Saturday, September 5, 2015

Citrus and PD, AD, dementia

First for comparison number of articles:
proanthocyanidins: PD, dementia, alzheimer's (7,9,20)
green tea: PD, dementia, alzheimer's (66,54, 102)
grape seed: PD, dementia, alzheimer's (6,16,26)

Citrus in general (not complete)
PD, dementia, AD: (12,22,36)
The anti-oxidant and anti-inflammatory properties of Citrus flavonoids can play a key role in their activity against several degenerative diseases and particularly brain diseases. The most abundant Citrus flavonoids are flavanones, such as hesperidin, naringin, or neohesperidin. However, generally, the flavones, such as diosmin, apigenin, or luteolin, exhibit higher biological activity, even though they occur in much lower concentrations. Diosmin and rutin have a demonstrated activity as a venotonic agent and are present in several pharmaceutical products. Apigenin and their glucosides have been shown a good anti-inflammatory activity without the side effects of other anti-inflammatory products.
 The main citrus flavonoids can also traverse the blood-brain barrier; hence, they are promising candidates for intervention in neurodegeneration and as constituents in brain foods....It is suggested that citrus fruits, which are rich in abundant sources of hesperetin and other flavonoids, are promising for the development of general food-based neuroprotection and brain foods.
potential candidates for use in the intervention for neurodegenerative diseases.
Other aglycones tested (chrysin, flavon, hesperetin, naringenin) increased [3H]vincristine uptake in the 10-50 microM range, and glycosides (hesperidin, naringin, rutin)
citris peel for dementia and AD
Studying effect of grapefruit  juice on chemicals crossing BBB.  Chrysin, flavon, hesperetin, naringenin increased 2 compounds crossing the BBB, but hesperidin, naringin, rutin did not help.
korea citrus:  flavanones in Citrus aurantium.  Flavones in Citrus leiocarpa Hort. et Tanaka (CLHT), and Citrus erythrosa Hort
"Flavonoid profiling in three citrus varieties native to the Republic of Korea using liquid chromatography coupled with tandem mass spectrometry: contribution to overall antioxidant activity"

Naringin (in PD, all are by Jung UJ, Kim SR)
PD, dementia, AD: (5,7,10)
50 to 200 mg/kg orally for 21 days in rats in AD model. ameliorates mitochondrial dysfunction mediated oxido-nitrosative stress and inflammatory surge.
prevented oxidation-caused cognitive impairment in rats, 40 and 80 mg/kg 25 days prior to insult. restoration of superoxide dismutase, catalase, glutathione S-transferase, and reduced glutathione levels, and acetylcholinesterase activity
100 mg/kg for 16 weeks in genetically amyloid-impaired AD mice reduced plaque and improve cognitive functioning and long term memory
 possesses antioxidant, anti-inflammatory, anti-apoptotic, anti-ulcer, anti-osteoporosis and anti-carcinogenic properties
studies have shown that naringin has neuroprotective effects by the induction of neurotrophic factors such as brain-derived neurotrophic factor and vascular endothelial growth factor, and by the activation of anti-apoptotic pathways .... these evidences suggest that naringin may be a potential natural compound involved in the prevention and treatment against neurodegenerative diseases ..... [in our study)  naringin treatment significantly increases glial cell line-derived neurotrophic factor (GDNF) expression and mTORC1 activity in the nigral DA neurons, and naringin-induced production of GDNF contributes to the protection of the nigrostriatal DA projection in a neurotoxin model of Parkinson's disease. Moreover, naringin decreases the level of tumor necrosis factor-alpha (TNF-a) in microglia increased by MPP+ -induced neurotoxicity. ... has not only pharmacological anti-inflammatory and antioxidant activities but also neuroprotective effects against neurodegenerative disorders. Recently, we have also demonstrated the ability of naringin to prevent neurodegeneration. In a neurotoxin model of PD, treatment with naringin protects the nigrostriatal DA projection by increasing GDNF expression and decreasing TNF-a expression in DA neurons and microglia, respectively, which suggests that naringin can impart to the adult DA neurons the ability to reproduce GDNF as a therapeutic agent against Parkinson's disease with anti-inflammatory effects on brain inflammation.   Taken together, our findings suggest that naringin may be a potential natural product to prevent degeneration of the nigrostriatal DA projection in the adult brain.   .....naringin can impart to the adult dopaminergic neurons the ability to produce glial cell line-derived neurotrophic factor against Parkinson's disease with anti-inflammatory effects. Based on these results, we would like to describe an important perspective on its possibility as a therapeutic agent for Parkinson's disease.
Naringin, a flavonoid in grapefruit and citrus fruits, has anti-inflammatory and antioxidative activities, resulting in neuroprotection in animal models from neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease...may have beneficial effects of preventing epileptic events and neuronal death through antiautophagic stress and antineuroinflammation in the hippocampus in vivo. {full text)
 naringin and nobiletin prote4ct against H2O2 in neural cells by many different pathways, increased SOD, GSH, and MMP,  and decreased ROS, LDH, MTT, and lipid peroxidation
After naringin administration, naringin was undetectable in the brain...When cyclosporin A (20 mg/kg) was concomitantly administered with naringin (30 mg/kg), the naringin was detected in brain dialysate....The blood-brain barrier penetration of naringin may be enhanced by P-glycoprotein inhibitor; however, the pathway of hepatobiliary excretion of naringin may not be related to the P-glycoprotein. (30 mg/kg)
Naringin is a potent antioxidant, which can cross the blood brain barrier protecting brain tissue and modulating brain chemistry. Chronic treatment with naringin dose dependently restored cognitive deficits in ICV-STZ (AD model)  rat along with mitigation of mitochondrial dysfunction mediated oxido-nitrosative stress and inflammatory response (cytokine release).  (50, 100 and 200mg/kg; oral 21 days)
Naringin and total naringenin were rapidly and widely distributed to all the tissues except brain in rats. They had difficulties in crossing the blood-brain barrier. There are no accumulations in rats.
naringin showed significant antiapoptotic effects in rotenone-treated human SH-SY5Y cells by inhibiting phosphorylation of JNK and P38, as well as the activation of CASP9, PARP, and CASP3. These findings indicate that naringin may have therapeutic potential for PD

restores impaired short and long term memory, protects hippocampus, especially in AD and dementia. PD, dementia, AD: (3, 16, 19 articles)
great review for nobiletin in AD. Nobiletin exhibited memory-improving effects in various animal models of dementia and exerted a wide range of beneficial effects against pathological features of AD including amyloid-ß (Aß) pathology, tau hyperphosphorylation, oxidative stress, cholinergic neurodegeneration and dysfunction of synaptic plasticity-related signaling, suggesting this natural compound could become a novel drug for the treatment and prevention of AD.  suggest nobiletin penetrates the BBB in mice and reaches a maximal level within 3-5 min after peripheral administration. Additionally, 4'-demethylnobiletin, a major urinary metabolite of nobiletin in rats and mice, can cross the BBB and exert memory-improving effects in the brain.
chinese medicine uses chinpi (0.05% nobiletin), aged mandarine peel (Citrus reticulata)
Nobiletin but even more so sinensetin with the help of tangeretin, 6-demethoxynobiletin, and 6-demethoxytangeretin facilitate cAMP/PKA/ERK/CREB signaling associated with learning and memory in cultured hippocampal neurons
concentrates in brain 10x blood rat brain in 1 hour:
 Maximum concentrations of nobiletin in both plasma and brain were observed at 1h after single oral dosing (50 mg/kg). The maximum concentration in plasma and brain were 1.78 and 4.20 µg/mL, respectively. The AUC(0-t) in plasma and brain were 7.49 and 20.66 µg·h/mL, respectively. The mean elimination half life (t(½) in plasma and brain were 1.80 and 11.42 h, respectively.
Our results showed that nobiletin treatment at 10 mg/kg bw i.p., but not at 1 or 20 mg/kg bw, significantly protected DA neurons in the substantia nigra (SN) of MPP(+)-treated rats.
nobiletin activity in brain and suggests that nobiletin rescues motor and cognitive dysfunction in MPTP-induced Parkinson model mice, in part by enhancing dopamine release. (50 mg/kg i.p. 2 weeks)
Nobiletin (NOB) exhibits a wide spectrum of beneficial biological properties including anti-inflammatory, antioxidant, anti-carcinogenic actions and contributes to reverse learning impairment in Alzheimer's disease rat.  Dramatically promoted the activities of Akt, CREB, BDNF and Bcl-2.  protected the brain from ischemic  damage maybe through activating the Akt/CREB signaling pathway and ameliorating BBB permeability.  10 and 25 mg/kg ip (injected) 3 days before hypoxic injury and 1 day after.
berberine better, by same group:
dramatically lessened neurological deficits scores, brain water contents and infarct sizes, upregulated the expression of pAkt, pGSK3ß, pCREB and claudin-5, and decreased the nuclear accumulation of NF-?B (P<0.05) in ischemic brain.  Applied same injury to rats and applied only once after injury, 10 and 40 mg/kg.
nobiletin, including neurotrophic and memory-enhancin
g action, in both in vitro and in vivo systems are well established...whether its metabolites do have such beneficial effects like nobiletin remains to be examined...4'-demethylnobiletin, a bioactive metabolite of nobiletin, may serve as a potential therapeutic agent, at least, for memory disorders associated with a dysregulated NMDA receptor ERK signaling, like nobiletin.

PD, dementia, AD  (3,2,1)
By affecting unfolded protein response and reduces endolpasmic reticulum stress.  Hesperidin may be similar.  ER stress-induced cell death have been demonstrated in a broad spectrum of pathological situations, including ischemia, diabetes, atherosclerosis, endocrine defects, and neurodegenerative disorders
pretreatment of mice with tangeretin, a methoxyflavone, enhanced expression of GRP78 and HO-1 without causing ER stress in renal tubular epithelium and prevented tunicamycin-induced cell death. Furthermore, preadministration of tangeretin in mice enhanced expression of GRP78 in the substantia nigra pars compacta and protected dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin that induces both oxidative and ER stress.  (10 mg/kg injected with DMSO
 tangeretin is a UDP (UGT) inhibitor like peperine, quercetin, salicylic acid (aspirin metabolite), EGCG (teas) and silibinin (milk thistle)
prevents bad protein folding:  Consistent with these results, administration of the UPR-activating reagent tangeretin (5,6,7,8,4'-pentamethoxyflavone; IN19) into mice enhanced the expression of UPR-target genes in both dopaminergic neurons and astrocytes, and promoted neuronal survival after MPTP/P injections. (10 mg/kg orally 2 days before insult)
(10 mg/kg/day for 28 days), significant levels of tangeretin were detected in the hypothalamus, striatum and hippocampus (3.88, 2.36 and 2.00 ng/mg, respectively). . (20 mg/kg/day for 4 days; oral) before  applied insult to rat PD model showed markedly reduced the loss of both TH+ cells and striatal dopamine content.  These studies, for the first time, give evidence that tangeretin crosses the blood-brain barrier.

PD, dementia, AD: (3,7,11)
Hesperidin potentially useful in PD because it crosses blood-brain barrier and prevent protein aggregation
protective effect of hesperidin on the neurotoxicity induced by 6-OHDA in aged mice, indicating that it could be useful as a therapy for the treatment of PD.
 hesperidin exerts its neuroprotective effect against rotenone due to its antioxidant, maintenance of mitochondrial function, and antiapoptotic in PD model ...  hesperidin can protect neurons against various types of insults associated with many neurodegenerative diseases (full text)
hesperidin can exhibit multiple neuroprotective effects.
hesperidin ameliorates heavy metal induced toxicity mediated by oxidative stress
Hesperidin  protects against hypoxia (low oxygen) injury
In AD mice, 100 mg/kg 10 days, mouse model of cerebral amyloidosis, hesperidin significantly restored deficits in non-cognitive nesting ability and social interaction. attenuated ß-amyloid deposition, plaque associated APP expression, microglial activation and TGF-ß immunoreactivity in brains of APP/PS1 mice, which suggests that ameliorated behavioral impairments might be attributable to reduced Aß deposition and attenuated neuro-inflammatory reaction.
In AD transgeneic mice 100 mg/kg for 16 weeks (same study in naringin) did not decrease amyloid plague but  showed reduction of learning and memory deficits, improved locomotor activity, and the increase of anti-oxidative defense and mitochondrial complex I-IV enzymes activities. Furthermore, Glycogen synthase kinase-3ß (GSK-3ß) phosphorylation significantly increased
In AD mice
treatment with hesperetin and hesperidin improved Aß-impaired glucose utilization by inhibiting Aß-induced autophagy in neuronal cells.

beberine (from barberry) (likely it is not bioavailable)
PD, dementia, AD (0,31, 22)
prevents unfolded protein, antidepressant, anti-fat, and a neuroprotector against neurodegenerative.
May act synergistically with  sugar that cancer like, 2-Deoxy-d-glucose, which is not safe above 4 g/day. Reduces fat by selectively activating unfolded protien which causes the cell to die.
However, treatment with berberine enhanced motor balance and coordination by preventing dopaminergic neuronal damage. Treatment with berberine also improved short-term memory by inhibiting apoptosis in the hippocampus. Berberine demonstrated maximal potency at 50 mg/kg. Based on these data, treatment with berberine may serve as a potential therapeutic strategy for the alleviation of memory impairment and motor dysfunction in patients with PD.  (mouse, 50 mg/kg orally 5 weeks)

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