment on mRNA and protein levels of CRF, CRF receptor 1 (CRFR1) and CRF binding protein (CRFBP), as well as sucrose intake in rats. Moreover, the levels of cyclic adenosine 3',5'-monophosphate (cAMP) response element binding protein (CREB), glucocorticoid receptor (GR) and 5-hydroxytryptamine 1A receptor (5-HTR1A) in hypothalamus, hippocampus and frontal cortex were simultaneously evaluated for their participations in CRF system in this model. We found that CMS procedure significantly increased CRF expression levels in the brain regions, and decreased GR and 5-HTR1A in hippocampus and frontal cortex, with sucrose intake reduction representing the hedonic deficit in rats. Icariin restored these alterations in CMS rats. These results confirmed the hypothesis that icariin exerted antidepressant-like effect via its regulation of central CRF system. And hippocampus was suggested as an important neural area controlling the LHPA stress circuit in icariin-treated CMS rats. These findings for the first time proved that the potential molecular mechanism of antidepressant action of icariin was targeted on the interaction of the LHPA stress circuit and serotonergic function in CMS rats.

I'm going to transfer these studies to a more relevant thread.

Please do so CS!

Very very interesting, I'm willing to try these things. I see icariin is found in Horny Goat Weed... the well known sexual tonic.

Why do you say it might be a better idea? What doses might be recommended to try it out?

Thanks

CS what brand and dose you recommend for icariin ?

Effects of Icariin on Serum CRF Levels As shown in Fig. 3, the CMS procedure induced serum CRF levels of
saline-treated rats a slightly higher. Icariin at 35 mg/kg significantly reduced serum CRF levels (p<0.05) in stressed animals, but at 70 mg/kg it failed to significantly alter serum CRF levels. There was no significant change of CRF levels in the non-stressed rats after icariin treatment. In this study fluoxetine showed no changes in serum CRF levels both in two groups.

Effects of Icariin on Serum Cortisol Levels As shown in Fig. 4, there was a significant increase in cortisol levels in
saline-treated CMS rats (p<0.01). Icariin at 35 mg/kg slightly but not remarkably reduced serum cortisol levels in the
CMS-treated rats, and icariin at 70 mg/kg attenuated the CMS-induced increase in these levels (p<0.05). Fluoxetine
exhibited a tendency to decrease these levels of CMS-treated animals. In the non-stressed groups, icariin had no significant effect on the cortisol levels. However, significant increase in these levels was observed after administration of fluoxetine (p<0.01).

For a human dose, I'm not really sure.

It would be pretty hard to get a dose of Icariin to match what the study had. Perhaps lower dosages would work.

Here's more:

Biol Pharm Bull. 2006 Dec;29(12):2399-403.
Effects of icariin on hypothalamic-pituitary-adrenal axis action and cytokine levels in stressed Sprague-Dawley rats.
Pan Y, Zhang WY, Xia X, Kong LD.

State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.

Icariin is one of the major active flavonoids constituents of Epimedium brevicornum MAXIM (Berberidaceae). Icariin and E. brevicornum have a wide range of pharmacological activities. Abnormality in the hypothalamic-pituitary-adrenal (HPA) axis is considered to be a key neurobilogical factor in major depression, and cytokines have a close relationship with the activation of the HPA axis. In the present study, the aim was to determine whether icariin possesses an antidepressant-like activity, and to explore the effects of icariin on the HPA axis and cytokine levels in chronic mild stress (CMS) model of depression in Sprague-Dawley rats. Icariin significantly increased the sucrose intake of CMS-treated rats from week 3. It not only attenuated the CMS-induced increases in serum corticotropin-releasing factor (CRF) and cortisol levels, but also reversed the abnormal levels of serum interleukin-6 (IL-6) and tumor-necrosis-factor alpha (TNF-alpha) to the normal in the stressed rats. These results suggested that icariin possessed an antidepressant-like property that was at least in part mediated by neuroendocrine and immune systems.

Full study:

http://www.jstage.jst.go.jp/article/bpb/29/12/2399/_pdf

lol i just realized LittleFighter asked same question about dose , pardon me

so Icariin is very specific in terms of dosing while L-ornithine seem to be more forgiving , NOW L-ornithine (500mg) contains 120 caps so that will not last a month .. if someone finds a better option please tell us ..

Here's an interesting study on Quercetin.

Prog Neuropsychopharmacol Biol Psychiatry. 2010 Aug 16;34(6):955-60. Epub 2010 May 3.
Reversal by quercetin of corticotrophin releasing factor induced anxiety- and depression-like effect in mice.
Bhutada P, Mundhada Y, Bansod K, Ubgade A, Quazi M, Umathe S, Mundhada D.

Agnihotri College of Pharmacy, Pharmacology Division, Bapuji Wadi, Sindhi Meghe, Wardha 442 001, Maharashtra, India. psbhutada@live.com

Quercetin is a bioflavonoid reported to produce variety of behavioral effects like anxiolytic, antidepressant, etc. Recent gathering evidences indicated that quercetin attenuates stress-induced behavioral and biochemical effects. It also decreases CRF expression in the brain. As CRF is commonly implicated in the high-anxiety and depression, we hypothesized that quercetin may involve CRF in its anxiolytic- and antidepressant-like effects. To support such possibility, we investigated the influence of quercetin on CRF or CRF antagonist (antalarmin) induced changes in social interaction time in social interaction test, and immobility time in forced swim test. Results indicated that quercetin (20-40 mg/kg, p.o.) or antalarmin (2-4 microg/mouse, i.c.v.) dose dependently increased social interaction time and decreased immobility time indicating anxiolytic- and antidepressant-like effect. These effects were comparable with the traditional anxiolytic (diazepam, 1-2mg/kg, i.p.) and antidepressant (fluoxetine, 10-20mg/kg, i.p.) agents. Administration of CRF (0.1 and 0.3 nmol/mouse, i.c.v.) produced just opposite effects to that of quercetin on these parameters. Further, it was seen that pretreatment with quercetin (20 or 40 mg/kg, p.o.) dose dependently antagonized the effects of CRF (0.1 or 0.3 nmol/mouse, i.c.v.) in social interaction and forced swim test. The sub-effective dose of antalarmin (1 microg/mouse) when administered along with the sub-effective dose of quercetin (10mg/kg) produced significant anxiolytic-and antidepressant-like effect. These observations suggest reciprocating role of quercetin on the CRF-induced anxiogenic and depressant-like effects.

I have wondered if Lead (Pb) exposure affects cortisol levels. Here is evidence in early life.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2235205/

Basic Clin Pharmacol Toxicol. 2008 Feb;102(2):218-27.
Lifetime consequences of combined maternal lead and stress.
Cory-Slechta DA, Virgolini MB, Rossi-George A, Thiruchelvam M, Lisek R, Weston D.

Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. deborah_cory-slechta@urmc.rochester.edu

Elevated lead (Pb) exposure and high stress both target low socio-economic status populations. Both also act on the hypothalamic-pituitary-adrenal (HPA) axis. Pb disrupts cognition through effects on the mesocorticolimbic dopamine pathway. Stress hormones act on this same pathway via the HPA axis. The fact that Pb and stress are likely interactive risk factors served as the rationale for a series of studies in our laboratory. These demonstrate that stress can modify Pb effects, that Pb can modify stress responsivity, and, notably, that Pb + stress effects can occur in the absence of an effect of either alone in rats. Furthermore, maternal only Pb exposure can permanently alter basal corticosterone levels, stress responsivity (i.e. permanent modification of HPA axis function) and brain catecholamines in offspring of both genders. Interactive effects of Pb + stress are not limited to early development: even Pb exposures initiated post-weaning alter basal corticosterone and stress responsivity. Outcomes differ in relation to gender, brain region, stressor and time of measurement, making Pb + stress interactions complex. Altered HPA axis function may serve as a mechanism for the behavioural and catecholaminergic neurotoxicity associated with Pb, as well as for the increased incidence of disease and dysfunctions associated with low socio-economic status. The permanent consequences of maternal only Pb exposure suggest that Pb screening programmes should include pregnant women at risk for elevated Pb exposure, and that stress should be considered as an additional risk factor. Pb + stress effects observed in the absence of either risk factor alone raise questions about the capacity of current hazard identification approaches to adequately identify human health risks posed by neurotoxicants.

Arsenic exposure looks to be a potential culprit also.

Neurotoxicology. 2008 Jul;29(4):647-55. Epub 2008 May 21.
Moderate perinatal arsenic exposure alters neuroendocrine markers associated with depression and increases depressive-like behaviors in adult mouse offspring.
Martinez EJ, Kolb BL, Bell A, Savage DD, Allan AM.

Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM 87131, United States.

Arsenic is one of the most common heavy metal contaminants found in the environment, particularly in water. We examined the impact of perinatal exposure to relatively low levels of arsenic (50 parts per billion, ppb) on neuroendocrine markers associated with depression and depressive-like behaviors in affected adult C57BL/6J mouse offspring. Whereas most biomedical research on arsenic has focused on its carcinogenic potential, a few studies suggest that arsenic can adversely affect brain development and neural function. Compared to controls, offspring exposed to 50 parts per billion arsenic during the perinatal period had significantly elevated serum corticosterone levels, reduced whole hippocampal CRFR 1 protein level and elevated dorsal hippocampal serotonin 5HT 1A receptor binding and receptor-effector coupling. 5HT 1A receptor binding and receptor-effector coupling were not different in the ventral hippocampal formation, entorhinal or parietal cortices, or inferior colliculus. Perinatal arsenic exposure also significantly increased learned helplessness and measures of immobility in a forced swim task. Taken together, these results suggest that perinatal arsenic exposure may disrupt the regulatory interactions between the hypothalamic-pituitary-adrenal axis and the serotonergic system in the dorsal hippocampal formation in a manner that predisposes affected offspring to depressive-like behavior. These results are the first to demonstrate that relatively low levels of arsenic exposure during development can have long-lasting adverse effects on behavior and neurobiological markers associated with these behavioral changes.

Full study: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585488/?tool=pubmed

LittleFighter wrote:Please do so CS!

Very very interesting, I'm willing to try these things. I see icariin is found in Horny Goat Weed... the well known sexual tonic.

Thanks

Ok, so I tried out the horny goat weed for the icariin (i'm a fast responder, my hair will change based on what I've eaten that day, supps included). Tried it topically and internally. Topically, noticed a little extra "pump", sort of like when you have a good day, supps, laser, etc. but have also gotten this effect from going the internal route from regimen(s) (biotin, B vitamins, zinc, etc.) Mixed it with water and rinsed it through, then combed after that. Slight cosmetic pump.

Internally, I do believe there are some phyto-estros in HGW, so there may be some sides, I felt like there were. I think more research/info chould be looked into on this - I didn't see any info on guys that took HGW for different reasons than ours and got favorable effects (other than libido, ED, etc)