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The Remarkable Antidepressent Nootropic Properties of Grapefruit

hesperidin naringin gdnf sirt1 diabetes obesity estrogen serotonin neuroprotection

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#1 gamesguru

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Posted 19 September 2016 - 04:37 PM


Grapefruit contains naringin and hesperidin.  Oranges contain only hesperidin.  Other foods contain hesperidin also, the bilberry, tangerines, plums.  The most remarkable effect is related to glial cell-derived neurotrophic factor (GDNF), which causes growth of the glial cells (including astrocytes and the whole immune system within the brain).

Naringin protects the nigrostriatal dopaminergic projection through induction of GDNF in a neurotoxin model of Parkinson's disease.
Leem E1, Nam JH2, Jeon MT1, Shin WH3, Won SY4, Park SJ5, Choi MS6, Jin BK2, Jung UJ6, Kim SR7. (2014)

This study investigated the effect of naringin, a major flavonoid in grapefruit and citrus fruits, on the degeneration of the nigrostriatal dopaminergic (DA) projection in a neurotoxin model of Parkinson's disease (PD) in vivo and the potential underlying mechanisms focusing on the induction of glia-derived neurotrophic factor (GDNF), well known as an important neurotrophic factor involved in the survival of adult DA neurons. 1-Methyl-4-phenylpyridinium (MPP(+)) was unilaterally injected into the medial forebrain bundle of rat brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. To ascertain whether naringin-induced GDNF contributes to neuroprotection, we further investigated the effects of intranigral injection of neutralizing antibodies against GDNF in the MPP(+) rat model of PD. Our observations demonstrate that naringin could increase the level of GDNF in DA neurons, contributing to neuroprotection in the MPP(+) rat model of PD, with activation of mammalian target of rapamycin complex 1. Moreover, naringin could attenuate the level of tumor necrosis factor-α in microglia increased by MPP(+)-induced neurotoxicity in the substantia nigra. These results indicate that naringin could impart to DA neurons the important ability to produce GDNF as a therapeutic agent against PD with anti-inflammatory effects, suggesting that naringin is a beneficial natural product for the prevention of DA degeneration in the adult brain.

 

Naringin treatment improves functional recovery by increasing BDNF and VEGF expression, inhibiting neuronal apoptosis after spinal cord injury.
Rong W1, Wang J, Liu X, Jiang L, Wei F, Hu X, Han X, Liu Z. (2012)

The aim of this study was to determine the therapeutic efficacy of starting naringin treatment 1 day after spinal cord injury (SCI) in rat and to investigate the underlying mechanism. SCI was induced using the modified weight-drop method in Sprague-Dawley rats. The SCI animals were randomly divided into three groups: vehicle-treated group; 20 mg/kg naringin-treated group; 40 mg/kg naringin-treated group, and additionally with sham group (laminectomy only). Locomotors functional recovery was assessed during the 6 weeks post operation period by performing open-field locomotors tests and inclined-plane tests. At the end of the study, the segments of spinal cord encompassing the injury site were removed for histopathological analysis. Immunohistochemistry was performed to observe the expression of the brain-derived neurotrophic factor (BDNF). The expression of vascular endothelial growth factor (VEGF), B-cell CLL/lymphoma-2 (Bcl-2), BCL-2-associated X protein (Bax) and caspase-3 were detected by Western blot analysis. The apoptotic neural cells were assessed using the TUNEL method. The results showed that the naringin-treated animals had significantly better locomotor function recovery, less myelin loss, and higher expression of BDNF and VEGF. In addition, naringin treatment significantly increased in Bcl-2:Bax ratio, reduced the enzyme activity of caspase-3 and decreased the number of apoptotic cells after SCI. These findings suggest that naringin treatment starting 1 day after SCI can significantly improve locomotor recovery, and this neuroprotective effect may be related to the upregulation of BDNF and VEGF and the inhibition of neural apoptosis. Therefore, naringin may be useful as a promising therapeutic agent for SCI.

 

Sirt1 is involved in energy metabolism: the role of chronic ethanol feeding and resveratrol.
Oliva J1, French BA, Li J, Bardag-Gorce F, Fu P, French SW. (2009)

Sirt1, a deacetylase involved in regulating energy metabolism in response to calorie restriction, is up regulated after chronic ethanol feeding using the intragastric feeding model of alcohol liver disease. PGC1 alpha is also up regulated in response to ethanol. These changes are consistent with activation of the Sirt1/PGC1 alpha pathway of metabolism and aging, involved in alcohol liver disease including steatosis, necrosis and fibrosis of the liver. To test this hypothesis, male rats fed ethanol intragastrically for 1 month were compared with rats fed ethanol plus resveratrol or naringin. Liver histology showed macrovesicular steatosis caused by ethanol and this change was unchanged by resveratrol or naringin treatment. Necrosis occurred with ethanol alone but was accentuated by resveratrol treatment, as was fibrosis. The expression of Sirt1 and PGC1 alpha was increased by ethanol but not when naringin or resveratrol was fed with ethanol. Sirt3 was also up regulated by ethanol but not when resveratrol was fed with ethanol. These results support the concept that ethanol induces the Sirt1/PGC1 alpha pathway of gene regulation and both naringin and resveratrol prevent the activation of this pathway by ethanol. However, resveratrol did not reduce the liver pathology caused by chronic ethanol feeding.

 

Protective effect of naringin, a citrus flavonoid, against colchicine-induced cognitive dysfunction and oxidative damage in rats.
Kumar A1, Dogra S, Prakash A. (2010)

Alzheimer's disease is a neurodegenerative disorder. Central administration of colchicine is well known to cause cognitive impairment and oxidative damage, which simulates sporadic dementia of the Alzheimer type in humans. The present study has been designed to investigate the protective effects of naringin against the colchicine-induced cognitive impairment and oxidative damage in rats. Colchicine (15 microg/5 microL), administered intracerebroventricularly, resulted in poor memory retention in both the Morris water maze and elevated plus maze task paradigms and caused marked oxidative damage. It also caused a significant decrease in acetylcholinesterase activity. Naringin (40 and 80 mg/kg, p.o.) treatment was given daily for a period of 25 days beginning 4 days prior to colchicine administration. Chronic treatment with naringin caused significant improvement in the cognitive performance and attenuated oxidative damage, as evidenced by lowering of malondialdehyde level and nitrite concentration and restoration of superoxide dismutase, catalase, luciferase, glutathione S-transferase, and reduced glutathione levels, and acetylcholinesterase activity compared to control. The present study highlights the therapeutic potential of naringin against colchicine-induced cognitive impairment and associated oxidative damage.

Naringin treatment induces neuroprotective effects in a mouse model of Parkinson's disease in vivo, but not enough to restore the lesioned dopaminergic system.
Kim HD1, Jeong KH2, Jung UJ3, Kim SR4. (2016)

We recently reported that treatment with naringin, a major flavonoid found in grapefruit and citrus fruits, attenuated neurodegeneration in a rat model of Parkinson's disease (PD) in vivo. In order to investigate whether its effects are universally applied to a different model of PD and whether its treatment induces restorative effects on the lesioned nigrostriatal dopaminergic (DA) projection, we observed the effects of pre-treatment or post-treatment with naringin in a mouse model of PD. For neuroprotective effects, 6-hydroxydopamine (6-OHDA) was unilaterally injected into the striatum of mouse brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. Our results showed that naringin protected the nigrostriatal DA projection from 6-OHDA-induced neurotoxicity. Moreover, similar to the effects in rat brains, this treatment induced the activation of mammalian target of rapamycin complex 1 (mTORC1), which is well known as an important survival factor for DA neurons, and inhibited microglial activation in the substantia nigra (SN) of mouse brains treated with 6-OHDA. However, there was no significant change of DA phenotypes in the SN and striatum post-treated with naringin compared with 6-OHDA-lesioned mice, despite the treatment being continued for 12 weeks. These results suggest that post-treatment with naringin alone may not be enough to restore the nigrostriatal DA projection in a mouse model of PD. However, our results apparently suggest that naringin is a beneficial natural product to prevent DA degeneration, which is involved in PD.

 

 

The net U.S. consumption of oranges (including store-bought juice) is about 80 oranges per person per year, or 24 billion oranges per year.  Yet if my recommendation for hesperidin is to be met, this must be increased to over 200 billion, roughly 730 oranges per person per year (two per day).  It's the same story with grapefruits... the average U.S. consumption is nowhere near the recommended 365 grapefruits per person per year.  It's a measly 30.  Some people are doing their work, stuffing their faces with good stuff.  But most aren't.

Consumption of grapefruit is associated with higher nutrient intakes and diet quality among adults, and more favorable anthropometrics in women, NHANES 2003–2008
Mary M. Murphy,  Leila M. Barraj, and Gail C. Rampersaud (2014)

Background
Dietary guidance recommends consumption of a nutrient-dense diet containing a variety of fruits. The purpose of this study was to estimate usual nutrient intakes and adequacy of nutrient intakes among adult grapefruit consumers and non-consumers, and to examine associations between grapefruit consumption and select health parameters.

Methods
The analysis was conducted with data collected in the National Health and Nutrition Examination Survey (NHANES) 2003–2008. Respondents reporting consumption of any amount of grapefruit or 100% grapefruit juice at least once during the 2 days of dietary recall were classified as grapefruit consumers.

Results
Among adults aged 19+ years with 2 days of dietary recall (n=12,789), 2.5% of males and 2.7% of females reported consumption of 100% grapefruit juice or fresh, canned, or frozen grapefruit during the recalls. Grapefruit consumers were less likely to have usual intakes of vitamin C (males: 0% vs. 47%; females: 0% vs. 43%; P<0.001) and magnesium (P<0.05) below the estimated average requirement (EAR) compared to non-consumers, and they were more likely to meet adequate intake levels for dietary fiber (P<0.05). Potassium and β-carotene intakes were significantly higher among grapefruit consumers (P<0.001). Diet quality as assessed by the Healthy Eating Index-2005 (HEI-2005) was higher in grapefruit consumers (males: 66.2 [95% CI: 61.0–71.5] vs. 55.4 [95% CI: 54.4–56.4]; females: 71.4 [95% CI: 65.1–77.6] vs. 61.2 [95% CI: 59.8–62.6]). Among women, grapefruit consumption was associated with lower body weight, waist circumference, body mass index (BMI), triglycerides, C-reactive protein (CRP), and higher high-density lipoprotein (HDL) cholesterol (P<0.05), However, risk of being overweight/obese was not associated with grapefruit consumption.

Conclusion
Consumption of grapefruit was associated with higher intakes of vitamin C, magnesium, potassium, dietary fiber, and improved diet quality. Grapefruit may provide a healthful option for adults striving to meet fruit recommendations.

 

 

Quercetin itself has interesting antiviral properties[!]  It also modulates allergies and "mast" cells, and is suspected to lower cholesterol and promote longevity.   A prevalent compound in grapefruit, quercetin is often  mistakenly assumed to underlie its interaction with medications and liver enzymes, but quercetin is only active in vitro[!], so other compounds are responsible.  Due to its wide array of healthful compounds, grapefruit plays a protective role in everything from encephalitis and dementia to Parkinson's (see first quote block)!  Even its scent has been reported to improve reaction time and to make one more discerning[!]

 

But the hesperidin is not to be underestimated.  It has a potent effect on ghrelin signalling[1], which is orexigenic and blocks the 5-HT2C receptor[2].  Blocking 5-HT2C is known to stimulate a global dopamine release, a favorable cascade achieved during coitus.  Hesperidin itself interacts with the 5-HT1A receptor, and this is responsible for most of its antidepressive qualities.

Evidence for the involvement of the serotonergic 5-HT(1A) receptors in the antidepressant-like effect caused by hesperidin in mice.
Souza LC1, de Gomes MG, Goes AT, Del Fabbro L, Filho CB, Boeira SP, Jesse CR. (2013)

The present study investigated a possible antidepressant-like activity of hesperidin using two predictive tests for antidepressant effect in mice: the forced swimming test (FST) and the tail suspension test (TST). Results demonstrated that hesperidin (0.1, 0.3 and 1 mg/kg, intraperitoneal, i.p.) decreased the immobility time in the FST and TST without affecting the locomotor activity in the open field test. The antidepressant-like effect of hesperidin (0.3 mg/kg) on the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (pCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis) and WAY100635 (0.1 mg/kg, subcutaneous, s.c., a selective 5-HT(1A) receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an α(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α(2)-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a β-adrenoceptor antagonist), AMPT (100 mg/kg, i.p., an inhibitor of tyrosine hydroxylase), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist), ketanserin (1mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist) or MDL72222 (1 mg/kg, i.p., a 5-HT(3) receptor antagonist) did not block the antidepressant-like effect of hesperidin (0.3 mg/kg, i.p.) in the TST. Administration of hesperidin (0.01 mg/kg, i.p.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. The antidepressant-like effect caused by hesperidin in mice in the TST was dependent on an interaction with the serotonergic 5-HT(1A) receptors. Taken together, these results suggest that hesperidin possesses antidepressant-like property and may be of interest source for therapeutic agent for the treatment of depressive disorders.

 

Protective effect of hesperidin and naringin against 3-nitropropionic acid induced Huntington's like symptoms in rats: possible role of nitric oxide.
Kumar P1, Kumar A. (2010)

3-Nitropropionic acid (3-NP) is a well known experimental model to study Huntington's disease (HD) and associated neuropsychiatric problems. Present study has been designed to explore the protective effects of hesperidin, naringin, and their nitric oxide mechanism (if any) against 3-nitropropionic acid induced neurotoxicity in rats. Systemic 3-nitropropionic acid (10 mg/kg) treatment for 14 days in rats significantly induced HD like symptoms in rats as indicated by reduced locomotor activity, body weight, grip strength, oxidative defense and mitochondrial complex enzymes (complex-I, -II, and -IV) activities in striatum. Naringin and hesperidin pretreatment significantly attenuated behavioral alterations, oxidative stress and mitochondrial enzymes complex dysfunction in 3-NP treated group. L-Arginine (50 mg/kg) pretreatment with lower dose of hesperidin (50 mg/kg) and naringin (50 mg/kg) significantly attenuated the protective effect of hesperidin and naringin respectively. Whereas L-NAME (10 mg/kg), a non-selective NOS inhibitor pretreatment with hesperidin (50 mg/kg) and naringin (50 mg/kg) significantly potentiated their protective effect which was significant as compared to their effect per se. Study highlights the therapeutic potential of hesperidin and naringin against Huntington's like conditions and further indicates that these drugs might act through nitric oxide mechanism.

 

 

Both flavonoids also have potential in the heart, the second most important organ, vitally supportive of brain health.  Whether supporting the capillaries and smooth muscle at the molecular level, the inflammation of the heart, or the recovery or prevention of stroke victims... grapefruit is a serious underdog!

Hesperidin contributes to the vascular protective effects of orange juice: a randomized crossover study in healthy volunteers
Christine Morand, Claude Dubray, Dragan Milenkovic, Delphine Lioger, Jean François Martin, Augustin Scalbert, and Andrzej Mazur (2010)

Background: Although numerous human studies have shown consistent effects of some polyphenol-rich foods on several intermediate markers for cardiovascular diseases, it is still unknown whether their action could be specifically related to polyphenols.
Objective: We investigated the effect of orange juice and its major flavonoid, hesperidin, on microvascular reactivity, blood pressure, and cardiovascular risk biomarkers through both postprandial and chronic intervention studies.
Design: Twenty-four healthy overweight men (age 50–65 y) were included in a randomized, controlled, crossover study. Throughout the three 4-wk periods, volunteers consumed daily 500 mL orange juice, 500 mL control drink plus hesperidin (CDH), or 500 mL control drink plus placebo (CDP). All measurements and blood collections were performed in overnight-fasted subjects before and after the 4-wk treatment periods. The postprandial study was conducted at the beginning of each experimental period.
Results: Diastolic blood pressure (DBP) was significantly lower after 4 wk consumption of orange juice or CDH than after consumption of CDP (P = 0.02), whereas microvascular endothelium-related reactivity was not significantly affected when measured after an overnight fast. However, both orange juice and CDH ingestion significantly improved postprandial microvascular endothelial reactivity compared with CDP (P < 0.05) when measured at the peak of plasma hesperetin concentration.
Conclusions: In healthy, middle-aged, moderately overweight men, orange juice decreases DBP when regularly consumed and postprandially increases endothelium-dependent microvascular reactivity. Our study suggests that hesperidin could be causally linked to the beneficial effect of orange juice. This trial is registered at clinicaltrials.gov as NCT00983086.

Effects of Hesperidin on cardiac electrophysiology of diabetic rats
W. Wang, J.-M. Cao, Z.-F. Yang, C.-Z. Li (2010)

Objective: To investigate the effects of Hesperidin on cardiac electrophysiology of diabetic rats.

Methods: Thirty SD rats were randomly divided into three groups. Diabetic model group (n = 12): diabetic model was induced by intraperitoneal injection of large amount of streptozotocin (STZ); Hesperidin intervention group (n = 12): diabetic model was established, and were intragastrically administrated with 10 mg/kg Hesperidin daily; control group (n = 6): without model establishment and intervention. After treatment for 4 weeks, in vivo and in vitro ECG and characteristics of action potentials of ventricular muscles were recorded and compared. Papillary muscles of ventricle of diabetic model group were perfused with 1 × 10 -6 mol/L or 5 × 10 -6 mol/L Hesperidin, and changes of action potentials were continuously recorded.

Results: In vivo ECG analysis revealed that the heart rates of diabetic model group and Hesperidin intervention group were much faster than that of control group (P < 0.01, P < 0.05), QT interval of diabetic model group significantly prolonged (P < 0.05), while there was no significant difference in QT interval between control group and Hesperidin intervention group (P > 0.05). In vitro ECG analysis indicated that the prevalence of tachyarrhythmia in diabetic model group was 75.0%, significantly higher than that of Hesperidin intervention group (16.7%) (P < 0.05). Analysis of action potentials of ventricular muscles revealed that the resting membrane potential, amplitude of action potential and maximum upstroke velocity of phase 0 of diabetic model group were significantly lower than those of control group, while the action potential duration was longer than that of control group. Compared with diabetic model group, the parameters of action potentials in Hesperidin intervention group were more approximate with those of control group. Perfusion tests with two concentrations of Hesperidin demonstrated that 5 × 10 -6 mol/L Hesperidin perfusion performed better than 1 × 10 -6 mol/L Hesperidin perfusion in recovery of action potentials of papillary muscles of ventricle of diabetic rats.

Conclusion: Hesperidin may dose-dependently decrease the prevalence of arrhythmia by reversing the abnormal electrophysiological activities in diabetic rats.

The effect of hesperidin on cardiac pumping function and heart rate variability of diabetic rat
WANG Wei;YANG Zhi-fang;WANG Hong-wei;ZHANG Ying;LI Ci-zhen;LIU Yuan-mou;CAO Jiu-mei;ZHAO Yong-ju (2010)

Objective To study the effects and mechanism of hesperidin on the pumping function of streptozotocin induced diabetic rat heart.

Methods Thirty rats were randomly divided into three groups: control(n=6),diabetic(n=12) and hesperidin-treated(n=12)groups.Diabetes was induced by streptozotocin.Langendorff perfusion system on isolated heart and heart rate variability(HRV) analysis were used to study the effect of hesperidin on cardiac contractility,coronary artery blood flow,QRS wave of electrocardiography and HRV.

Results Hesperidin 10��10-6 mol/L could increase the coronary blood flow and contractility of the diabetic rat heart by 106.0% and 87.3%,respectively;meanwhile it shortened the QRS wave by 33.3%.In diabetic rats,the heart rate increased,standard deviation of sinus RR intervals(SDNN)decreased and ratio of sympathetic and vagal tone(LF/HF)increased.All these three parameters recovered somewhat after treated with hesperidin.

Conclusions Hesperidin could improve the coronary blood flow and heart pumping function of streptozotocin induced diabetic rat heart and could reverse the changes of HRV produced by diabetes as well.

 

Effect of Citrus Flavonoids, Naringin and Naringenin, on Metabolic Syndrome and Their Mechanisms of Action
M. Ashraful Alam, Nusrat Subhan, M. Mahbubur Rahman, Shaikh J. Uddin, Hasan M. Reza, and Satyajit D. Sarker (2014)

Flavonoids are important natural compounds with diverse biologic activities. Citrus flavonoids constitute an important series of flavonoids. Naringin and its aglycone naringenin belong to this series of flavonoids and were found to display strong anti-inflammatory and antioxidant activities. Several lines of investigation suggest that naringin supplementation is beneficial for the treatment of obesity, diabetes, hypertension, and metabolic syndrome. A number of molecular mechanisms underlying its beneficial activities have been elucidated. However, their effect on obesity and metabolic disorder remains to be fully established. Moreover, the therapeutic uses of these flavonoids are significantly limited by the lack of adequate clinical evidence. This review aims to explore the biologic activities of these compounds, particularly on lipid metabolism in obesity, oxidative stress, and inflammation in context of metabolic syndrome.

Preventive Effects of Hesperidin, Glucosyl Hesperidin and Naringin on Hypertension and Cerebral Thrombosis in Stroke-prone Spontaneously Hypertensive Rats
Dr Yasuto Sasaki and Kobe Gakuin (2012)

The effects of hesperidin, glucosyl hesperidin (G-hesperidin), a water-soluble derivative of hesperidin, and naringin on blood pressure and cerebral thrombosis were investigated using stroke-prone spontaneously hypertensive rats (SHRSP). Hesperidin, G-hesperidin and naringin were mixed with diet and fed to the animals for 4 weeks. No effect was evident on body weight, but the supplements significantly suppressed the age related increase in blood pressure. Thrombotic tendency, as assessed using a He-Ne laser technique in the cerebral blood vessels, was significantly decreased in the treated animals compared with the control animals. Measurements of 8-hydroxy-2′-deoxyguanosine (8-OHdG) demonstrated that the supplements had strong antioxidant activity. Furthermore, these supplements significantly increased the production of nitric oxide (NO) metabolites in urine measured with Griess reagent. Vasodilation induced by acetylcholine-mediated NO production in the endothelium was assessed using thoracic aortic ring preparations and indicated that endothelial function was significantly improved by the administration of these supplements.

These findings suggest that the strong antioxidant properties of hesperidin, G-hesperidin and naringin could modulate the inactivation of NO and protect endothelial function from reactive oxygen species (ROS). In this manner, the flavonoids could contribute beneficial effects on the mechanisms of hypertension and thrombosis by increasing the bioavailability of NO.

 

Nitric oxide mechanism in the protective effect of naringin against post-stroke depression (PSD) in mice.
Aggarwal A1, Gaur V, Kumar A. (2010)

AIM:
The present study has been designed to explore the nitric oxide mechanism in the protective effect of naringin against I/R induced neurobehavioral alterations, oxidative damage and mitochondrial dysfunction in mice.

MAIN METHODS:
Laca mice (25-30 g) were subjected twice to BCCAO occlusion (5 min) at the interval of 10 min, followed by 96 h reperfusion. Naringin (50 and 100 mg/kg) was administered for 10 days, starting 7 days before the animals were subjected to I/R injury. On day 10, various neurobehavioral parameters followed by biochemical parameters and mitochondrial enzyme complex activities were assessed.

KEY FINDINGS:
Ischemia reperfusion injury caused significant (increased immobility period, neurological score and decreased locomotor activity) oxidative damage (increased lipid peroxidation and nitrite concentration and depleted reduced glutathione, glutathione-S-transferase, superoxide dismutase and catalase) and altered mitochondrial enzyme complex activities (complex I to IV) as compared to sham treatment. Naringin (50 and 100 mg/kg) treatment significantly attenuated neurobehavioral alterations, oxidative damage and restored mitochondrial enzyme complex activities as compared to control (ischemia reperfusion) group. Further, protective effect of naringin (50 mg/kg) was attenuated by l-arginine (100 mg/kg) or sildenafil (5 mg/kg) pretreatment. Further, L-NAME (10 mg/kg) or 7-NI (10 mg/kg) pretreatment with naringin (50 mg/kg) significantly potentiated their protective effect as compared to their treatment alone.

SIGNIFICANCE:
The present study suggests the involvement of nitric oxide mechanism in the protective effect of naringin against post-stroke depression induced neurobehavioral, biochemical and cellular alterations in mice.


Edited by gamesguru, 19 September 2016 - 04:59 PM.

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#2 jack black

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Posted 19 September 2016 - 04:56 PM

Very interesting. I do feel better and less hungry when I eat grapefruits. I always though it was the p450 inhibition that potentiated coffee. Maybe it's more than that.
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#3 gamesguru

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Posted 26 September 2016 - 01:15 AM

The other week Kroger ran out of grapefruit.  They still haven't re-upped.  I thought the universe was trying to annoy me, but apparently it just wanted me to explore local produce markets.  The grapefruit there is much sweeter!

 

Not certain of a synergy with caffeine[1], [2] but yeah, on a scale of 1 to berberine, naringin is pretty darn versatile.  It restores the function of such critical cell components[3], [4] as the endoplasm and mitochondria (see below).  And by no means limited in scope to the mind, the assortment of healthful components (including hesperidin and naringin) found in citrus fruits will improve the function of everything from the spleen to the pancreas.

 

Hesperidin inhibits HeLa cell proliferation through apoptosis mediated by endoplasmic reticulum stress pathways and cell cycle arrest.
Wang Y1, Yu H2, Zhang J3, Gao J4, Ge X5, Lou G6. (2015)

BACKGROUND: Hesperidin (30, 5, 9-dihydroxy-40-methoxy-7-orutinosyl flavanone) is a flavanone that is found mainly in citrus fruits and has been shown to have some anti-neoplastic effects. The aim of the present study was to investigate the effect of hesperidin on apoptosis in human cervical cancer HeLa cells and to identify the mechanism involved.
METHODS: Cells were treated with hesperidin (0, 20, 40, 60, 80, and 100 μM) for 24, 48, or 72 h and relative cell viability was assessed using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay.
RESULTS: Hesperidin inhibited the proliferation of HeLa cells in a concentration- and time-dependent manner. Hesperidin-induced apoptosis in HeLa cells was characterized by increased nuclear condensation and DNA fragmentation. Furthermore, increased levels of GADD153/CHOP and GRP78 indicated hesperidin-induced apoptosis in HeLa cells involved a caspase-dependent pathway, presumably downstream of the endoplasmic reticulum stress pathway. Both of these proteins are hallmarks of endoplasmic reticulum stress. Hesperidin also promoted the formation of reactive oxygen species, mobilization of intracellular Ca(2+), loss of mitochondrial membrane potential (ΔΨm), increased release of cytochrome c and apoptosis-inducing factor from mitochondria, and promoted capase-3 activation. It also arrested HeLa cells in the G0/G1 phase in the cell cycle by downregulating the expression of cyclinD1, cyclinE1, and cyclin-dependent kinase 2 at the protein level. The effect of hesperidin was also verified on the human colon cancer cell HT-29 cells.
CONCLUSION: We concluded that hesperidin inhibited HeLa cell proliferation through apoptosis involving endoplasmic reticulum stress pathways and cell cycle arrest.


Naringin inhibits high glucose-induced cardiomyocyte apoptosis by attenuating mitochondrial dysfunction and modulating the activation of the p38 signaling pathway
Haili Huang Keng Wu Qiong You Ruina Huang Shanghai Li (2013)

Recently, naringin (NAR; 4',5,7-trihydroxyflavanone-7-rhamnoglucoside) has been shown to have cardioprotective properties. However, the specific mechanisms underlying its cardioprotective effects remain unclear. In this study, we aimed to investigate the cardioprotective effects of NAR and the possible underlying molecular mechanisms in cardiomyocytes using high glucose (HG) to induce apoptosis in H9c2 cells. The effect of NAR on apoptosis was assessed by Annexin V and propidium iodide staining, and by determining the levels of active caspase-3, -8 and -9. The effect of NAR on mitochondrial dysfunction was assessed by the loss of mitochondrial membrane potential (MMP). Our results demonstrated that exposure to HG induced apoptosis and mitochondrial dysfunction in cardiomyocytes. Treatment with NAR significantly increased MMP and inhibited the activation of caspase-3, -8 and -9. NAR attenuated the HG-induced p38 and p53 phosphorylation, decreased mitochondrial Bax and Bak expression, prevented the release of cytochrome c and increased Bcl-2 expression. Pre-treatment with SB203580, a p38 inhibitor, also suppressed p53 phosphorylation and prevented the loss of MMP, as well as apoptosis in the HG-treated H9c2 cells. Taken together, these data demonstrate that naringin inhibits HG-induced apoptosis by attenuating mitochondrial dysfunction and modulating the activation of the p38 signaling pathway.

Naringin alleviates cognitive impairment, mitochondrial dysfunction and oxidative stress induced by D-galactose in mice.
Kumar A1, Prakash A, Dogra S. (2010)

Role of mitochondrial dysfunction and oxidative stress has been well documented in aging and related disorders such as Alzheimer's disease. Bioflavonoids have been reported to have a therapeutic potential against several age related processes. Bioflavonoids are being used as a neuroprotectants in the treatment of various neurological disorders including aging. Therefore, present study has been conducted in order to explore the possible role of naringin against D-galactose induced cognitive dysfunction, oxidative damage and mitochondrial dysfunction in mice. Chronic administration of D-galactose (100 mg/kg) for 6 weeks significantly impaired cognitive performance (both in Morris water maze and elevated plus maze), locomotor activity, oxidative defense and mitochondrial complex (I, II and III) enzymes activities as compared to sham group. Six weeks naringin (40 and 80 mg/kg) treatment significantly improved cognitive performance, oxidative defense and restored mitochondria complex enzyme activities as compared to control (D-galactose). Naringin treatment significantly attenuated acetylcholine esterase activity in D-galactose treated mice. In conclusion, present study highlights the potential role of naringin against D-galactose induced cognitive impairment, biochemical and mitochondrial dysfunction in mice.



#4 Junk Master

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Posted 26 September 2016 - 02:53 AM

Nice post.  You will definitely notice synergy with caffeine if you remember the majority of the naringin in grapefruit is in the white part beneath the peel.  Old bodybuilding trick was to combine it with aspirin, ephedrine (or ephedra), and coffee/caffeine during cutting phases.

 

 Honestly, NOT the best idea because as soon as there was a crack down on pure ephedrine (meth precursor), we'd end up with Mau Hung for ephedra and you could never be sure how potent it was.

 

Can't tell you the number of times my heart suddenly felt like it was going to blow out my chest, or worse, I'd get a clammy sweat, nauseous, and start to black out during a set of heavy squats.  Good times!

 

Swanson's sells both naringin and a Citrus Bioflavonoid Complex for those who aren't keen on eating grapefruit with the white part on it.

 

 


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#5 gamesguru

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Posted 26 September 2016 - 02:27 PM

post-13945-0-84920000-1474899352.jpg

 

 

I'll have to make use of the peel.. maybe the pith has a disproportionate amount too?  This is the examine quote:

One study using a lone grapefruit (to reduce variability of components) and subjecting segments to different processing techniques (juicing, hand squeezing, and blending the entire grapefruit with peel as the third group) noted that the blended juice (with peel) had 7-fold higher levels of naringin (160.79mg/100mL) relative to juiced (26.25) and hand-squeezed (22.51) and this trend of the peel-containing juice having more bioactives extends to poncirin and didymin; however, it also possessed a higher limonin content which confers a bitter taste, having 2.45mg/100mL relative to 0.14 and 0.09 with juiced and hand-squeezed grapefruit juice.[5]

 

 

Unfortunately when talking about interactions with medicines.. a lot of variance in effect is due to individual differences (e.g. gut bacteria) and differences between grapefruit samples.

The fate of naringin in humans: a key to grapefruit juice-drug interactions?
Fuhr U1, Kummert AL. (1995)

The increase of concentrations observed for many drugs when administered concomitantly with grapefruit juice was attributed to inhibition of cytochrome P450 enzymes by naringenin, the aglycone of the grapefruit flavonoid naringin. However, this explanation is equivocal, and formation of naringenin after ingestion of grapefruit juice has not been proved. We investigated renal excretion of naringin, naringenin, and its glucuronides after administration of 20 ml grapefruit juice (621 mumol/L naringin) per kilogram of body weight to six healthy adults. Urine was collected for 24 hours, and flavonoids were measured by HPLC in aliquots with and without glucuronidase pretreatment. Naringin or naringin glucuronides were not found. Naringenin and its glucuronides appeared in urine after a median lag-time of 2 hours and reached 0.012% to 0.37% and 5.0% to 57%, respectively, of the molar naringin dose. In additional investigations, low concentrations (< 4 mumol/L) of naringenin glucuronides, but neither naringin nor naringenin were found in plasma samples from previous grapefruit juice interaction studies, and metabolization of naringin to naringenin occurred during 24 hours of incubation (37 degrees C) in three of five feces samples tested. The data suggest that cleavage of the sugar moiety, presumably by intestinal bacteria, is the first step of naringin metabolism. Naringenin formation is thought to be the crucial step in determination of bioavailability of the compound, which undergoes rapid glucuronidation. The pronounced interindividual variability of naringin kinetics provides a possible explanation for some of the apparently contradictory results of drug interaction studies with grapefruit and naringin.

Variation of Flavonoids and Furanocoumarins in Grapefruit Juices:  A Potential Source of Variability in Grapefruit Juice−Drug Interaction Studies
Whocely Victor De Castro, Susanne Mertens-Talcott, Anke Rubner, Veronika Butterweck, and Hartmut Derendorf (2006)

Grapefruit juice (GFJ) has been found to interact with several medications, increasing their oral bioavailability and the risk of toxicity. Inhibition of CYP3A4 in the small intestine by flavonoids (such as naringin and naringenin) and furanocoumarins (including bergamottin and 6‘,7‘-dihydroxybergamottin) present in GFJ seems to be the predominant mechanism, although P-glycoprotein and influx transporters in the small intestine are also involved. The quantity of interactive compounds ingested may affect the magnitude and mechanism of the food−drug interaction. Therefore, these four compounds were quantified by HPLC analysis in commercially available and fresh-squeezed GFJ and in grapefruit tissues. Considerable variability in naringin (174−1492 μmol/L), bergamottin (1.0−36.6 μmol/L), and 6‘,7‘-dihydroxybergamottin (0.22−52.5 μmol/L) was observed, whereas naringenin could not be detected. White grapefruit showed higher concentrations of naringin and furanocoumarins located in the albedo and flavedo compared with red varieties. Findings from this study suggest considering concentrations of components with a potential for drug interactions in GFJ−drug interaction studies. The concentration of potentially contributing compounds may crucially influence the magnitude of observed interaction and impair direct comparison of studies in which different juices have been used.

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#6 Wingless

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Posted 27 September 2016 - 11:02 PM

Interesting stuff. Is there any reason to eat a whole grapefruit over 100% grapefruit juice? I was always under the impression that juice is far less beneficial.



#7 psychejunkie

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Posted 28 September 2016 - 06:02 AM

thank you all for these interesting information and facts.

 

by the way, one can cut grapefruit's peel into small slices, let them dry and encapsulate them with gelatin caps.


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#8 jack black

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Posted 28 September 2016 - 12:59 PM

Pardon my ignorance but what do you mean by peel? Is it the pigmented outer skin, or the white thing under, or both?

#9 gamesguru

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Posted 28 September 2016 - 01:52 PM

My understanding is it's both. The inner bit is the pith, the outer bit is the rind.

The idea with capsuling it up is interesting. But I might try just swallowing little ground up bits with water.

#10 Godof Smallthings

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Posted 25 October 2016 - 09:28 AM

Interesting stuff, but given that CYP3A4 450 and CYP1A2 inhibition alters the metabolism of a shitload of compounds, if you're on any pharmaceutical or other powerful and/or poorly researched supplements, it would seem like a pretty risky thing to do.

 

Pesticide use in citrus fruit orchards would make me hesitant to use the outer peel, as well.

 


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#11 gamesguru

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Posted 25 October 2016 - 02:08 PM

You can look grapefruit-drug interactions up on Wikipedia or mayoclinic, that's what your doctor does when he leaves the room for goodness' sake. No one memorizes that.

The pesticide is another good concern, as the grapefruit made neither the dirty dozon nor the clean fifteen, however, this can be addressed with organic grapefruit. It's often available at Kroger, and you can safely mix that peel with conventional juice.

Edit: doh, they made the clean fifteen. no cause for concern (who memorizes that sh*t?)

Edited by gamesguru, 25 October 2016 - 02:11 PM.


#12 sentics

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Posted 25 October 2016 - 05:26 PM

ha good one Godof, i take a load of ADs and yesterday i took a some Grapefruitseedextract and sure enough, i lay awake at night, my trittico/lyrica combo for sleep hardly worked at all



#13 normalizing

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Posted 25 October 2016 - 09:10 PM

i had very nasty side effects exaggeration from taking grapefruit and various supps and pharms. its very bad idea to eat any if you are experimenting with new substances either natural or synthetic. i just wanna warn on this as i thought i know what im doing and it happened to me few times and its not fun! 

 

also i must say grapefruit has no antidepressant effect whatsoever. ive taken dozen of them many many times my depression actually got worse on few occasions (considering its interactions with so many things i wouldnt be surprised) but even by itself in the mornings i have taken few, not 1 or 3 but up to 4 and except that super bitter feeling in my mouth, nothing made my depression better.

conclusion; another overrated natural product to cure depression!


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#14 gamesguru

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Posted 26 October 2016 - 12:34 AM

that's interesting, norm.  i was having a shit day but squeezed some citrus (for the first time in days) with dinner.. and suddenly i'm grabbing drinks with my first date in months.  care to explain that, norm?noway2.gif  anddd everything's gonna be good.  why?  coz i'm stirring tea for the road.  you really need to give things a chance.  can't just drink 7 cups of tea or 3 grapefruits ONCE and expect cumulative benefits.  they take time, like SSRIs.  be consistent57.gif

Neurochem Res. 2016 Sep;41(9):2352-66.

Naringin and Sertraline Ameliorate Doxorubicin-Induced Behavioral Deficits Through Modulation of Serotonin Level and Mitochondrial Complexes Protection Pathway in Rat Hippocampus.

Kwatra M1,2, Jangra A3, Mishra M4, Sharma Y3, Ahmed S3, Ghosh P5, Kumar V6, Vohora D6, Khanam R6,7.

 

Abstract

The present study was designed to investigate the neuroprotective effect of naringin (NR) alone as well as its combination with sertraline (SRT) against doxorubicin (DOX)-induced neurobehavioral and neurochemical anomalies. DOX (15 mg/kg; i.p.) administration caused behavioral alterations, oxidative stress, neuroinflammation, mitochondrial dysfunction and monoamines alteration in male Wistar rats. NR (50 and 100 mg/kg; i.p.) and SRT (5 mg/kg; i.p.) treatment significantly attenuated DOX-induced anxiety and depressive-like behavior as evident from elevated plus maze (EPM) and modified forced swimming test (mFST), respectively. NR treatment significantly attenuated DOX-induced raised plasma corticosterone (CORT), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) levels in the hippocampus (HC). Furthermore, we found that combination of NR and SRT regimen ameliorated DOX-induced behavioral anomalies through modulation of the 5-HT level and mitochondrial complexes protection pathway along with alleviation of oxidative stress in the HC region. Therefore, NR treatment alone or in combination with SRT could be beneficial against DOX-induced neurotoxicity.

 

Prog Neuropsychopharmacol Biol Psychiatry. 2012 Oct 1;39(1):175-81.

Antidepressant-like behavioral, neurochemical and neuroendocrine effects of naringenin in the mouse repeated tail suspension test.

Yi LT1, Li J, Li HC, Su DX, Quan XB, He XC, Wang XH.

 

Abstract

Our previous study demonstrated that the citrus bioflavonoid naringenin ameliorated behavioral alterations via the central serotonergic and noradrenergic systems in the tail suspension test (TST) induced mice. To better understand its pharmacological activity, mice were submitted to three 6min-TSTs one week apart (Day 1: test, Day 7: retest 1, Day 14: retest 2) followed by hippocampal glucocorticoid receptor (GR), monoamine neurotransmitters and serum corticosterone measurement. The results suggested that repeated TST detected the gradual increase in the efficacy of naringenin over time, additionally 1-day (20 mg/kg), 7-day (10, 20 mg/kg) and 14-day (5, 10, 20 mg/kg) naringenin treatment markedly decreased the immobility time. Moreover, administration of naringenin for 14 days (20 mg/kg) increased hippocampal serotonin (5-HT), norepinephrine (NE) and GR levels, and reduced serum corticosterone levels in mice exposed to the repeated TST. Overall, the present study indicated that the re-exposure would facilitate the detection of the anti-immobility effects of antidepressant drugs in the mouse TST, and clearly demonstrated that the antidepressant-like effect of naringenin may be mediated by an interaction with neuroendocrine and neurochemical systems.


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#15 normalizing

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Posted 26 October 2016 - 02:46 AM

uhm gameguru you dont have depression and you dont know how complex depression is for humans, not rats. in rats you can only test antidepressive effect through anxiety tests. its different for humans as we are much different than rats (naturally) but we have such different brain not really comparable. now, most of your studies are done on rats or mice or some animal, those two studies you just posted are really quite irrelevant sorry


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#16 Godof Smallthings

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Posted 26 October 2016 - 05:26 AM

You can look grapefruit-drug interactions up on Wikipedia or mayoclinic, that's what your doctor does when he leaves the room for goodness' sake. No one memorizes that.

The pesticide is another good concern, as the grapefruit made neither the dirty dozon nor the clean fifteen, however, this can be addressed with organic grapefruit. It's often available at Kroger, and you can safely mix that peel with conventional juice.

Edit: doh, they made the clean fifteen. no cause for concern (who memorizes that sh*t?)

 

You don't have to memorize it, but you do have to mention it to people who may not be aware of the mechanism and the associated risks, or they'll take grapefruit or naringin extract with their other medications or supplements, and in a worst case scenario could end up in a life-threatening situation.

 

Inhibiting these enzymes is like opening a door that evolution thinks it is usually best to keep closed. Substances that are normally without effect can suddenly have an effect - some normally harmless substances can become carcinogenic.

So again - super interesting research - thanks for posting it, but I would still not advise anyone to experiment with this one unless they do not use other pharmaceuticals or supplements, and have a good understanding of the chemistry of what they are eating and drinking.


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#17 gamesguru

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Posted 26 October 2016 - 10:04 AM

Any chance of it turning ginkgo or ginseng carcinogenic?

Most people are aware, and this poster was lucky enough to have metabolism accelerated, as opposed to slowed, where the pharm can build up to toxic levels.
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#18 ta5

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Posted 30 October 2016 - 08:34 PM

Grapefruit juice has significant effects on liver enzymes. Naringin's effects appear to be minimal, except maybe when combined with grapefruit juice.

 

Wikipedia mentions that naringin can effect CYP3A4 enzyme, but several statements lack references, and those that do are not so clear cut or convincing at implicating naringin specifically.

 

"To explore this last possibility in depth we tested the in vitro capacity of bergamottin, naringin and dihydroxybergamottin to inhibit the activity of CYP1A and 2B subfamilies and found that bergamottin showed the strongest inhibitory effect and naringin showed no inhibition at all."
PMID: 22705772

 

"Although, GFJ presents high amounts of flavonoids (e.g. naringin, naringenin), furanocoumarins (e.g. 6',7'-dihydroxybergamottin, bergamottin) are the main chemicals involved in the pharmacokinetic interactions."
PMID: 21682192

 

"Naringin most probably directly inhibited enteric OATP1A2 to decrease oral fexofenadine bioavailability. Inactivation of enteric CYP3A4 was probably not involved."
PMID: 17301733

 

"The results showed that the inhibition of quinine 3-hydroxylation (CYP3A4 activity) by bergapten (67%), and quercetin (55%) was greater than naringenin (39%) and naringin (6%), at the same inhibitor concentration of 100 M."
PMID: 11737987

 

"Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans."
PMID: 9723817

 

"While increasing amounts of grapefruit juice delay the excretion of 7-hydroxycoumarin by 2 h, increasing doses of naringin in water up to twofold (i.e. naringin content of 2 L grapefruit juice) do not cause any alteration in the time course of excretion. Experiments with increasing amounts of juice, keeping the dose of naringin constant, indicate that the inhibitory potency of small amounts of grapefruit juice can be amplified by naringin. The same is true when the ratio between juice constituents and naringin is enhanced up to threefold by adding naringin.
CONCLUSION: As naringin alone is ineffective, the inhibitory effect of grapefruit juice on the metabolism of coumarin is caused by at least one compound other than naringin. The persistency of the primary inhibitor not identified yet can obviously be modulated by the naring(en)in-system."
PMID: 9476043

 

"Flavonoids, which are major constituents of grapefruit juice, are not known to be mechanism-based inactivators. Naringin, the major flavonoid present in grapefruit juice, and quercetin do not reproduce the grapefruit juice effect when administered orally, also suggesting that flavonoids are not the active compounds (8, 13)."
PMID: 9351897

 

Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice

"These data suggest that grapefruit juice inhibits CYP3A activity in vitro and that neither naringin nor naringenin are primarily responsible for this effect."
PMID: 8809221

 

"However, the autoinhibition of the juice is correlated neither to the concentration of naringin nor to that of scopoletin."
PMID: 8737764

 


Edited by ta5, 30 October 2016 - 08:44 PM.

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#19 Godof Smallthings

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Posted 02 November 2016 - 05:25 AM

^Nice one, thanks for adding to the knowledge.



#20 Synaptik

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Posted 23 November 2016 - 10:29 PM

OP, is Hesperidin a Kappa Opioid agonist as well, and if so, to what degree. I'm having trouble finding the answers to these questions, other than it's claimed to be a KOR agonist in forums like this. I just ate a tangerine-sized orange peel and I can feel some effects mentally. 

 

Anyhow, I'm on week 2 of my nightly peppermint oil regimen, with the aim of down regulating KOR activity during the day. I'm experiencing success with this from an anxiety-easing perspective, although it destroys libido and causes me to be edgy until I take my dopamine stimulators in the morning (ginkgo, coffee). I was wondering whether Hesperin (as another KOR agonist source + 5-HT2C antagonist) might have even better effects.

 

Thoughts?

 


Edited by Synaptik, 23 November 2016 - 10:29 PM.


#21 gamesguru

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Posted 24 November 2016 - 01:31 PM

It is, but I believe activity at 5-HT1A is responsible for the other half of the antidepressive effect.  Menthol also has effects on dopamine and nicotine receptors, that may explain some negative effects.  For hesperidin, the rat study on the KOR was, I think, 0.3mg/kg, so for a 65kg male it's 3.25mg.  Definitely obtainable from juice, and of course the peel too.

 

And last I checked, navel oranges have up to 5 times more hesperidin than grapefruit.  I usually do 3-4 oranges with 2 grapefruit.  It produces about 350mL of each juice, for a 700mL big gulp.  I was doing just 2 oranges and 1 grapefruit, but it wasn't enough.

 

So if you're just doing grapefruit juice, there's no much hesperidin, and the KOR activity is equivalent to that of a very small toke.  With a similar half-life to THC, hesperidin would be expected to produce a similar KOR downregulation.   Doing the tangerine or navel orange peel at night is going to have an effect like smoking a lot of hash oil, not sure how it would leave you feeling the next day.   But again, because of the involvement of other NTs, the acute and chronic effects of THC will differ from hesperidin.



#22 Synaptik

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Posted 24 November 2016 - 06:11 PM

It is, but I believe activity at 5-HT1A is responsible for the other half of the antidepressive effect.  Menthol also has effects on dopamine and nicotine receptors, that may explain some negative effects.  For hesperidin, the rat study on the KOR was, I think, 0.3mg/kg, so for a 65kg male it's 3.25mg.  Definitely obtainable from juice, and of course the peel too.

 

And last I checked, navel oranges have up to 5 times more hesperidin than grapefruit.  I usually do 3-4 oranges with 2 grapefruit.  It produces about 350mL of each juice, for a 700mL big gulp.  I was doing just 2 oranges and 1 grapefruit, but it wasn't enough.

 

So if you're just doing grapefruit juice, there's no much hesperidin, and the KOR activity is equivalent to that of a very small toke.  With a similar half-life to THC, hesperidin would be expected to produce a similar KOR downregulation.   Doing the tangerine or navel orange peel at night is going to have an effect like smoking a lot of hash oil, not sure how it would leave you feeling the next day.   But again, because of the involvement of other NTs, the acute and chronic effects of THC will differ from hesperidin.

 

Thanks very much for your input. Yesterday I read an EXAMINE report on Hesperidin and it stated that it does indeed have KOR activity, although maybe not straight forward like Salvinorin A. Curiously, it also stated that Hesperidin has no dopaminergic activity whatsover, or activity atserotonin and norepinephrine receptors

 

I'm guessing although KOR activity levels are easily obtained eating peels and drinking a fair amount of juice, the binding is weak (less than menthol for example). That said, there's definitely some action (pleasant) to be had after eating an orange peel.


Edited by Synaptik, 24 November 2016 - 06:12 PM.


#23 gamesguru

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Posted 26 November 2016 - 04:11 AM

Thanks very much for your input. Yesterday I read an EXAMINE report on Hesperidin and it stated that it does indeed have KOR activity, although maybe not straight forward like Salvinorin A. Curiously, it also stated that Hesperidin has no dopaminergic activity whatsover, or activity atserotonin and norepinephrine receptors

 

I'm guessing although KOR activity levels are easily obtained eating peels and drinking a fair amount of juice, the binding is weak (less than menthol for example). That said, there's definitely some action (pleasant) to be had after eating an orange peel.

 

If I had to rank them by receptor affinity (guesswork): salvia, weed, menthol, hesperidin.  It's strange, because kappa is generally dysphoric.  And consistent to this, quitting weed (tho generally not fun) contributes to your day a euphoric backnote component.

 

Examine is not correct about the serotonin (you can find a study on dopamine and Parkinson's, but it is due to hesperidin's antioxidant effect and lends no evidence to dopamine modulation).  Naringin is also active at GDNF/dopamine and serotonin, but not opioid (in case anyone wants to avoid opioidergic effects, pure grapefruit would be a good choice).

Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jan 10;40:103-9.

Evidence for the involvement of the serotonergic 5-HT(1A) receptors in the antidepressant-like effect caused by hesperidin in mice.

Souza LC1, de Gomes MG, Goes AT, Del Fabbro L, Filho CB, Boeira SP, Jesse CR.

Abstract

The present study investigated a possible antidepressant-like activity of hesperidin using two predictive tests for antidepressant effect in mice: the forced swimming test (FST) and the tail suspension test (TST). Results demonstrated that hesperidin (0.1, 0.3 and 1 mg/kg, intraperitoneal, i.p.) decreased the immobility time in the FST and TST without affecting the locomotor activity in the open field test. The antidepressant-like effect of hesperidin (0.3 mg/kg) on the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (pCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis) and WAY100635 (0.1 mg/kg, subcutaneous, s.c., a selective 5-HT(1A) receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an α(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α(2)-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a β-adrenoceptor antagonist), AMPT (100 mg/kg, i.p., an inhibitor of tyrosine hydroxylase), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist), ketanserin (1mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist) or MDL72222 (1 mg/kg, i.p., a 5-HT(3) receptor antagonist) did not block the antidepressant-like effect of hesperidin (0.3 mg/kg, i.p.) in the TST. Administration of hesperidin (0.01 mg/kg, i.p.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. The antidepressant-like effect caused by hesperidin in mice in the TST was dependent on an interaction with the serotonergic 5-HT(1A) receptors. Taken together, these results suggest that hesperidin possesses antidepressant-like property and may be of interest source for therapeutic agent for the treatment of depressive disorders.



#24 AlexCanada

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Posted 09 July 2017 - 12:09 AM

Any updates on this?  I am planning on ordering some GrapeFruit Seed Extract and grapefruit nasal spray. 

 

I have fungal infections, sinus problems, allergic rhinitus, depression, anhedonia, and low hormone levels.  

 

 

Eating grapefruits has actually had some positive benefits for me at times I just haven't been able to find them in local grocery stores lately though. 



#25 gamesguru

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Posted 11 July 2017 - 10:35 AM

yeah what happened to all the grapefruit at the grocery store?  they must go out of season in the Fall or something idk.  since the harvest ran out i've been supplementing with extra blueberry and kiwifruit, two really unique antioxidants.  a lot of these fruits actually have a positive inflammatory rating (as opposed to turmeric and stuff), but this discrepancy is balanced out by a plethora of interesting effects.  makes the joints feel a lot better, relaxes the muscles including the lower back, and it also improves the spatial memory so you have the feeling of like being in a video game or the matrix with every precise movement.  a cup of grapefruit juice just brightens your day, gives you energy, like a cup of chamomile or rooibos brightens your day.  sometimes if you sit alone by the river and just focus on the sound of the wind blowing the leaves, you can just smile and laugh and really feel the naringen doing work on your dopamine system.

 

one of the things with the high histamine content of citrus, has been an aggravation of the eczema by my hands.  i've cut oranges out to the exclusion of grapefruit, because i think it's better.  tho i do miss hesperidin and rutin

 

not convinced the grapeseed is what was studied.  it's not what i take, these ones are pretty much seedless.  granted, most fragments making it past my strainer would probably be small enough to undergo digestion.

i'm also not too sure of snorting tinctures to treat some unknown nasal infection, but i'm sure if you try enough you'll eventually find something that works.  berberine maybe?  i would make a point to treat it internally as well.. exercise.. foods like broccoli, garlic, mushies.. etc


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#26 normalizing

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Posted 14 July 2017 - 03:00 AM

i guess thats the cure for all those depressed suicidal people out there. you should inform clinics and establishments, promote grapefruit juice as cure for depression so millions of depressed and suffering people get benefit. spread the word, grapefruit would have prevented so many suicides worldwide, why was this not known earlier!? what a shame!!!


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#27 AlexCanada

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Posted 14 July 2017 - 07:09 AM

i guess thats the cure for all those depressed suicidal people out there. you should inform clinics and establishments, promote grapefruit juice as cure for depression so millions of depressed and suffering people get benefit. spread the word, grapefruit would have prevented so many suicides worldwide, why was this not known earlier!? what a shame!!!

 

Too bad they don't cure the asshole out of you.  

 

 

It's not about grapefruit outright curing depression for anyone but the various anti-fungal, anti-microbial properties and a combination of other factors could help treat underlying conditions and some which would be contributing to depression and decreased sense of well being.    Severe fungal infections do actually lead to depressive symptoms in many people.

 

How about you look into the actual science behind it.

 

 

https://draxe.com/gr...t-seed-extract/

 

There are various published studies on the benefits of grapefruit.  


Edited by AlexCanada, 14 July 2017 - 07:14 AM.

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#28 gamesguru

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Posted 14 July 2017 - 11:55 AM

fungal infections?  nice theory m8, i like how you completely snuffed the life out of the discussion concerning dopamine, serotonin and mitochondrion.  or did you?


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#29 Jiminy Glick

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Posted 15 July 2017 - 04:51 AM

I think they taste better then oranges.


Edited by Jiminy Glick, 15 July 2017 - 04:56 AM.


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#30 AlexCanada

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Posted 15 July 2017 - 06:15 PM

fungal infections?  nice theory m8, i like how you completely snuffed the life out of the discussion concerning dopamine, serotonin and mitochondrion.  or did you?

 

 

 

News flash:  The entire discussion was dead for months.   I guess you'd prefer it that way?  God forbid anyone has anything to contribute.   I never poured cold water on dopamine, serotonin etc and just merely offered what I knew on the subject. Dopamine and Serotonin related research for grapefruit isn't exactly booming. 

 

I guess this is what ''bro culture'' looks like.   This place is just brimming with unfriendly nasty people.  Maybe it's from all the stimulant abuse going on? 

 

This is Frequently the most unfriendly nasty forum on the internet.    Learn to treat people with some respect. 


Edited by AlexCanada, 15 July 2017 - 06:21 PM.

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