Studies related to Hesperidin

Related Research.
If we are now to look at the human evidence for oral Hesperidin, it appears to promote blood flow (mildly to moderately) and may have a weaker effect on blood pressure. That said, oral hesperidin at doses similar to those used in humans appears to be a very potent cardioprotective agent in animal studies and has comparable brain protection against a variety of stressors; the protection is essentially antioxidant in nature but appears to work through a currently uncharacterized genomic antioxidant response. In addition to its protective effects (most notably in the heart and brain, but essentially extending to every organ), hesperidin may be able to reduce loss of appetite and have less antiallergic properties.

0.1-1 mg/kg hesperidin (intraperitoneal) appears to have an antidepressant mechanism, is metabolized through κ-opioid receptors without inhibiting signaling through δ-opioids, μ-opioids, or peripherally-acting κ-opioid antagonists or caffeine adenosine, caffeine, and possibly opioid receptors, and at a sub-effective dose of hesperidin (10 μg/kg intraperitoneal) appears to have a synergistic effect with morphine has a synergistic effect.

In isolated PC12 cells, low concentrations (100-1000 nM) of hesperidin were found to activate neuronal growth factors (Akt/ERK and CREB) and antioxidant factors (seladin-1 and PGC-1α) in a manner that was dependent on TrkA receptors and estrogen signaling. Due to the neuroprotective effects of estrogen associated with Akt and seladin-1, it is thought that seladin is an estrogen mimetic with neuroprotective effects, although all of these effects are dependent on two factors (TrkA and estrogen signaling), and the increase in seladin-1 is entirely dependent on estrogen signaling.

Injection of 0.1-1 mg/kg hesperidin (intraperitoneal) to mice subjected to the stress swim test was able to exert antidepressant effects, whereas 10 μg/ kg was ineffective by itself, and this has been replicated elsewhere in the forced swim and tail suspension tests, with potency comparable to promethazine (15 mg/kg injectable) and fluoxetine (32 mg/kg injectable), at doses of 0.3- 1mg/kg.

In one study, intraperitoneal injections of hesperidin (0.1-1mg/kg) were found to provide antidepressant effects but no significant anxiolytic effects, and forced anxiolytic effects could be produced in mice with high doses of hesperidin injections (2-30mg/kg) during oral ingestion of 20-100mg/kg of hesperidin, which is thought to be related to opioid receptor signaling. Unless injected at high doses, hesperidin does not appear to have sizable but inherent anxiolytic properties. It appears that under the specific condition of stress-induced nerve damage leading to anxiety, there may be anxiety-reducing properties because the damage is attenuated by hesperidin (and anxiety is reduced due to less damage).

Rats administered orally at 5 mg/kg (in which anorexia was induced with cisplatin) appeared to reduce the reduction in food intake observed with cisplatin by 59%. Hesperidin has been shown to positively inhibit anorexia after oral administration in a manner thought to be mediated by 5-hydroxytryptamine signaling and dependent on the action of growth hormone.

Hesperidin given orally at 100 mg/kg for 90 days to young and aged rats was able to partially reverse the deterioration of antioxidant enzymes seen in cardiac tissue during aging, whereas changes in these enzymes were not significant in young hearts; lipid peroxidation and protein carbonylation, which is thought to be due to the increased expression of Nrf2 in aging hearts that decreases with aging (and does not increase in the young).

Hesperidin appears to protect the heart after oral administration of various stimulants and can work in a preventive or rehabilitative manner within a week. Although there are no human studies available, it appears to be surprisingly effective in reducing lipid peroxidation and markers of cardiotoxicity.

In hyperlipidemia (baseline TG above 150 mg/dL) given 500 mg G-hesperidin daily for 24 weeks, serum triglycerides were significantly reduced (up to 34%) after four weeks, which were maintained at a fixed magnitude at 24 weeks of supplementation and normalized to baseline values after four weeks of cessation.

In mice that suffered frostbite (tibia) and were subsequently injected with hesperidin at a dose of 50 mg/kg for six days, muscle regeneration appeared to be significantly enhanced compared to controls.

In healthy rats given 0.5% hesperidin (55mg/kg) in the diet for three months a study noted that in adolescent rats, but not older rats, hesperidin intake resulted in increased bone growth.

In young rats, a relatively reasonable dose of hesperidin (found in supplements or orange peels) increased the rate of bone growth; this increase in bone growth rate was not seen in older adults with fully developed bones.

In male mice given hesperidin (0.5%) or G-hesperidin (0.7% diet) for 4 weeks, bone loss associated with androgen deficiency was reduced relative to controls.

Oral supplementation with 0.5% hesperidin (approximately 55 mg/kg) in ovariectomized rats (a model of menopause) was able to partially attenuate bone loss seen from ovariectomy, with no significant effect on uterine weights, suggesting no associated estrogenic effect; these effects were associated with a plasma concentration of 3.57 +/- 0.68 μM hesperidin.

Hesperidin appears to orchestrate the increase in antioxidant defenses and pro-survival proteins through estrogen signaling and TrkA (BDNF receptor) acting, which is thought to be the mechanism for inhibiting oxidative toxin or stressor-induced cell death.

In irradiated rats (resulting in reduced mitochondrial capacity of the brain and reduced neurotransmitter levels due to oxidative damage), daily oral ingestion of 50 mg/kg of hesperidin before and two weeks after 10 days of irradiation was able to attenuate oxidative (40% reduction in thiols) and neurotransmitter changes (49-60% attenuation), whereas in the absence of radiation, hesperidin had no effect. Mitochondrial capacity is known to be maintained with a two-week preload (50-100 mg/kg in mice) prior to immobilization stress testing (which is known to increase NOS activity).

In the brain, hesperidin appears to have an antioxidant effect, in which hesperidin reduces the increase in lipid peroxidation during cognitive impairment, but this appears to be an indirect effect through nitric oxide signaling (inhibition) rather than a direct antioxidant effect.

Hesperidin appears to have multiple neuroprotective effects at relatively standard oral doses, and these also appear to be dependent on inhibiting faulty nitric oxide signaling (leading to antioxidant and anti-inflammatory defenses).