Naringin and Naringenin Polyphenols in Neurological Diseases: Understandings from a Therapeutic Viewpoint

The glycosides of two flavonoids, naringin and naringenin, are found in various citrus fruits, bergamots, tomatoes, and other fruits. These phytochemicals are associated with multiple biological functions, including neuroprotective, antioxidant, anticancer, antiviral, antibacterial, anti-inflammatory, antiadipogenic, and cardioprotective effects. The higher glutathione/oxidized glutathione ratio in 3-NP-induced rats is attributed to the ability of naringin to reduce hydroxyl radical, hydroperoxide, and nitrite. However, although progress has been made in treating these diseases, there are still global concerns about how to obtain a solution. Thus, natural compounds can provide a promising strategy for treating many neurological conditions. Possible therapeutics for neurodegenerative disorders include naringin and naringenin polyphenols. New experimental evidence shows that these polyphenols exert a wide range of pharmacological activity; particular attention was paid to neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, as well as other neurological conditions such as anxiety, depression, schizophrenia, and chronic hyperglycemic peripheral neuropathy. Several preliminary investigations have shown promising evidence of neuroprotection. The main objective of this review was to reflect on developments in understanding the molecular mechanisms underlying the development of naringin and naringenin as potential neuroprotective medications. Furthermore, the configuration relationships between naringin and naringenin are discussed, as well as their plant sources and extraction methods.


Introduction
The term "neurological disease" is often used to refer to anything that affects the nervous system. In the brain, spinal cord, or other nerves, structural, metabolic, or electrical dysfunctions may cause a broad range of symptoms. These symptoms include altered states of consciousness, convulsions, muscular weakness, poor coordination, a loss of feeling, and a lack of sensation. Other symptoms include disorientation, pain, and discomfort. Extensive study has led to the discovery of several neurological abnormalities, some of which are somewhat common while others are relatively uncommon [1,2]. Some of these problems are inherited while others are not. Neurology and clinical neuropsychology can identify and treat these illnesses using the appropriate diagnostic and therapeutic methods. Although encased in the skull and spinal vertebrae and chemically isolated by the blood-brain barrier, the brain and spinal cord are susceptible organs [3]. Because of Figure 1. Flowchart depicting the steps to be followed when selecting published data for the current study; n stands for the number of literature reports.

Naringin and Naringenin
The flavanone naringenin and the glycosylated derivative naringin are in high concentrations in grapefruit and other citrus fruits. The antioxidant and anti-inflammatory properties of flavonoids have gained widespread recognition [17]. When naringenin is added to SH-SY5Y cells or when 6-OHDA is injected into mice, the cells are protected in an Nrf2-dependent manner, just like the dopaminergic neurons [18]. This is due to the complete elimination of protective effects and expression of Nrf2-dependent cytoprotective genes after treatment with Nrf2 short interfering RNA [19]. Naringenin prevented rotenone-induced structural alterations in muscle and motor impairment in rat models when given after the administration of the medication. The expression of DJ-1 and chaperone-associated E3 ligase was increased in the striatum and SN after treatment with naringenin [20]. Target proteins are ubiquitinated by DJ-1 and a chaperone-associated E3 ligase and then sent on to be degraded by the proteasome. In a rotenone model of Parkinson's disease, naringenin was found to have neuroprotective effects [21,22]. Naringin may aid dopaminergic neuron recovery after injury if given soon after the damage occurs. Dopaminergic neurons were preserved, GDNF levels in the SN were restored, and the number of ionized calcium-binding adaptor molecule 1 (Iba-1) and tumor necrosis factor-alpha (TNF-α) immunoreactive neurons in the striatum were reduced after pretreatment with naringin in rats with a unilateral MPP+-lesion. Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and growth differentiation and neurotrophic factor (GDNF) were upregulated in the SN after a single injection of naringin [23].
On top of that, it is an effective antioxidant. During fasting and stimulated states, rapid glucose uptake is impaired in BC. Insulin stimulates phosphoinositide 3-kinase PIP3/Akt and mitogen-activated protein kinase (MAPK) activity, and naringenin prevents Figure 1. Flowchart depicting the steps to be followed when selecting published data for the current study; n stands for the number of literature reports.

Naringin and Naringenin
The flavanone naringenin and the glycosylated derivative naringin are in high concentrations in grapefruit and other citrus fruits. The antioxidant and anti-inflammatory properties of flavonoids have gained widespread recognition [17]. When naringenin is added to SH-SY5Y cells or when 6-OHDA is injected into mice, the cells are protected in an Nrf2-dependent manner, just like the dopaminergic neurons [18]. This is due to the complete elimination of protective effects and expression of Nrf2-dependent cytoprotective genes after treatment with Nrf2 short interfering RNA [19]. Naringenin prevented rotenoneinduced structural alterations in muscle and motor impairment in rat models when given after the administration of the medication. The expression of DJ-1 and chaperone-associated E3 ligase was increased in the striatum and SN after treatment with naringenin [20]. Target proteins are ubiquitinated by DJ-1 and a chaperone-associated E3 ligase and then sent on to be degraded by the proteasome. In a rotenone model of Parkinson's disease, naringenin was found to have neuroprotective effects [21,22]. Naringin may aid dopaminergic neuron recovery after injury if given soon after the damage occurs. Dopaminergic neurons were preserved, GDNF levels in the SN were restored, and the number of ionized calcium-binding adaptor molecule 1 (Iba-1) and tumor necrosis factor-alpha (TNF-α) immunoreactive neurons in the striatum were reduced after pretreatment with naringin in rats with a unilateral MPP+-lesion. Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and growth differentiation and neurotrophic factor (GDNF) were upregulated in the SN after a single injection of naringin [23].
On top of that, it is an effective antioxidant. During fasting and stimulated states, rapid glucose uptake is impaired in BC. Insulin stimulates phosphoinositide 3-kinase PIP3/Akt and mitogen-activated protein kinase (MAPK) activity, and naringenin prevents this MAPK. It decreases TNF-α and COX-2 levels and raises the transcription factor Nrf2 [24,25].

Botanical Sources
Flavonoids are phenolic compounds associated with a wide range of biological functions. There are more than 4000 different flavonoids known to science, most of which are found in their natural, unaltered plant-based forms. Flavonoids can be a dietary supplement [26,27]. Grapefruit and other citrus fruits get their distinctive bitter taste from flavonoid naringin. Although the number of flavonoids taken from food may be large and the flavonoids exhibit potential biological action, they have attracted significantly less attention than flavanols and isoflavones [28,29].
In most cases, the researchers focused on flavanols and isoflavones-intracellular cycling of naringenin, hesperidin, and its glycosylated derivatives, naringenin, hesperidin, and rutin. Grapefruit, bergamot, sour orange, tart cherry, tomato, chocolate, Greek oregano, water mint, and beans are all foods and plants that contain norepinephrine or its glycosides [29,30].

Alzheimer's Disease
Alzheimer's disease (AD) is the most common type of dementia in the industrialized world and is a severe public health problem [31]. Several different molecular processes caused AD, but its exact pathophysiology is still poorly understood. In several pre-clinical studies, naringin and some of its derivatives, such as naringenin, changed these pathways in ways that could be used to treat AD [32,33]. The disease is caused by the death of cholinergic neurons in the frontal lobe and the formation of Amyloid-β (Aβ) plaques outside the body [34].
Memantine, an antagonist of the NMDA glutamate receptor, breaks down at a much slower rate than acetylcholinesterase (AChE) inhibitors, such as donepezil aricept, which is often used to treat the symptoms of AD [35,36]. Synaptic dysfunction, in which synapses are damaged, cells are killed, and mental impairments occur, results from consuming too much. This dysfunction can be fixed entirely with the proper treatment. It is essential to understand how Aβ is currently in charge of producing and storing memories and how this affects synaptic plasticity in the brain network. Evidence suggests that calcium/calmodulindependent protein kinase II (CaMKII) is a critical synaptic target for Aβ-induced synaptic depression [37,38]. Several plant species high in flavonoids have been used in traditional medicine for hundreds of years. Epidemiological and dietary studies on both people and animals have shown that these flavonoids protect against and slow down neurodegeneration, especially regarding the cognitive decline that accompanies aging [39]. The flavonoid glycoside naringin, found in citrus fruits in large amounts, is effective against many diseases and conditions, such as cancer, inflammation, ulcers, osteoporosis, and apoptosis. Naringin has been shown to improve behavior and thinking in animal models of epilepsy caused by kainic acid and Huntington's disease caused by 3-nitropropionic acid [40]. The effects of colchicine and D-galactose on learning and memory are also undone by treatment with naringin. Naringenin has been shown to improve insulin signaling and cognitive ability in the brain and reduce the effects of intracerebroventricular-streptozotocin on neurodegeneration caused by AD (Table 1 and Figure 2) [41].

Parkinson's Disease
Parkinson's disease (PD) is a degenerative neurological disease that results in impaired motor function due to dopaminergic neuropathy in the substantia nigra [42][43][44]. Genetic predisposition may play a role in developing mitochondrial damage and oxidative stress; however, additional molecular routes exist. In recent years, oxidative stress has been investigated as a potential mechanism in neurodegeneration, which is only one example of many similarities between AD and PD. The antioxidant properties of flavonoids, alkaloids, and other polyphenols are coming to the fore. Plant chemicals may modulate enzymes and metabolic signaling pathways to reduce ROS production. Bioactive metabolite flavonoids have anti-oxidative actions on the liver's metabolic pathway [45][46][47].
The antioxidant and neuroprotective properties of naringin have been studied. Asahina and Inubuse found the blueprints for naringin in 1928 [48,49]. Naringenin is linked to naringin through the C-7 hydroxyl group. Metabolites of naringenin may be found in phases I and II of the drug's metabolism. Glucose is the source of naringin's bitter flavor. It reacts with potassium hydroxide or other essential substances to form 1,3-diphenylpropan-1-one, which has a scent reminiscent of menthol [50][51][52]. It has been shown that naringin may neutralize ROS, scavenge superoxide, suppress xanthine oxide, decrease lipid peroxidation, and decrease the permeability of oxygen-stimulated K+ erythrocytes. Naringin's antioxidant potentials may aid in treating neurology and diabetes. Degeneration of nerve cells in the striatum and substantia nigra pars compacta kills dopamine-producing brain cells, leading to Parkinson's disease (Table 1 and Figure 3) [53]. Neurons in the substantia nigra are affected as microglia are activated, and protein clumps form. Causes of neurodegeneration include oxidative stress, dopamine depletion, and neuroinflammation. In addition to boosting dopamine, naringenin also reduces inflammation [54]. By activating Nrf2/ARE and its downstream target genes, including HO-1 and glutathione cysteine ligase regulatory subunit, naringenin protects mice against 6-hydroxydopamine-induced dopaminergic neurodegeneration and oxidative damage. By inhibiting and caspase 3, naringenin was able to prevent apoptosis. Grapefruit suppresses CYP3A4 much more so than naringin. With less naringin than grapefruit juice, orange juice also stops CYP3A4. Preclinical tests have shown that naringin is not transformed into naringenin in cultivated cells [55][56][57].

Cerebral Ischemia
Cerebral ischemia is a disorder that may trigger a cascade of unfavorable biochemical responses in the brain, leading to malfunction of key brain regions and, commonly, neuropathy [113,114]. An inflammatory reaction and the production of ROS following an ischemia event may damage brain tissue and lead to neuronal death [115]. Ischemiainduced damage involves several kinases, including mitogen-activated protein kinases, extracellular signal-regulated kinases, signal transducers and activators of transcription 1, calcium/calmodulin-dependent kinases, etc. ROS initiate the caspase cascade and encourage the synthesis of pro-inflammatory cytokines including interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha, all of which contribute to cell death. Although progress has been made, a full understanding of the molecular mechanisms behind post-ischemic neuronal damage remains elusive. However, naringin and naringenin have been shown to have a neuroprotective effect after ischemia [116][117][118][119].
There is evidence that naringenin may help reduce the adverse effects of oxidative stress on the body, making it a potentially beneficial treatment option for various chronic illnesses. In addition to modulating the activity of antioxidant enzymes and regulating the expression of antioxidant genes, the flavonoid may have direct antioxidant effects, such as scavenging reactive species and reducing oxidative damage [124,125]. When Nrf2 is activated, antioxidant defenses are enhanced by maintaining redox equilibrium and decreasing oxidative stress and inflammation. TNF-α and IL-1β, two key inflammatory activators, are elevated in response to oxidative stress, whereas naringenin suppresses mRNA expression in the substantia nigra, hippocampus, and BV2 microglial cells [126,127]. For example, studies on rat hippocampus and BV cells have revealed that naringenin reduces NF-kB activation. Naringenin inhibited NF-kB, COX-2, iNOS, and their immunoreactivity, preventing the inflammatory cascade that leads to neurological diseases [51,128].

Anxiety and Depression
Anxiety and depression are two of the most common mental illnesses, both of which have complex origins at the intersection of several biological systems. Li et al. performed the first studies on the antidepressant effects of naringin and naringenin. The chemicals were tested on mice models of depression brought on by chronic unpredictable mild stress (CUMS) [129]. Anxiety may cause a variety of uncomfortable physical and emotional symptoms, including but not limited to: irritation, impatience, weariness, difficulty concentrating, a racing heart, chest pain, and an upset stomach. Anxiety comes in a variety of forms, and each is treated differently [130]. The serotonergic and noradrenergic systems have been connected to mood disorders such as depression and anxiety. The serotonergic system has far-reaching effects on cognitive processes in the brain, in addition to its role in regulating mood and appetite. Memory and focus are only two of the cognitive functions that are controlled by the noradrenergic system. Increases in serotonin (5-HT) and norepinephrine (NE) receptors, activation of brain-derived neurotrophic factor (BDNF), and decreased blood corticosterone are hypothesized to underlie NRG's antidepressant-like effects [131,132]. It inhibits monoamine oxidase, which may also help those who are depressed. Increased rearing activity, decreased immobility, and increased social communication was seen in mice administered NRG intraperitoneally (at doses of 2.5, 5, and 10 mg/kg), which is consistent with anti-depressant-like and anxiolytic-like effects. Reductions were seen in nitrosative stress, lipid peroxidation, and cholinergic transmission. Mental diseases, often known as mental illnesses or psychiatric disorders, are characterized by persistent patterns of thinking or behavior that significantly impair an individual's capacity to function in everyday life. Both the frequency and length of time that these symptoms will persist are unknown at this time. Various diseases and disorders have been identified, and each has its signs. In some instances, seeking the assistance of a clinical psychologist or psychiatrist specializing in evaluating and managing mental health conditions may be beneficial [133][134][135][136].
Neuronal inflammatory mediator release exacerbates tissue damage and reactive oxygen and nitrogen species (ROS/RNS) production, perpetuating the neuronal degeneration in stress-induced neuropsychiatric diseases, including depression and cognitive loss. Decreased antioxidant defenses in neurons promote neuroinflammation and neurodegeneration [137]. Several mediators and intracellular signaling molecules have been connected to neuroinflammatory responses to hypoxia damage. When hypoxia occurs, inflammatory transcription factors, including the NF-κB pathway, are activated, increasing pro-inflammatory cytokine production [137]. Physical changes in the brain's dendritic arbourization and synaptic architecture have been linked to psychological and neurological issues, including depression, anxiety, and memory loss. Naringenin, a dietary flavanone, may be abundant in various foods, including citrus fruits, vegetables, and other berries and nuts [138]. Chronic illnesses and ailments may benefit from consuming a diet high in NG-rich fruits and vegetables. Animal pharmacokinetic studies have shown that NG rapidly undergoes intermediate glucuronide metabolism in the liver and readily crosses the blood-brain barrier (BBB). NG's high permeability across the BBB has been attributed to its association with a broad range of CNS effects. However, the oral bioavailability of naringenin is limited by its metabolism in the liver and its degradation by bacterial enzymes in the colon. Lowered levels of inflammatory mediators were seen in rats, including TNF-α, cyclooxygenase-2, and inducible nitric oxide synthase (iNOS). Studies of naringenin's effects on the brain and spinal cord show it may help treat various neurological disorders [139][140][141].

Schizophrenia
Schizophrenia is a disabling brain illness characterized by a wide range of neurotic symptoms including but not limited to hallucinations, delusions, cognitive impairment, disorganized speech, and aberrant motor activities [142]. Many different causes contribute to the development of schizophrenia. These include structural brain abnormalities, impaired neurotransmission, and stress-induced signaling cascades. Disruptions in epidermal growth factor (EGF) signaling and abnormalities in the processing or expression of the EGF receptors ErbB1 and ErbB2 are common in all schizophrenias [143]. As the pathophysiology of schizophrenia worsens, oxidative stress has been suspected to be a contributing factor. Several signs of oxidative stress, including ROS, reduced antioxidant enzyme activity (catalase), depleted glutathione, and oxidized lipids, have been associated with schizophrenia [144].
Schizophrenia and apoptosis have been connected via both intrinsic (mitochondrial death) and extrinsic (death receptor) pathways [145]. Cytochrome C interacts with proapoptotic and anti-apoptotic proteins to trigger the release of activated caspase-3 (primarily Bax and Bcl-2). Diabetes was prevented in streptozotocin-treated rats by administration of naringin, which inhibited the production of inflammatory and oxidative stress mediators [146]. Reduced free radical production, decreased release of proinflammatory cytokines (such as interleukin-6 and TNF-α), and down-regulation of inflammatory proteins such as NF-κB have all been linked to its anti-inflammatory effects in diabetic, chronic bronchitis, and walker carcinosarcoma rats. To evaluate if naringenin protects interendothelial tight junctions, we analyzed the expression and localization of ZO-1, occludin, claudin-1, and claudin-2 across experimental groups. ZO-1 protein expression was significantly reduced in the TNF-α treated group compared to the control group (p < 0.05) [147][148][149][150][151].
However, in TNF-α induced RIMVECs (p < 0.05), treatment with naringin dramatically increased ZO-1 protein expression. Immunofluorescence's structured cell death also showed ZO-1 distribution. As proposed here, the medication that acts as a positive allosteric modulator of GABA neurotransmission from chandelier neurons is thought to improve the function of dorsolateral prefrontal cortex circuitry in people with schizophrenia by increasing gamma-band synchronization of pyramidal neuron activity [152][153][154][155].

Concluding Remarks and Future Directions
Although technological advances have substantially sped up research on phytochemicals, we still have a long way to go before we gather more definitive evidence regarding the neurotherapeutic benefits of herbal medicines. Our data and other researchers' data lead us to believe that naringin and naringenin may be beneficial as neurotherapeutic medications because of their ability to alter several signaling pathways. The outcomes thus far are in line with this theory.
Despite the limitations of ongoing clinical studies, naringenin and naringin are promising therapies for various neurological conditions, including AD, PD, cerebral ischemia, anxiety, depression, schizophrenia, and chronic hyperglycemic peripheral neuropathy. Given these obstacles, it is essential that pharmacokinetic research on naringin and naringenin administration be performed, that more accurate dosage designs for different illnesses be developed, and that innovative drug delivery strategies be developed to boost bioavailability in healthcare situations.

Informed Consent Statement: Not applicable.
Data Availability Statement: All data used to support the findings of this study are included within the article.

Conflicts of Interest:
The authors declare that they have no conflict of interest.