Maybe you want to DEMAND YOUR DOCTOR give you a protocol on this. Not a guideline, they are useless
Neuroinflammation and Neurodegeneration: The Promising Protective Role of the Citrus Flavanone Hesperetin
National Research Council (CNR) Institute of Clinical Physiology (IFC), 73100 Lecce, Italy
Nutrients 2020, 12(8), 2336; https://doi.org/10.3390/nu12082336
Received: 22 July 2020 / Accepted: 31 July 2020 / Published: 5 August 2020
Over the past 20 years, there has been a remarkable
increase in the scientific interest in polyphenols, bioactive compounds
naturally present in plant foods and beverages, due to the recognition
of their biological actions, their great abundance in the human diet,
and their plausible role in the prevention of various chronic
degenerative diseases, such as cancer, cardiovascular and
neurodegenerative diseases [1].
Great advancements have been made in understanding the health effects
of polyphenols in several pathophysiological settings, their
mechanism(s) of action, as well as their bioavailability and metabolism,
opening up new opportunities for the food and nutraceutical industry.
Over
500 different molecules with a polyphenol structure (i.e., several
hydroxyl groups on aromatic rings) with different properties and
bioavailabilities have been identified in edible plants, where they are
synthetized as secondary metabolites for defense against biotic and
abiotic stress. They are divided into five main groups according to
structure: phenolic acids, flavonoids, stilbenes, lignans and others.
The flavonoid class is further divided into six subclasses, including
flavonols, flavones, isoflavones, flavanones, anthocyanidins, and
flavanols [2].
Flavonoids
are among the most consumed polyphenols: in the European cohort of the
PREDIMED (PREvencion con DIeta MEDiterranea) study aimed at assessing
the effect of the Mediterranean diet, rich in polyphenols, on the
primary prevention of cardiovascular disease, the mean total polyphenol
intake was 820 ± 323 mg daily, of which 443 ± 218 mg daily was provided
by flavonoids [3],
mainly from fruits, vegetables, alcoholic and non-alcoholic beverages,
and cereals. In US adults, the estimated mean daily intake of flavonoids
was 189.7 ± 11.2 mg, mainly from tea, citrus fruit juices, wine, and
citrus fruits [4].
Epidemiological
studies found an inverse association between dietary consumption of
flavonoids and the risk of cardiovascular diseases, metabolic diseases,
neurodegenerative diseases and cancer, with experimental evidence
highlighting the contributory role by several flavonoid
classes/subclasses and individual compounds to the observed health
benefits [5].
Among flavonoids drawing growing scientific attention, there are the
flavanones hesperidin (hesperetin-7-O-rutinoside) and its aglycone
hesperetin, which are present in high concentrations in citrus fruit and
juices, although they can be found in tomatoes and certain aromatic
plants, such as mint [6].
Considering the high intake of citrus fruits and juices worldwide,
flavanones significantly contribute to the dietary intake of flavonoids [3,4,7].
Hesperidin represents 90% of total flavanones in oranges and orange
juices. Orange juice contains between 200 and 600 mg hesperidin/L, and a
much higher concentration of flavanones can be found in the whole fruit
where the solid parts (the albedo and the membranes) are particularly
rich in flavanones [6].
The average daily intake of flavanones in a large cohort of European
countries was estimated to be 25.7 ± 27.1 mg, being most often consumed
as fruits (72.0%), juices (17.2%), wine (5.4%), and soft drinks (1.7%) [8].
In the Spanish PREDIMED cohort, flavanones were among the most consumed
polyphenols, with a daily intake of 132 ± 125, mainly provided by
oranges (91%), orange juice (8%), red wine (0.5%), tomatoes (0.1%) [3].
Specifically, the hesperidin daily intake was 90.29 ± 85.89 mg, mostly
contributed by the consumption of oranges and their products [3].
In US adults, the total flavanone intake was 14.4 ± 0.6 mg, mostly from
fruit and fruit juices, precisely citrus fruit juices [4].
Interestingly, flavanones are among the flavonoid compounds with the highest bioavailability [2].
Once ingested, hesperidin is first metabolized by intestinal bacteria
into its aglycone hesperetin, which is more absorbable and bioavailable
than hesperidin, and is subsequently transformed into various phenolics
and mostly conjugated into glucuronides and sulfates. As such, the
biological effects of flavanones, as for polyphenols in general, are
likely contributed by the original compounds and mostly their
circulating metabolites [9].
After an intake of 130–220 mg hesperetin given as orange juice, the
plasma concentrations of hesperetin metabolites have been shown to reach
1.3–2.2 µmol/L [2,10].
These
interesting data have spurred intensive research on the
health-promoting effects of flavanone-rich foods and extracts, and
particularly on their most abundant representatives, hesperidin and
hesperetin, in cell and animal models, as well as in humans. Preclinical
and clinical findings indeed show that hesperidin, hesperetin and their
metabolites possess various physiological activities, including
antioxidant, anti-inflammatory, hypolipidemic, antihypertensive,
insulin-sensitizing, vasculoprotective and anti-atherosclerotic
activities, which could explain the beneficial effects of flavanone-rich
foods and beverages against cancer, cardiovascular, metabolic and joint
arthritis diseases [11,12,13,14].
The antioxidant properties are likely due to both direct radical
scavenging activity and an increase in cellular antioxidant defenses via
the upregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf-2)
pathway [11].
Furthermore, hesperidin and hesperetin have been reported to inhibit
inflammatory responses via the attenuation of the activation of the
master pro-inflammatory and redox-sensitive transcription factor nuclear
factor (NF)-κB, which induces the expression of cytokines, chemokines,
and enzymes with pro-inflammatory action [15,16].
The modulation of the MAPK signaling pathways involved in inflammation,
cell survival, apoptosis, and oxidative stress responses also
contributes to the anti-inflammatory effects of hesperidin and
hesperetin in different pathophysiological settings [17,18].
A
relatively new field of research regards the protective effects of
citrus flavanones on the central nervous system, as first suggested by
their antioxidant and anti-inflammatory activities in peripheral tissues
coupled with their known ability to cross the blood–brain barrier [2].
This is particularly interesting because neurodegenerative diseases,
including Alzheimer’s diseases, Parkinson’s disease, Huntington’s
disease, and amyotrophic lateral sclerosis, are debilitating disorders
that are increasingly prevalent in modern ageing societies, and are
major causes of cognitive and motor dysfunction. Known basic pathogenic
pathways in neurodegenerative diseases include neuroinflammation,
altered synaptic transmission, deposition of protein aggregates,
apoptosis, mitochondrial dysfunction, and oxidative stress [19].
A common feature in neurodegenerative diseases playing a crucial
pathophysiological role in their onset and progression is
neuroinflammation, which occurs in response to central nervous system
trauma, infection, toxins, misfolded and aggregated proteins or as a
consequence of autoimmunity, and is mediated by the activation of glial
cells, including microglia and astrocytes, that represent the resident
innate immune cells in the brain [20].
Once activated through the involvement of MAPK and NF-κB pathways,
glial cells increase the production of pro-inflammatory mediators
including cytokines, chemokines, adhesion molecules, receptors, and
enzymes, and of reactive oxygen species (ROS), as well as nitric oxide
(NO), with a consequent unbalance between their neuroprotective and
neurotoxic effects and alteration of the cross-talk with neurons, which
leads to compromised neuronal functional integrity and further
inflammatory response in a chronic vicious manner, resulting in neuronal
death and central nervous system injury [20].
Strategies targeting these pathogenic neuroinflammatory processes are
currently a rapidly emerging field of research in the search for
innovative therapeutic approaches in neurodegenerative diseases.
Different
flavonoids have been demonstrated to exert neuroprotective and
anti-inflammatory effects in vitro and in vivo by modulating key
cellular processes implicated in neurodegeneration [21]. As previously reviewed [22],
citrus flavanones including hesperidin, hesperetin and naringenin
exhibit a plethora of interesting protective properties in neurons and
glial cells with relevance to central nervous system disorders.
Hesperidin
and hesperitin have indeed been found to protect neurons against
cytotoxicity induced by oxidative, inflammatory stimuli, and neurotoxic
substances, both in vitro and in animal models of neurodegeneration [22].
Hesperidin and hesperetin promote neuron survival through the
activation of the pro-survival PI3-Akt and MAPK pathways, and the
recruitment of neural progenitor cells via effects on astrocytes [23].
Protective underlying mechanisms may include the antioxidant and
anti-inflammatory action of citrus flavanones, as well as improvement of
mitochondrial dysfunction and energy metabolism, attenuation of calcium
levels, caspase activity, increase in brain-derived neurotrophic factor
(BDNF), modulation of apoptotic effector proteins, inhibition of
nitrosative stress and the nitrergic pathway [22].
In
addition, citrus flavanones significantly modulate the inflammatory
responses by glial cells. Hesperetin has been demonstrated to decrease
the over-expression of inducible NO synthase (iNOS), and
pro-inflammatory cytokines (IL-1β, TNF-α and IL-6) as well as the
activation of MAPK ERK1/2 and p38, and the transcription factor NF-κB in
lipopolysaccharide (LPS)-stimulated BV-2 microglial cells [18]. Moreover, hesperetin significantly suppressed astrocyte and microglial activation in the LPS-challenged mouse brain [18].
The
antioxidant, anti-inflammatory and signaling pathway-modulating
activities of flavanones might contribute to the observed improvement of
cognitive and/or motor impairments as previously reported by hesperidin
in animal models of Alzheimer’s disease, Parkinson’s disease,
Huntington’s disease and epilepsy [24], and by hesperetin in animal models of Alzheimer’s diseases [25], Parkinson’s disease [26], and epilepsy [27].
Furthermore, benefits in psychiatric disorders exerted by hesperidin
and hesperetin have been previously suggested through their
anti-depressant and anxiolytic effects, as documented in animal models [22].
In
line with these findings and expanding the neuropharmacological
properties of the less studied but more bioavailable flavanone
hesperetin, a preclinical study published in Nutrients
addressed the neuroprotective role and potential mechanisms of
hesperetin against LPS-induced Toll like receptor (TLR)-4-mediated
neuroinflammation and related neurodegeneration [28].
In particular, Muhammad et al. pretreated mice with hesperetin (50
mg/kg daily) for three weeks before LPS challenge for further two weeks,
inducing neurodegenerative features. They monitored markers of
neuroinflammation, neuronal apoptosis, and oxidative stress, as well as
memory impairments in the brain, and confirmed some results in vitro in
LPS-stimulated neuronal and microglial cell lines cotreated with 50
µmol/L hesperetin. Hesperetin was found to significantly rescue
LPS-induced activation of microglia (gliosis) and astrocytes
(astrocytosis) in cortical and hippocampal regions of mouse brain, and
the corresponding proinflammatory activation as indexed by the reduced
activation of NF-κB and expression of the cytokines IL-1β and TNF-α in
the mouse brain and BV-2 microglial cells. Concordantly, hesperetin
overcame the overproduction of ROS and the reduction in antioxidant
proteins such as Nrf2 and heme-oxygenase (HO)-1 stimulated by LPS in
mouse brain. This was further supported by cytoprotective effects
against LPS-induced cytotoxicity and oxidative stress in the mouse
hippocampal neuronal HT-22 cell line. Accordingly, hesperetin was able
to prevent LPS-induced neuronal apoptosis and neuronal loss in vivo [28].
In
agreement with these beneficial effects against neuroinflammation,
apoptosis and oxidative stress, critical processes in neurodegeneration,
hesperetin has been found to improve synaptic dysfunction as well as
memory, learning and cognitive impairments following LPS stimulation.
Besides the known increase in BDNF level in the hippocampus that could
mediate the hesperetin-induced memory-enhancing effect, the authors
demonstrated that these effects might also be mediated by the recovery
of the activation of cAMP response element binding protein (CREB) [28], a transcription factor implicated in memory formation, as observed in the cortex and hippocampus of treated mice.
A previous study by the same group [29]
showed similar findings in an animal model of Alzheimer’s disease-like
neurodegeneration. Indeed, hesperetin counterbalanced abnormal ROS
production, activation of astrocytes and microglia, apoptotic cell
death, neuroinflammation, and synaptic dysfunction in an in vivo amyloid
β (Aβ)-injected mouse model of Alzheimer’s disease, and confirmed in
vitro in Aβ-treated neuronal and microglial cells. Improvements in
markers of Aβ pathology in the mice brain and in cultured neuronal
cells, as well as in memory dysfunction in response to Aβ injection,
were also here documented for hesperetin [29].
Therefore, a common underlying anti-neuroinflammatory and antioxidant
action by hesperetin may be suggested as a mechanism preventing
neurodegeneration in response to different agents detrimental to the
central nervous system.
Collectively, this
evidence in animals and in vitro lays the foundation for novel
perspectives in the prevention of neurodegeneration, and contributes to
explaining earlier human evidence from observational and interventional
studies indicating improved cognitive function and lowered risk of
dementia with frequent consumption of flavanone-rich citrus fruits or
juices. Indeed, in a randomized controlled human intervention trial, 8
week daily consumption of 500 mL flavanone-rich (305 mg with 549 mg
hesperidin/L) orange juice improved cognitive function compared with the
consumption of a flavanone-low (37 mg with 64 mg hesperidin/L) orange
juice in healthy older adults [30].
Similarly, the consumption of 240 mL of orange juice containing 220.46
mg hesperidin acutely enhanced cognitive performance in healthy
middle-aged men [31],
and citrus consumption was inversely and dose-dependently correlated
with the risk of incident dementia in a cohort of elderly subjects [32].
Translation
of preclinical data to humans may be challenging, and further
investigations are required on the flavanone molecular targets and
bioactive metabolites, doses, length of treatment, patient population,
and interindividual variability in biological responses, as well as the
interaction with drugs. The work of Muhammad et al. [28]
provided novel mechanistic insights into the neuroprotective effects of
hesperetin, and called for future flavanone-based dietary intervention
studies in humans to substantiate them as new potential agents
contributing to the prevention and/or treatment of neurodegenerative
disorders.
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