Nobiletin

Generic name: 2-(3,4)-dimethoxyphenyl)-5,6,7,8-tetramethoxychromen-4-one
Brand names: Hexamethoxyflavone

Usage of Nobiletin

No clinical trials of nobiletin alone for any purpose have been conducted. Nobiletin has shown antioxidant, anti-inflammatory, antitumor/anticancer, and antiangiogenic activity in vitro and in vivo.(NCBI 2022) Animal and in vitro data also demonstrate nobiletin's potential ability to suppress bone loss, lower cholesterol, reduce atherosclerosis, and improve hyperglycemia and insulin resistance.(Lee 2010, Murakami 2007, Sasaki 2002, Whitman 2005) The low bioavailability of nobiletin may be increased via preparation as a nano-emulsion using docosahexaenoic acid–enriched phosphatidylcholine.(Ju 2022)

Anti-inflammatory activity

Animal and in vitro data

The anti-inflammatory effects of nobiletin on human synovial fibroblasts and mouse macrophage J774A have been studied.(Lin 2003) Nobiletin, at a concentration of 64 mcM, inhibited cyclooxygenase 2 production by 50%. A study of the effect of nobiletin on neuroinflammation found that nobiletin 50 mcM inhibited lipopolysaccharide (LPS)–induced inducible nitric oxide synthase (iNOS) expression by 71% compared with LPS alone.(Cui 2010) Nobiletin also had a positive inhibitory effect on skin inflammation.(Murakami 2000)

Nobiletin 32 mcM decreased the production of proinflammatory cytokines in mouse J774A macrophages.(Lin 2003)

Nobiletin 50 mg/kg intravenously for 1 week prior to liver transplantation suppressed inflammatory response in rats, with less hepatocyte swelling and inflammatory cell infiltration and decreased ALT, AST, and lactate dehydrogenase compared with a group receiving saline only.(Wu 2017)

Though nobiletin showed protective activity for keratinocytes exposed to ultraviolet B (UVB) radiation, negative effects of UVA radiation were enhanced, resulting in increased cell death.(Cvammen 2022)

Bone loss

Animal data

One study evaluated the effects of nobiletin on bone loss and arthritis in DBA/1J mice. Suppression of the reduction of whole bone mineral density comparable to that with 17beta-estradiol was observed, suggesting a potential role in prevention or treatment of osteoclastogenesis-related disorders, including osteoporosis.(Murakami 2007)

Cancer

Animal and in vitro data

Nobiletin had a dose-dependent suppressive effect on the proliferation of A549 lung cancer cells.(Luo 2008) Administration of a mixture of nobiletin and its major metabolites for 19 weeks to mice with colitis-associated colon carcinogenesis resulted in a decrease in cell cycle progression in the colon tissue, which was at least partially related to downregulation of iNOS.(Wu 2017) In vitro studies have demonstrated differential efficacies and mechanisms of nobiletin and its derivatives in inhibiting and killing colon cancer cells. The chemopreventive potential of nobiletin has also been demonstrated in several in vivo colon carcinogenesis animal models. Nobiletin and its derivatives target multiple pathways in cancer progression and inhibit several of the hallmark features of colorectal cancer pathophysiology, including by arresting the cell cycle, inhibiting cell proliferation, inducing apoptosis, preventing tumor formation, reducing inflammatory effects, and limiting angiogenesis.(Goh 2019) A review article concluded that nobiletin induces apoptosis and cell cycle arrest in cancer cells; chemopreventive effects are related to suppression of migration and invasion of cancer cells via inhibition of epithelial-to-mesenchymal transition (EMT) and EMT-related factors, and targeting of various oncogene and oncosuppressor pathways.(Ashrafizadeh 2020)

There are relatively few studies on the anticancer effects of Citrus folium and nobiletin in vivo. Clinical application of C. folium and nobiletin as cancer treatment products would require in vivo verification and further anticancer mechanism research.(Wu 2021)

Cardiovascular activity

Animal data

In rats with streptozotocin-induced diabetes, 4 weeks of nobiletin 10 mg/kg or 25 mg/kg orally daily resulted in improved mean arterial pressure, heart rate, and left ventricular end diastolic pressure. The 25 mg/kg dose also improved maximal left ventricular systolic pressure.(Parkar 2016) Mechanistic, observational, and interventional studies have also demonstrated health benefits of citrus bioactives in minimizing the risk of metabolic syndrome.(Saini 2022)

CNS effects

Animal data

In various animal models, polymethoxylated flavones had a neuroprotective effect and improved cognitive dysfunction in neurological disorders by exerting favorable effects against pathological features, including oxidative stress, neuroinflammation, neurodegeneration, and synaptic dysfunction as well as its related mechanisms.(Matsuzaki 2021) The effects of nobiletin on cholinergic neurodegeneration in mice have been studied; in one study, intraperitoneal administration of 50 mg/kg/day for 11 days resulted in improvement in impaired memory.(Nakajima 2007)

When nobiletin was administered to rats for 9 days prior to induction of brain ischemia, an increase in the neuroprotective effects of propofol was observed, with a decrease in infarct area, apoptotic cell counts, and brain edema.(Zheng 2017) In a study of rats with 1-methyl-4-phenylpyridinium (MPP)–induced Parkinson disease, intraperitoneal injections of nobiletin at doses of 1 mg/kg, 10 mg/kg, and 20 mg/kg for 7 days resulted in variable effects: A dose of 10 mg/kg prevented MPP-induced neuronal death compared with controls (P<0.01), while 1 mg/kg and 20 mg/kg doses did not result in significant differences.(Jeong 2015)

Nobiletin may have antidepressant activity, as it has a similar mechanism to the antidepressant minaprine, which has demonstrated effects in the hippocampus of mice.(Nakajima 2007)

In a review survey of substances from natural sources with potential antidementia and neuroprotective activity, nobiletin from the peel of Citrus depressa improved cognitive deficits and pathological features of Alzheimer disease, such as amyloid-beta pathology, hyperphosphorylation of tau, and oxidative stress, in animal models of Alzheimer disease. In addition, nobiletin improved motor and cognitive deficits in Parkinson disease animal models. These observations suggest a potential role for nobiletin in the treatment and prevention of these neurodegenerative diseases.(Nakajima 2019)

One study using animal models of diseases and aging proposed that nobiletin impinges on circadian clock machinery to activate temporal control of downstream processes within the cell and throughout the body. Findings illustrate potent beneficial effects of nobiletin on cellular energetics in both periphery and brain. The authors concluded that nobiletin may represent a candidate molecule for nutraceutical and chronotherapeutic development against chronic and age-related neurodegenerative diseases.(Mileykovskaya 2020)

Clinical data

No clinical trials of nobiletin alone for any purpose have been conducted. A clinical trial in healthy older Japanese volunteers 60 to 85 years of age (N=49) compared supplementation of a combination of nobiletin and alpha-linolenic acid–enriched perilla seed oil to perilla seed oil alone. At 12 months, only the combination group demonstrated improvements in outcome scores signaling stable or improved cognitive function.(Hashimoto 2022)

Diabetes/Metabolic disturbances

Animal data

A review article concluded that nobiletin treatment attenuated obesity, hepatic steatosis, dyslipidemia, and insulin resistance, and protected metabolism in 3 mouse models independently of AMPK activation. The authors emphasized the potential therapeutic convenience of citrus flavonoids, including nobiletin, specifically in the management of diabetes and its related complications (metabolic syndromes, obesity). Further in-depth studies are warranted to investigate the primary mechanism of action that influences insulin sensitivity.(Gandhi 2020)

Nobiletin 17 mg/kg/day for 16 weeks improved glucose tolerance, insulin resistance, and total cholesterol levels in mice fed a high-fat diet, but did not affect food intake, body weight, or adiposity.(Kim 2017) In a 5-week study of obese diabetic mice, nobiletin 200 mg/kg/day was associated with improved hyperglycemia and insulin resistance, with no significant differences in body weight gain and mean daily food intake observed between vehicle-treated and nobiletin-treated groups.(Lee 2010)

Nobiletin side effects

There are no known adverse reactions associated with nobiletin.

Before taking Nobiletin

Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.

How to use Nobiletin

Clinical trial data are lacking to support specific dosing recommendations.

Warnings

Safety data sheets state that the lowest dose of nobiletin that caused a toxic effect in a mouse model was 25 mg/kg of body weight if administered intraperitoneally and 70 mg/kg of body weight if administered orally.(Cayman 2022) Several citrus flavonoids, including nobiletin, tangeretin, and naringin, have shown good safety profiles.(Saini 2022)

What other drugs will affect Nobiletin

No studies have been conducted to determine possible interactions of nobiletin with other drugs or compounds. Nobiletin suppresses platelet activity(Vaiyapuri 2015) and therefore may increase the bleeding risk of antiplatelet or antithrombotic agents. Nobiletin is metabolized via CYP-450.

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